Human papillomavirus (HPV) is one of the most common sexually transmitted infections in the United States. It is the causative agent of genital warts, as well as cervical, anal, penile, vulvar, vaginal, and some head and neck cancers.¹ Development of the HPV vaccine and its introduction into the scheduled vaccine series recommended by the Centers for Disease Control and Prevention (CDC) represented a major public health milestone. The CDC recommends the HPV vaccine for all children beginning at 11 or 12 years of age, even as early as 9 years, regardless of gender identity or sexuality. As of late 2016, the 9-valent formulation (Gardasil 9 [Merck]) is the only HPV vaccine distributed in the United States, and the vaccination schedule depends specifically on age. The Advisory Committee on Immunization Practices (ACIP) of the CDC revised its recommendations in 2019 to include “shared clinical decision-making regarding HPV vaccination . . . for some adults aged 27 through 45 years.”² This change in policy has notable implications for sexual and gender minority populations, such as lesbian, gay, bisexual, transgender, and queer or questioning (LGBTQ) patients, especially in the context of dermatologic care. Herein, we discuss HPV-related conditions for LGBTQ patients, barriers to vaccine administration, and the role of dermatologists in promoting an increased vaccination rate in the LGBTQ community.

HPV-Related Conditions

A 2019 review of dermatologic care for LGBTQ patients identified many specific health disparities of HPV.³ Specifically, men who have sex with men (MSM) are more likely than heterosexual men to have oral, anal, and penile HPV infections, including high-risk HPV types.³ From 2011 to 2014, 18% and 13% of MSM had oral HPV infection and high-risk oral HPV infection, respectively, compared to only 11% and 7%, respectively, of men who reported never having had a same-sex sexual partner.⁴

Similarly, despite the CDC’s position that patients with perianal warts might benefit from digital anal examination or referral for standard or high-resolution anoscopy to detect intra-anal warts, improvements in morbidity have not yet been realized. In 2017, anal cancer incidence was 45.9 cases for every 100,000 person-years among human immunodeficiency (HIV)–positive MSM and 5.1 cases for every 100,000 person-years among HIV-negative MSM vs only 1.5 cases for every 100,000 person-years among men in the United States overall.³ Yet the CDC states that there is insufficient evidence to recommend routine anal cancer screening among MSM, even when a patient is HIV positive. Therefore, current screening practices and treatments are insufficient as MSM continue to have a disproportionately higher rate of HPV-associated disease compared to other populations.

Barriers to HPV Vaccine Administration

The HPV vaccination rate among MSM in adolescent populations varies across reports.^5-7 Interestingly, a 2016 survey study found that MSM had approximately 2-times greater odds of initiating the HPV vaccine than heterosexual men.⁸ However, a study specifically sampling young gay and bisexual men (N=428) found that only 13% had received any doses of the HPV vaccine.⁶

Regardless, HPV vaccination is much less common among all males than it is among all females, and the low rate of vaccination among sexual minority men has a disproportionate impact, given their higher risk for HPV infection.⁴ Although the HPV vaccination rate increased from 2014 to 2017, the HPV vaccination rate in MSM overall is less than half of the Healthy People 2020 goal of 80%.⁹ A 2018 review determined that HPV vaccination is a cost-effective strategy for preventing anal cancer in MSM¹⁰; yet male patients might still view the HPV vaccine as a “women’s issue” and are less likely to be vaccinated if they are not prompted by health care providers. Additionally, HPV vaccination is remarkably less likely in MSM when patients are older, uninsured, of lower socioeconomic status, or have not disclosed their sexual identity to their health care provider.⁹ Dermatologists should be mindful of these barriers to promote HPV vaccination in MSM before, or soon after, sexual debut.

Other members of the LGBTQ community, such as women who have sex with women, face notable HPV-related health disparities and would benefit from increased vaccination efforts by dermatologists. Adolescent and young adult women who have sex with women are less likely than heterosexual adolescent and young adult women to receive routine Papanicolaou tests and initiate HPV vaccination, despite having a higher number of lifetime sexual partners and a higher risk for HPV exposure.¹¹ A 2015 survey study (N=3253) found that after adjusting for covariates, only 8.5% of lesbians and 33.2% of bisexual women and girls who had heard of the HPV vaccine had initiated vaccination compared to 28.4% of their heterosexual counterparts.¹¹ The HPV vaccine is an effective public health tool for the prevention of cervical cancer in these populations. A study of women aged 15 to 19 years in the HPV vaccination era (2007-2014) found significant (P<.05) observed population-level decreases in cervical intraepithelial neoplasia incidence across all grades.¹²

Transgender women also face a high rate of HPV infection, HIV infection, and other structural and financial disparities, such as low insurance coverage, that can limit their access to vaccination. Transgender men have a higher rate of HPV infection than cisgender men, and those with female internal reproductive organs are less likely to receive routine Papanicolaou tests. A 2018 survey study found that approximately one-third of transgender men and women reported initiating the HPV vaccination series,¹³ but further investigation is required to make balanced comparisons to cisgender patients.

The Role of the Dermatologist

Collectively, these disparities emphasize the need for increased involvement by dermatologists in HPV vaccination efforts for all LGBTQ patients. Adult patients may have concerns about ties of the HPV vaccine to drug manufacturers and the general safety of vaccination. For pediatric patients, parents/guardians also may be concerned about an assumed but not evidence-based increase in sexual promiscuity following HPV vaccination.¹⁴ These topics can be challenging to discuss, but dermatologists have the duty to be proactive and initiate conversation about HPV vaccination, as opposed to waiting for patients to express interest. Dermatologists should stress the safety of the vaccine as well as its potential to protect against multiple, even life-threatening diseases. Providers also can explain that the ACIP recommends catch-up vaccination for all individuals through 26 years of age, regardless of sexual orientation or gender identity.

With the ACIP having recently expanded the appropriate age range for HPV vaccination, we encourage dermatologists to engage in education and shared decision-making to ensure that adult patients with specific risk factors receive the HPV vaccine. Because the expanded ACIP recommendations are aimed at vaccination before HPV exposure, vaccination might not be appropriate for all LGBTQ patients. However, eliciting a sexual history with routine patient intake forms or during the clinical encounter ensures equal access to the HPV vaccine.

Greater awareness of HPV-related disparities and barriers to vaccination in LGBTQ populations has the potential to notably decrease HPV-associated mortality and morbidity. Increased involvement by dermatologists contributes to the efforts of other specialties in universal HPV vaccination, regardless of sexual orientation or gender identity—ideally in younger age groups, such that patients receive the vaccine prior to coitarche.

There are many ways that dermatologists can advocate for HPV vaccination. Those in a multispecialty or academic practice can readily refer patients to an associated internist, primary care physician, or vaccination clinic in the same building or institution. Dermatologists in private practice might be able to administer the HPV vaccine themselves or can advocate for patients to receive the vaccine at a local facility of the Department of Health or at a nonprofit organization, such as a Planned Parenthood center. Although pediatricians and family physicians remain front-line providers of these services, dermatologists represent an additional member of a patient’s care team, capable of advocating for this important intervention.

Human papillomavirus (HPV) is one of the most common sexually transmitted infections in the United States. It is the causative agent of genital warts, as well as cervical, anal, penile, vulvar, vaginal, and some head and neck cancers.¹ Development of the HPV vaccine and its introduction into the scheduled vaccine series recommended by the Centers for Disease Control and Prevention (CDC) represented a major public health milestone. The CDC recommends the HPV vaccine for all children beginning at 11 or 12 years of age, even as early as 9 years, regardless of gender identity or sexuality. As of late 2016, the 9-valent formulation (Gardasil 9 [Merck]) is the only HPV vaccine distributed in the United States, and the vaccination schedule depends specifically on age. The Advisory Committee on Immunization Practices (ACIP) of the CDC revised its recommendations in 2019 to include “shared clinical decision-making regarding HPV vaccination . . . for some adults aged 27 through 45 years.”² This change in policy has notable implications for sexual and gender minority populations, such as lesbian, gay, bisexual, transgender, and queer or questioning (LGBTQ) patients, especially in the context of dermatologic care. Herein, we discuss HPV-related conditions for LGBTQ patients, barriers to vaccine administration, and the role of dermatologists in promoting an increased vaccination rate in the LGBTQ community.

HPV-Related Conditions

A 2019 review of dermatologic care for LGBTQ patients identified many specific health disparities of HPV.³ Specifically, men who have sex with men (MSM) are more likely than heterosexual men to have oral, anal, and penile HPV infections, including high-risk HPV types.³ From 2011 to 2014, 18% and 13% of MSM had oral HPV infection and high-risk oral HPV infection, respectively, compared to only 11% and 7%, respectively, of men who reported never having had a same-sex sexual partner.⁴

Similarly, despite the CDC’s position that patients with perianal warts might benefit from digital anal examination or referral for standard or high-resolution anoscopy to detect intra-anal warts, improvements in morbidity have not yet been realized. In 2017, anal cancer incidence was 45.9 cases for every 100,000 person-years among human immunodeficiency (HIV)–positive MSM and 5.1 cases for every 100,000 person-years among HIV-negative MSM vs only 1.5 cases for every 100,000 person-years among men in the United States overall.³ Yet the CDC states that there is insufficient evidence to recommend routine anal cancer screening among MSM, even when a patient is HIV positive. Therefore, current screening practices and treatments are insufficient as MSM continue to have a disproportionately higher rate of HPV-associated disease compared to other populations.

Barriers to HPV Vaccine Administration

The HPV vaccination rate among MSM in adolescent populations varies across reports.^5-7 Interestingly, a 2016 survey study found that MSM had approximately 2-times greater odds of initiating the HPV vaccine than heterosexual men.⁸ However, a study specifically sampling young gay and bisexual men (N=428) found that only 13% had received any doses of the HPV vaccine.⁶

Regardless, HPV vaccination is much less common among all males than it is among all females, and the low rate of vaccination among sexual minority men has a disproportionate impact, given their higher risk for HPV infection.⁴ Although the HPV vaccination rate increased from 2014 to 2017, the HPV vaccination rate in MSM overall is less than half of the Healthy People 2020 goal of 80%.⁹ A 2018 review determined that HPV vaccination is a cost-effective strategy for preventing anal cancer in MSM¹⁰; yet male patients might still view the HPV vaccine as a “women’s issue” and are less likely to be vaccinated if they are not prompted by health care providers. Additionally, HPV vaccination is remarkably less likely in MSM when patients are older, uninsured, of lower socioeconomic status, or have not disclosed their sexual identity to their health care provider.⁹ Dermatologists should be mindful of these barriers to promote HPV vaccination in MSM before, or soon after, sexual debut.

Other members of the LGBTQ community, such as women who have sex with women, face notable HPV-related health disparities and would benefit from increased vaccination efforts by dermatologists. Adolescent and young adult women who have sex with women are less likely than heterosexual adolescent and young adult women to receive routine Papanicolaou tests and initiate HPV vaccination, despite having a higher number of lifetime sexual partners and a higher risk for HPV exposure.¹¹ A 2015 survey study (N=3253) found that after adjusting for covariates, only 8.5% of lesbians and 33.2% of bisexual women and girls who had heard of the HPV vaccine had initiated vaccination compared to 28.4% of their heterosexual counterparts.¹¹ The HPV vaccine is an effective public health tool for the prevention of cervical cancer in these populations. A study of women aged 15 to 19 years in the HPV vaccination era (2007-2014) found significant (P<.05) observed population-level decreases in cervical intraepithelial neoplasia incidence across all grades.¹²

Transgender women also face a high rate of HPV infection, HIV infection, and other structural and financial disparities, such as low insurance coverage, that can limit their access to vaccination. Transgender men have a higher rate of HPV infection than cisgender men, and those with female internal reproductive organs are less likely to receive routine Papanicolaou tests. A 2018 survey study found that approximately one-third of transgender men and women reported initiating the HPV vaccination series,¹³ but further investigation is required to make balanced comparisons to cisgender patients.

The Role of the Dermatologist

Collectively, these disparities emphasize the need for increased involvement by dermatologists in HPV vaccination efforts for all LGBTQ patients. Adult patients may have concerns about ties of the HPV vaccine to drug manufacturers and the general safety of vaccination. For pediatric patients, parents/guardians also may be concerned about an assumed but not evidence-based increase in sexual promiscuity following HPV vaccination.¹⁴ These topics can be challenging to discuss, but dermatologists have the duty to be proactive and initiate conversation about HPV vaccination, as opposed to waiting for patients to express interest. Dermatologists should stress the safety of the vaccine as well as its potential to protect against multiple, even life-threatening diseases. Providers also can explain that the ACIP recommends catch-up vaccination for all individuals through 26 years of age, regardless of sexual orientation or gender identity.

With the ACIP having recently expanded the appropriate age range for HPV vaccination, we encourage dermatologists to engage in education and shared decision-making to ensure that adult patients with specific risk factors receive the HPV vaccine. Because the expanded ACIP recommendations are aimed at vaccination before HPV exposure, vaccination might not be appropriate for all LGBTQ patients. However, eliciting a sexual history with routine patient intake forms or during the clinical encounter ensures equal access to the HPV vaccine.

Greater awareness of HPV-related disparities and barriers to vaccination in LGBTQ populations has the potential to notably decrease HPV-associated mortality and morbidity. Increased involvement by dermatologists contributes to the efforts of other specialties in universal HPV vaccination, regardless of sexual orientation or gender identity—ideally in younger age groups, such that patients receive the vaccine prior to coitarche.

There are many ways that dermatologists can advocate for HPV vaccination. Those in a multispecialty or academic practice can readily refer patients to an associated internist, primary care physician, or vaccination clinic in the same building or institution. Dermatologists in private practice might be able to administer the HPV vaccine themselves or can advocate for patients to receive the vaccine at a local facility of the Department of Health or at a nonprofit organization, such as a Planned Parenthood center. Although pediatricians and family physicians remain front-line providers of these services, dermatologists represent an additional member of a patient’s care team, capable of advocating for this important intervention.

Human papillomavirus (HPV) is one of the most common sexually transmitted infections in the United States. It is the causative agent of genital warts, as well as cervical, anal, penile, vulvar, vaginal, and some head and neck cancers.¹ Development of the HPV vaccine and its introduction into the scheduled vaccine series recommended by the Centers for Disease Control and Prevention (CDC) represented a major public health milestone. The CDC recommends the HPV vaccine for all children beginning at 11 or 12 years of age, even as early as 9 years, regardless of gender identity or sexuality. As of late 2016, the 9-valent formulation (Gardasil 9 [Merck]) is the only HPV vaccine distributed in the United States, and the vaccination schedule depends specifically on age. The Advisory Committee on Immunization Practices (ACIP) of the CDC revised its recommendations in 2019 to include “shared clinical decision-making regarding HPV vaccination . . . for some adults aged 27 through 45 years.”² This change in policy has notable implications for sexual and gender minority populations, such as lesbian, gay, bisexual, transgender, and queer or questioning (LGBTQ) patients, especially in the context of dermatologic care. Herein, we discuss HPV-related conditions for LGBTQ patients, barriers to vaccine administration, and the role of dermatologists in promoting an increased vaccination rate in the LGBTQ community.

HPV-Related Conditions

A 2019 review of dermatologic care for LGBTQ patients identified many specific health disparities of HPV.³ Specifically, men who have sex with men (MSM) are more likely than heterosexual men to have oral, anal, and penile HPV infections, including high-risk HPV types.³ From 2011 to 2014, 18% and 13% of MSM had oral HPV infection and high-risk oral HPV infection, respectively, compared to only 11% and 7%, respectively, of men who reported never having had a same-sex sexual partner.⁴

Similarly, despite the CDC’s position that patients with perianal warts might benefit from digital anal examination or referral for standard or high-resolution anoscopy to detect intra-anal warts, improvements in morbidity have not yet been realized. In 2017, anal cancer incidence was 45.9 cases for every 100,000 person-years among human immunodeficiency (HIV)–positive MSM and 5.1 cases for every 100,000 person-years among HIV-negative MSM vs only 1.5 cases for every 100,000 person-years among men in the United States overall.³ Yet the CDC states that there is insufficient evidence to recommend routine anal cancer screening among MSM, even when a patient is HIV positive. Therefore, current screening practices and treatments are insufficient as MSM continue to have a disproportionately higher rate of HPV-associated disease compared to other populations.

Barriers to HPV Vaccine Administration

The HPV vaccination rate among MSM in adolescent populations varies across reports.^5-7 Interestingly, a 2016 survey study found that MSM had approximately 2-times greater odds of initiating the HPV vaccine than heterosexual men.⁸ However, a study specifically sampling young gay and bisexual men (N=428) found that only 13% had received any doses of the HPV vaccine.⁶

Regardless, HPV vaccination is much less common among all males than it is among all females, and the low rate of vaccination among sexual minority men has a disproportionate impact, given their higher risk for HPV infection.⁴ Although the HPV vaccination rate increased from 2014 to 2017, the HPV vaccination rate in MSM overall is less than half of the Healthy People 2020 goal of 80%.⁹ A 2018 review determined that HPV vaccination is a cost-effective strategy for preventing anal cancer in MSM¹⁰; yet male patients might still view the HPV vaccine as a “women’s issue” and are less likely to be vaccinated if they are not prompted by health care providers. Additionally, HPV vaccination is remarkably less likely in MSM when patients are older, uninsured, of lower socioeconomic status, or have not disclosed their sexual identity to their health care provider.⁹ Dermatologists should be mindful of these barriers to promote HPV vaccination in MSM before, or soon after, sexual debut.

Other members of the LGBTQ community, such as women who have sex with women, face notable HPV-related health disparities and would benefit from increased vaccination efforts by dermatologists. Adolescent and young adult women who have sex with women are less likely than heterosexual adolescent and young adult women to receive routine Papanicolaou tests and initiate HPV vaccination, despite having a higher number of lifetime sexual partners and a higher risk for HPV exposure.¹¹ A 2015 survey study (N=3253) found that after adjusting for covariates, only 8.5% of lesbians and 33.2% of bisexual women and girls who had heard of the HPV vaccine had initiated vaccination compared to 28.4% of their heterosexual counterparts.¹¹ The HPV vaccine is an effective public health tool for the prevention of cervical cancer in these populations. A study of women aged 15 to 19 years in the HPV vaccination era (2007-2014) found significant (P<.05) observed population-level decreases in cervical intraepithelial neoplasia incidence across all grades.¹²

Transgender women also face a high rate of HPV infection, HIV infection, and other structural and financial disparities, such as low insurance coverage, that can limit their access to vaccination. Transgender men have a higher rate of HPV infection than cisgender men, and those with female internal reproductive organs are less likely to receive routine Papanicolaou tests. A 2018 survey study found that approximately one-third of transgender men and women reported initiating the HPV vaccination series,¹³ but further investigation is required to make balanced comparisons to cisgender patients.

The Role of the Dermatologist

Collectively, these disparities emphasize the need for increased involvement by dermatologists in HPV vaccination efforts for all LGBTQ patients. Adult patients may have concerns about ties of the HPV vaccine to drug manufacturers and the general safety of vaccination. For pediatric patients, parents/guardians also may be concerned about an assumed but not evidence-based increase in sexual promiscuity following HPV vaccination.¹⁴ These topics can be challenging to discuss, but dermatologists have the duty to be proactive and initiate conversation about HPV vaccination, as opposed to waiting for patients to express interest. Dermatologists should stress the safety of the vaccine as well as its potential to protect against multiple, even life-threatening diseases. Providers also can explain that the ACIP recommends catch-up vaccination for all individuals through 26 years of age, regardless of sexual orientation or gender identity.

With the ACIP having recently expanded the appropriate age range for HPV vaccination, we encourage dermatologists to engage in education and shared decision-making to ensure that adult patients with specific risk factors receive the HPV vaccine. Because the expanded ACIP recommendations are aimed at vaccination before HPV exposure, vaccination might not be appropriate for all LGBTQ patients. However, eliciting a sexual history with routine patient intake forms or during the clinical encounter ensures equal access to the HPV vaccine.

Greater awareness of HPV-related disparities and barriers to vaccination in LGBTQ populations has the potential to notably decrease HPV-associated mortality and morbidity. Increased involvement by dermatologists contributes to the efforts of other specialties in universal HPV vaccination, regardless of sexual orientation or gender identity—ideally in younger age groups, such that patients receive the vaccine prior to coitarche.

There are many ways that dermatologists can advocate for HPV vaccination. Those in a multispecialty or academic practice can readily refer patients to an associated internist, primary care physician, or vaccination clinic in the same building or institution. Dermatologists in private practice might be able to administer the HPV vaccine themselves or can advocate for patients to receive the vaccine at a local facility of the Department of Health or at a nonprofit organization, such as a Planned Parenthood center. Although pediatricians and family physicians remain front-line providers of these services, dermatologists represent an additional member of a patient’s care team, capable of advocating for this important intervention.

Case Report

A 50-year-old woman presented with a sore, tender, red lump on the right superior buttock of 5 months’ duration. Five months prior to presentation the patient used this area to attach the infusion set for an insulin pump, which was left in place for 7 days as opposed to the 2 or 3 days recommended by the device manufacturer. A firm, slightly tender lump formed, similar to prior scars that had developed from use of the insulin pump. However, the lump began to grow and get softer. It was intermittently warm and red. Although the area was sore and tender, she never had any major pain. She also denied any fever, malaise, or other systemic symptoms.

The patient indicated a medical history of type 1 diabetes mellitus diagnosed at 9 years of age; hypertension; asthma; gastroesophageal reflux disease; allergic rhinitis; migraine headaches; depression; hidradenitis suppurativa that resolved after surgical excision; and recurrent vaginal yeast infections, especially when taking antibiotics. She had a surgical history of hidradenitis suppurativa excision at the inguinal folds, bilateral carpal tunnel release, tubal ligation, abdominoplasty, and cholecystectomy. The patient’s current medications included insulin aspart, mometasone furoate, inhaled fluticasone, pantoprazole, cetirizine, spironolactone, duloxetine, sumatriptan, fluconazole, topiramate, and enalapril.

Physical examination revealed normal vital signs and the patient was afebrile. She had no swollen or tender lymph nodes. There was a 5.5×7.0-cm, soft, tender, erythematous subcutaneous mass with no visible punctum or overlying epidermal change on the right superior buttock (Figure 1). Based on the history and physical examination, the differential diagnosis included subcutaneous fat necrosis, epidermal inclusion cyst, and an abscess.

Comment

Achromobacter xylosoxidans is a nonfermentative, non–spore-forming, motile, gram-negative, aerobic, catalase-positive and oxidase-positive flagellate bacterium. It is an emerging pathogen that was first isolated in 1971 from patients with chronic otitis media.¹ Since its recognition, it has been documented to cause a variety of infections, including pneumonia, meningitis, osteomyelitis, endocarditis, and bacteremia, as well as abdominal, urinary tract, ocular, and skin and soft tissue infections.^2,3 Those affected usually are immunocompromised, have hematologic disorders, or have indwelling catheters.⁴ Strains of A xylosoxidans have shown resistance to multiple antibiotics including penicillins, cephalosporins, carbapenems, aminoglycosides, macrolides, fluoroquinolones, and TMP-SMX. Achromobacter xylosoxidans has been documented to form biofilms on plastics, including on contact lenses, urinary and intravenous catheters, and reusable tissue dispensers treated with disinfectant solution.^4-6 One study demonstrated that A xylosoxidans is even capable of biodegradation of plastic, using the plastic as its sole source of carbon.⁷

Our case illustrates an indolent infection with A xylosoxidans forming a granulomatous abscess at the site of an insulin pump that was left in place for 7 days in an immunocompetent patient. Although infections with A xylosoxidans in patients with urinary or intravenous catheters have been reported,⁴ our case is unique, as the insulin pump was the source of such an infection. It is possible that the subcutaneous focus of acellular material described on the pathology report represented a partially biodegraded piece of the insulin pump catheter that broke off and was serving as a nidus of infection for A xylosoxidans. Although multidrug resistance is common, the culture grown from our patient was susceptible to TMP-SMX, among other antibiotics. Our patient was treated successfully with surgical excision, drainage, and a 10-day course of TMP-SMX.

Conclusion

Health care providers should recognize A xylosoxidans as an emerging pathogen that is capable of forming biofilms on “disinfected” surfaces and medical products, especially plastics. Achromobacter xylosoxidans may be resistant to multiple antibiotics and can cause infections with various presentations.

Case Report

A 50-year-old woman presented with a sore, tender, red lump on the right superior buttock of 5 months’ duration. Five months prior to presentation the patient used this area to attach the infusion set for an insulin pump, which was left in place for 7 days as opposed to the 2 or 3 days recommended by the device manufacturer. A firm, slightly tender lump formed, similar to prior scars that had developed from use of the insulin pump. However, the lump began to grow and get softer. It was intermittently warm and red. Although the area was sore and tender, she never had any major pain. She also denied any fever, malaise, or other systemic symptoms.

The patient indicated a medical history of type 1 diabetes mellitus diagnosed at 9 years of age; hypertension; asthma; gastroesophageal reflux disease; allergic rhinitis; migraine headaches; depression; hidradenitis suppurativa that resolved after surgical excision; and recurrent vaginal yeast infections, especially when taking antibiotics. She had a surgical history of hidradenitis suppurativa excision at the inguinal folds, bilateral carpal tunnel release, tubal ligation, abdominoplasty, and cholecystectomy. The patient’s current medications included insulin aspart, mometasone furoate, inhaled fluticasone, pantoprazole, cetirizine, spironolactone, duloxetine, sumatriptan, fluconazole, topiramate, and enalapril.

Physical examination revealed normal vital signs and the patient was afebrile. She had no swollen or tender lymph nodes. There was a 5.5×7.0-cm, soft, tender, erythematous subcutaneous mass with no visible punctum or overlying epidermal change on the right superior buttock (Figure 1). Based on the history and physical examination, the differential diagnosis included subcutaneous fat necrosis, epidermal inclusion cyst, and an abscess.

Comment

Achromobacter xylosoxidans is a nonfermentative, non–spore-forming, motile, gram-negative, aerobic, catalase-positive and oxidase-positive flagellate bacterium. It is an emerging pathogen that was first isolated in 1971 from patients with chronic otitis media.¹ Since its recognition, it has been documented to cause a variety of infections, including pneumonia, meningitis, osteomyelitis, endocarditis, and bacteremia, as well as abdominal, urinary tract, ocular, and skin and soft tissue infections.^2,3 Those affected usually are immunocompromised, have hematologic disorders, or have indwelling catheters.⁴ Strains of A xylosoxidans have shown resistance to multiple antibiotics including penicillins, cephalosporins, carbapenems, aminoglycosides, macrolides, fluoroquinolones, and TMP-SMX. Achromobacter xylosoxidans has been documented to form biofilms on plastics, including on contact lenses, urinary and intravenous catheters, and reusable tissue dispensers treated with disinfectant solution.^4-6 One study demonstrated that A xylosoxidans is even capable of biodegradation of plastic, using the plastic as its sole source of carbon.⁷

Our case illustrates an indolent infection with A xylosoxidans forming a granulomatous abscess at the site of an insulin pump that was left in place for 7 days in an immunocompetent patient. Although infections with A xylosoxidans in patients with urinary or intravenous catheters have been reported,⁴ our case is unique, as the insulin pump was the source of such an infection. It is possible that the subcutaneous focus of acellular material described on the pathology report represented a partially biodegraded piece of the insulin pump catheter that broke off and was serving as a nidus of infection for A xylosoxidans. Although multidrug resistance is common, the culture grown from our patient was susceptible to TMP-SMX, among other antibiotics. Our patient was treated successfully with surgical excision, drainage, and a 10-day course of TMP-SMX.

Conclusion

Health care providers should recognize A xylosoxidans as an emerging pathogen that is capable of forming biofilms on “disinfected” surfaces and medical products, especially plastics. Achromobacter xylosoxidans may be resistant to multiple antibiotics and can cause infections with various presentations.

Case Report

A 50-year-old woman presented with a sore, tender, red lump on the right superior buttock of 5 months’ duration. Five months prior to presentation the patient used this area to attach the infusion set for an insulin pump, which was left in place for 7 days as opposed to the 2 or 3 days recommended by the device manufacturer. A firm, slightly tender lump formed, similar to prior scars that had developed from use of the insulin pump. However, the lump began to grow and get softer. It was intermittently warm and red. Although the area was sore and tender, she never had any major pain. She also denied any fever, malaise, or other systemic symptoms.

The patient indicated a medical history of type 1 diabetes mellitus diagnosed at 9 years of age; hypertension; asthma; gastroesophageal reflux disease; allergic rhinitis; migraine headaches; depression; hidradenitis suppurativa that resolved after surgical excision; and recurrent vaginal yeast infections, especially when taking antibiotics. She had a surgical history of hidradenitis suppurativa excision at the inguinal folds, bilateral carpal tunnel release, tubal ligation, abdominoplasty, and cholecystectomy. The patient’s current medications included insulin aspart, mometasone furoate, inhaled fluticasone, pantoprazole, cetirizine, spironolactone, duloxetine, sumatriptan, fluconazole, topiramate, and enalapril.

Physical examination revealed normal vital signs and the patient was afebrile. She had no swollen or tender lymph nodes. There was a 5.5×7.0-cm, soft, tender, erythematous subcutaneous mass with no visible punctum or overlying epidermal change on the right superior buttock (Figure 1). Based on the history and physical examination, the differential diagnosis included subcutaneous fat necrosis, epidermal inclusion cyst, and an abscess.

Comment

Achromobacter xylosoxidans is a nonfermentative, non–spore-forming, motile, gram-negative, aerobic, catalase-positive and oxidase-positive flagellate bacterium. It is an emerging pathogen that was first isolated in 1971 from patients with chronic otitis media.¹ Since its recognition, it has been documented to cause a variety of infections, including pneumonia, meningitis, osteomyelitis, endocarditis, and bacteremia, as well as abdominal, urinary tract, ocular, and skin and soft tissue infections.^2,3 Those affected usually are immunocompromised, have hematologic disorders, or have indwelling catheters.⁴ Strains of A xylosoxidans have shown resistance to multiple antibiotics including penicillins, cephalosporins, carbapenems, aminoglycosides, macrolides, fluoroquinolones, and TMP-SMX. Achromobacter xylosoxidans has been documented to form biofilms on plastics, including on contact lenses, urinary and intravenous catheters, and reusable tissue dispensers treated with disinfectant solution.^4-6 One study demonstrated that A xylosoxidans is even capable of biodegradation of plastic, using the plastic as its sole source of carbon.⁷

Our case illustrates an indolent infection with A xylosoxidans forming a granulomatous abscess at the site of an insulin pump that was left in place for 7 days in an immunocompetent patient. Although infections with A xylosoxidans in patients with urinary or intravenous catheters have been reported,⁴ our case is unique, as the insulin pump was the source of such an infection. It is possible that the subcutaneous focus of acellular material described on the pathology report represented a partially biodegraded piece of the insulin pump catheter that broke off and was serving as a nidus of infection for A xylosoxidans. Although multidrug resistance is common, the culture grown from our patient was susceptible to TMP-SMX, among other antibiotics. Our patient was treated successfully with surgical excision, drainage, and a 10-day course of TMP-SMX.

Conclusion

Health care providers should recognize A xylosoxidans as an emerging pathogen that is capable of forming biofilms on “disinfected” surfaces and medical products, especially plastics. Achromobacter xylosoxidans may be resistant to multiple antibiotics and can cause infections with various presentations.

Leishmaniasis is a neglected parasitic disease with an estimated annual incidence of 1.3 million cases, the majority of which manifest as cutaneous leishmaniasis.¹ The cutaneous and mucosal forms demonstrate substantial global burden with morbidity and socioeconomic repercussions, while the visceral form is responsible for up to 30,000 deaths annually.² Despite increasing prevalence in the United States, awareness and diagnosis remain relatively low.³ We describe 2 cases of cutaneous leishmaniasis in New England, United States, in travelers returning from Central America, both successfully treated with miltefosine. We also review prevention, diagnosis, and treatment options.

Case Reports

Patient 1
A 47-year-old woman presented with an enlarging, 2-cm, erythematous, ulcerated nodule on the right dorsal hand of 2 weeks’ duration with accompanying right epitrochlear lymphadenopathy (Figure 1A). She noticed the lesion 10 weeks after returning from Panama, where she had been photographing the jungle. Prior to the initial presentation to dermatology, salicylic acid wart remover, intramuscular ceftriaxone, and oral trimethoprim had failed to alleviate the lesion. Her laboratory results were notable for an elevated C-reactive protein level of 5.4 mg/L (reference range, ≤4.9 mg/L). A punch biopsy demonstrated pseudoepitheliomatous hyperplasia with diffuse dermal lymphohistiocytic inflammation and small intracytoplasmic structures within histiocytes consistent with leishmaniasis (Figure 2). Immunohistochemistry was consistent with leishmaniasis (Figure 3), and polymerase chain reaction performed by the Centers for Disease Control and Prevention (CDC) identified the pathogen as Leishmania braziliensis.

Patient 2
An 18-year-old man presented with an enlarging, well-delineated, tender ulcer of 6 weeks’ duration measuring 2.5×2 cm with an erythematous and edematous border on the right medial forearm with associated epitrochlear lymphadenopathy (Figure 4). Nine weeks prior to initial presentation, he had returned from a 3-month outdoor adventure trip to the Florida Keys, Costa Rica, and Panama. He had used bug repellent intermittently, slept under a bug net, and did not recall any trauma or bite at the ulcer site. Biopsy and tissue culture were obtained, and histopathology demonstrated an ulcer with a dense dermal lymphogranulomatous infiltrate and intracytoplasmic organisms consistent with leishmaniasis. Polymerase chain reaction by the CDC identified the pathogen as Leishmania panamensis.

Comment

Epidemiology and Prevention
Risk factors for leishmaniasis include weak immunity, poverty, poor housing, poor sanitation, malnutrition, urbanization, climate change, and human migration.⁴ Our patients were most directly affected by travel to locations where leishmaniasis is endemic. Despite an increasing prevalence of endemic leishmaniasis and new animal hosts in the southern United States, most patients diagnosed in the United States are infected abroad by Leishmania mexicana and L braziliensis, both cutaneous New World species.³ Our patients were infected by species within the New World subgenus Viannia that have potential for mucocutaneous spread.⁴

Because there is no chemoprophylaxis or acquired active immunity such as vaccines that can mitigate the risk for leishmaniasis, public health efforts focus on preventive measures. Although difficult to achieve, avoidance of the phlebotomine sand fly species that transmit the obligate intracellular Leishmania parasite is a most effective measure.⁴ Travelers entering geographic regions with higher risk for leishmaniasis should be aware of the inherent risk and determine which methods of prevention, such as N,N-diethyl-meta-toluamide (DEET) insecticides or permethrin-treated protective clothing, are most feasible. Although higher concentrations of DEET provide longer protection, the effectiveness tends to plateau at approximately 50%.⁵

Presentation and Prognosis
For patients who develop leishmaniasis, the disease course and prognosis depend greatly on the species and manifestation. The most common form of leishmaniasis is localized cutaneous leishmaniasis, which has an annual incidence of up to 1 million cases. It initially presents as macules, usually at the site of inoculation within several months to years of infection.⁶ The macules expand into papules and plaques that reach maximum size over at least 1 week⁴ and then progress into crusted ulcers up to 5 cm in diameter with raised edges. Although usually painless and self-limited, these lesions can take years to spontaneously heal, with the risk for atrophic scarring and altered pigmentation. Lymphatic involvement manifests as lymphadenitis or regional lymphadenopathy and is common with lesions caused by the subgenus Viannia.⁶

Leishmania braziliensis and L panamensis, the species that infected our patients, can uniquely cause cutaneous leishmaniasis that metastasizes into mucocutaneous leishmaniasis, which always affects the nasal mucosa. Risk factors for transformation include a primary lesion site above the waist, multiple or large primary lesions, and delayed healing of primary cutaneous leishmaniasis. Mucocutaneous leishmaniasis can result in notable morbidity and even mortality from invasion and destruction of nasal and oropharyngeal mucosa, as well as intercurrent pneumonia, especially if treatment is insufficient or delayed.⁴

Diagnosis
Prompt treatment relies on accurate and timely diagnosis, which is complicated by the relative unfamiliarity with leishmaniasis in the United States. The differential diagnosis for cutaneous leishmaniasis is broad, including deep fungal infection, Mycobacterium infection, cutaneous granulomatous conditions, nonmelanoma cutaneous neoplasms, and trauma. Taking a thorough patient history, including potential exposures and travels; having high clinical suspicion; and being aware of classic presentation allows for identification of leishmaniasis and subsequent stratification by manifestation.⁷

Diagnosis is made by detecting Leishmania organisms or DNA using light microscopy and staining to visualize the kinetoplast in an amastigote, molecular methods, or specialized culturing.⁷ The CDC is a valuable diagnostic partner for confirmation and speciation. Specific instructions for specimen collection and transportation can be found by contacting the CDC or reading their guide.⁸ To provide prompt care and reassurance to patients, it is important to be aware of the coordination effort that may be needed to send samples, receive results, and otherwise correspond with a separate institution.

Treatment
Treatment of cutaneous leishmaniasis is indicated to decrease the risk for mucosal dissemination and clinical reactivation of lesions, accelerate healing of lesions, decrease local morbidity caused by large or persistent lesions, and decrease the reservoir of infection in places where infected humans serve as reservoir hosts. Oral treatments include ketoconazole, itraconazole, and fluconazole, recommended at doses ranging from 200 to 600 mg daily for at least 28 days. For severe, refractory, or visceral leishmaniasis, parenteral choices include pentavalent antimonials, amphotericin B deoxycholate, and pentamidine isethionate, each with known toxicity or limited data on efficacy.⁶ Pentavalent antimonials can cause life-threatening cardiotoxicity and are more difficult to administer.⁹ Furthermore, they are not approved by the US Food and Drug Administration or commercially available in the United States, with only sodium stibogluconate available through the CDC.⁶

Miltefosine is becoming a more common treatment of leishmaniasis because of its oral route, tolerability in nonpregnant patients, and commercial availability. It was approved by the US Food and Drug Administration in 2014 for cutaneous leishmaniasis due to L braziliensis, L panamensis, and Leishmania guyanensis; mucosal leishmaniasis due to L braziliensis; and visceral leishmaniasis due to Leishmania donovani in patients at least 12 years of age. For cutaneous leishmaniasis, the standard dosage of 50 mg twice daily (for patients weighing 30–44 kg) or 3 times daily (for patients weighing 45 kg or more) for 28 consecutive days has cure rates of 48% to 85% by 6 months after therapy ends. Cure is defined as epithelialization of lesions, no enlargement greater than 50% in lesions, no appearance of new lesions, and/or negative parasitology. The antileishmanial mechanism of action is unknown and likely involves interaction with lipids, inhibition of cytochrome c oxidase, and apoptosislike cell death. Miltefosine is contraindicated in pregnancy. The most common adverse reactions in patients include nausea (35.9%–41.7%), motion sickness (29.2%), headache (28.1%), and emesis (4.5%–27.5%). With the exception of headache, these adverse reactions can decrease with administration of food, fluids, and antiemetics. Potentially more serious but rarer adverse reactions include elevated serum creatinine (5%–25%) and transaminases (5%). Although our patients had mild hyperkalemia, it is not an established adverse reaction. However, renal injury has been reported.¹⁰

Conclusion

Cutaneous leishmaniasis is increasing in prevalence in the United States due to increased foreign travel. Providers should be familiar with the cutaneous presentation of leishmaniasis, even in areas of low prevalence, to limit the risk for mucocutaneous dissemination from infection with the subgenus Viannia. Prompt treatment is vital to ensuring the best prognosis, and first-line treatment with miltefosine should be strongly considered given its efficacy and tolerability.

Leishmaniasis is a neglected parasitic disease with an estimated annual incidence of 1.3 million cases, the majority of which manifest as cutaneous leishmaniasis.¹ The cutaneous and mucosal forms demonstrate substantial global burden with morbidity and socioeconomic repercussions, while the visceral form is responsible for up to 30,000 deaths annually.² Despite increasing prevalence in the United States, awareness and diagnosis remain relatively low.³ We describe 2 cases of cutaneous leishmaniasis in New England, United States, in travelers returning from Central America, both successfully treated with miltefosine. We also review prevention, diagnosis, and treatment options.

Case Reports

Patient 1
A 47-year-old woman presented with an enlarging, 2-cm, erythematous, ulcerated nodule on the right dorsal hand of 2 weeks’ duration with accompanying right epitrochlear lymphadenopathy (Figure 1A). She noticed the lesion 10 weeks after returning from Panama, where she had been photographing the jungle. Prior to the initial presentation to dermatology, salicylic acid wart remover, intramuscular ceftriaxone, and oral trimethoprim had failed to alleviate the lesion. Her laboratory results were notable for an elevated C-reactive protein level of 5.4 mg/L (reference range, ≤4.9 mg/L). A punch biopsy demonstrated pseudoepitheliomatous hyperplasia with diffuse dermal lymphohistiocytic inflammation and small intracytoplasmic structures within histiocytes consistent with leishmaniasis (Figure 2). Immunohistochemistry was consistent with leishmaniasis (Figure 3), and polymerase chain reaction performed by the Centers for Disease Control and Prevention (CDC) identified the pathogen as Leishmania braziliensis.

Patient 2
An 18-year-old man presented with an enlarging, well-delineated, tender ulcer of 6 weeks’ duration measuring 2.5×2 cm with an erythematous and edematous border on the right medial forearm with associated epitrochlear lymphadenopathy (Figure 4). Nine weeks prior to initial presentation, he had returned from a 3-month outdoor adventure trip to the Florida Keys, Costa Rica, and Panama. He had used bug repellent intermittently, slept under a bug net, and did not recall any trauma or bite at the ulcer site. Biopsy and tissue culture were obtained, and histopathology demonstrated an ulcer with a dense dermal lymphogranulomatous infiltrate and intracytoplasmic organisms consistent with leishmaniasis. Polymerase chain reaction by the CDC identified the pathogen as Leishmania panamensis.

Comment

Epidemiology and Prevention
Risk factors for leishmaniasis include weak immunity, poverty, poor housing, poor sanitation, malnutrition, urbanization, climate change, and human migration.⁴ Our patients were most directly affected by travel to locations where leishmaniasis is endemic. Despite an increasing prevalence of endemic leishmaniasis and new animal hosts in the southern United States, most patients diagnosed in the United States are infected abroad by Leishmania mexicana and L braziliensis, both cutaneous New World species.³ Our patients were infected by species within the New World subgenus Viannia that have potential for mucocutaneous spread.⁴

Because there is no chemoprophylaxis or acquired active immunity such as vaccines that can mitigate the risk for leishmaniasis, public health efforts focus on preventive measures. Although difficult to achieve, avoidance of the phlebotomine sand fly species that transmit the obligate intracellular Leishmania parasite is a most effective measure.⁴ Travelers entering geographic regions with higher risk for leishmaniasis should be aware of the inherent risk and determine which methods of prevention, such as N,N-diethyl-meta-toluamide (DEET) insecticides or permethrin-treated protective clothing, are most feasible. Although higher concentrations of DEET provide longer protection, the effectiveness tends to plateau at approximately 50%.⁵

Presentation and Prognosis
For patients who develop leishmaniasis, the disease course and prognosis depend greatly on the species and manifestation. The most common form of leishmaniasis is localized cutaneous leishmaniasis, which has an annual incidence of up to 1 million cases. It initially presents as macules, usually at the site of inoculation within several months to years of infection.⁶ The macules expand into papules and plaques that reach maximum size over at least 1 week⁴ and then progress into crusted ulcers up to 5 cm in diameter with raised edges. Although usually painless and self-limited, these lesions can take years to spontaneously heal, with the risk for atrophic scarring and altered pigmentation. Lymphatic involvement manifests as lymphadenitis or regional lymphadenopathy and is common with lesions caused by the subgenus Viannia.⁶

Leishmania braziliensis and L panamensis, the species that infected our patients, can uniquely cause cutaneous leishmaniasis that metastasizes into mucocutaneous leishmaniasis, which always affects the nasal mucosa. Risk factors for transformation include a primary lesion site above the waist, multiple or large primary lesions, and delayed healing of primary cutaneous leishmaniasis. Mucocutaneous leishmaniasis can result in notable morbidity and even mortality from invasion and destruction of nasal and oropharyngeal mucosa, as well as intercurrent pneumonia, especially if treatment is insufficient or delayed.⁴

Diagnosis
Prompt treatment relies on accurate and timely diagnosis, which is complicated by the relative unfamiliarity with leishmaniasis in the United States. The differential diagnosis for cutaneous leishmaniasis is broad, including deep fungal infection, Mycobacterium infection, cutaneous granulomatous conditions, nonmelanoma cutaneous neoplasms, and trauma. Taking a thorough patient history, including potential exposures and travels; having high clinical suspicion; and being aware of classic presentation allows for identification of leishmaniasis and subsequent stratification by manifestation.⁷

Diagnosis is made by detecting Leishmania organisms or DNA using light microscopy and staining to visualize the kinetoplast in an amastigote, molecular methods, or specialized culturing.⁷ The CDC is a valuable diagnostic partner for confirmation and speciation. Specific instructions for specimen collection and transportation can be found by contacting the CDC or reading their guide.⁸ To provide prompt care and reassurance to patients, it is important to be aware of the coordination effort that may be needed to send samples, receive results, and otherwise correspond with a separate institution.

Treatment
Treatment of cutaneous leishmaniasis is indicated to decrease the risk for mucosal dissemination and clinical reactivation of lesions, accelerate healing of lesions, decrease local morbidity caused by large or persistent lesions, and decrease the reservoir of infection in places where infected humans serve as reservoir hosts. Oral treatments include ketoconazole, itraconazole, and fluconazole, recommended at doses ranging from 200 to 600 mg daily for at least 28 days. For severe, refractory, or visceral leishmaniasis, parenteral choices include pentavalent antimonials, amphotericin B deoxycholate, and pentamidine isethionate, each with known toxicity or limited data on efficacy.⁶ Pentavalent antimonials can cause life-threatening cardiotoxicity and are more difficult to administer.⁹ Furthermore, they are not approved by the US Food and Drug Administration or commercially available in the United States, with only sodium stibogluconate available through the CDC.⁶

Miltefosine is becoming a more common treatment of leishmaniasis because of its oral route, tolerability in nonpregnant patients, and commercial availability. It was approved by the US Food and Drug Administration in 2014 for cutaneous leishmaniasis due to L braziliensis, L panamensis, and Leishmania guyanensis; mucosal leishmaniasis due to L braziliensis; and visceral leishmaniasis due to Leishmania donovani in patients at least 12 years of age. For cutaneous leishmaniasis, the standard dosage of 50 mg twice daily (for patients weighing 30–44 kg) or 3 times daily (for patients weighing 45 kg or more) for 28 consecutive days has cure rates of 48% to 85% by 6 months after therapy ends. Cure is defined as epithelialization of lesions, no enlargement greater than 50% in lesions, no appearance of new lesions, and/or negative parasitology. The antileishmanial mechanism of action is unknown and likely involves interaction with lipids, inhibition of cytochrome c oxidase, and apoptosislike cell death. Miltefosine is contraindicated in pregnancy. The most common adverse reactions in patients include nausea (35.9%–41.7%), motion sickness (29.2%), headache (28.1%), and emesis (4.5%–27.5%). With the exception of headache, these adverse reactions can decrease with administration of food, fluids, and antiemetics. Potentially more serious but rarer adverse reactions include elevated serum creatinine (5%–25%) and transaminases (5%). Although our patients had mild hyperkalemia, it is not an established adverse reaction. However, renal injury has been reported.¹⁰

Conclusion

Cutaneous leishmaniasis is increasing in prevalence in the United States due to increased foreign travel. Providers should be familiar with the cutaneous presentation of leishmaniasis, even in areas of low prevalence, to limit the risk for mucocutaneous dissemination from infection with the subgenus Viannia. Prompt treatment is vital to ensuring the best prognosis, and first-line treatment with miltefosine should be strongly considered given its efficacy and tolerability.

Leishmaniasis is a neglected parasitic disease with an estimated annual incidence of 1.3 million cases, the majority of which manifest as cutaneous leishmaniasis.¹ The cutaneous and mucosal forms demonstrate substantial global burden with morbidity and socioeconomic repercussions, while the visceral form is responsible for up to 30,000 deaths annually.² Despite increasing prevalence in the United States, awareness and diagnosis remain relatively low.³ We describe 2 cases of cutaneous leishmaniasis in New England, United States, in travelers returning from Central America, both successfully treated with miltefosine. We also review prevention, diagnosis, and treatment options.

Case Reports

Patient 1
A 47-year-old woman presented with an enlarging, 2-cm, erythematous, ulcerated nodule on the right dorsal hand of 2 weeks’ duration with accompanying right epitrochlear lymphadenopathy (Figure 1A). She noticed the lesion 10 weeks after returning from Panama, where she had been photographing the jungle. Prior to the initial presentation to dermatology, salicylic acid wart remover, intramuscular ceftriaxone, and oral trimethoprim had failed to alleviate the lesion. Her laboratory results were notable for an elevated C-reactive protein level of 5.4 mg/L (reference range, ≤4.9 mg/L). A punch biopsy demonstrated pseudoepitheliomatous hyperplasia with diffuse dermal lymphohistiocytic inflammation and small intracytoplasmic structures within histiocytes consistent with leishmaniasis (Figure 2). Immunohistochemistry was consistent with leishmaniasis (Figure 3), and polymerase chain reaction performed by the Centers for Disease Control and Prevention (CDC) identified the pathogen as Leishmania braziliensis.

Patient 2
An 18-year-old man presented with an enlarging, well-delineated, tender ulcer of 6 weeks’ duration measuring 2.5×2 cm with an erythematous and edematous border on the right medial forearm with associated epitrochlear lymphadenopathy (Figure 4). Nine weeks prior to initial presentation, he had returned from a 3-month outdoor adventure trip to the Florida Keys, Costa Rica, and Panama. He had used bug repellent intermittently, slept under a bug net, and did not recall any trauma or bite at the ulcer site. Biopsy and tissue culture were obtained, and histopathology demonstrated an ulcer with a dense dermal lymphogranulomatous infiltrate and intracytoplasmic organisms consistent with leishmaniasis. Polymerase chain reaction by the CDC identified the pathogen as Leishmania panamensis.

Comment

Epidemiology and Prevention
Risk factors for leishmaniasis include weak immunity, poverty, poor housing, poor sanitation, malnutrition, urbanization, climate change, and human migration.⁴ Our patients were most directly affected by travel to locations where leishmaniasis is endemic. Despite an increasing prevalence of endemic leishmaniasis and new animal hosts in the southern United States, most patients diagnosed in the United States are infected abroad by Leishmania mexicana and L braziliensis, both cutaneous New World species.³ Our patients were infected by species within the New World subgenus Viannia that have potential for mucocutaneous spread.⁴

Because there is no chemoprophylaxis or acquired active immunity such as vaccines that can mitigate the risk for leishmaniasis, public health efforts focus on preventive measures. Although difficult to achieve, avoidance of the phlebotomine sand fly species that transmit the obligate intracellular Leishmania parasite is a most effective measure.⁴ Travelers entering geographic regions with higher risk for leishmaniasis should be aware of the inherent risk and determine which methods of prevention, such as N,N-diethyl-meta-toluamide (DEET) insecticides or permethrin-treated protective clothing, are most feasible. Although higher concentrations of DEET provide longer protection, the effectiveness tends to plateau at approximately 50%.⁵

Presentation and Prognosis
For patients who develop leishmaniasis, the disease course and prognosis depend greatly on the species and manifestation. The most common form of leishmaniasis is localized cutaneous leishmaniasis, which has an annual incidence of up to 1 million cases. It initially presents as macules, usually at the site of inoculation within several months to years of infection.⁶ The macules expand into papules and plaques that reach maximum size over at least 1 week⁴ and then progress into crusted ulcers up to 5 cm in diameter with raised edges. Although usually painless and self-limited, these lesions can take years to spontaneously heal, with the risk for atrophic scarring and altered pigmentation. Lymphatic involvement manifests as lymphadenitis or regional lymphadenopathy and is common with lesions caused by the subgenus Viannia.⁶

Leishmania braziliensis and L panamensis, the species that infected our patients, can uniquely cause cutaneous leishmaniasis that metastasizes into mucocutaneous leishmaniasis, which always affects the nasal mucosa. Risk factors for transformation include a primary lesion site above the waist, multiple or large primary lesions, and delayed healing of primary cutaneous leishmaniasis. Mucocutaneous leishmaniasis can result in notable morbidity and even mortality from invasion and destruction of nasal and oropharyngeal mucosa, as well as intercurrent pneumonia, especially if treatment is insufficient or delayed.⁴

Diagnosis
Prompt treatment relies on accurate and timely diagnosis, which is complicated by the relative unfamiliarity with leishmaniasis in the United States. The differential diagnosis for cutaneous leishmaniasis is broad, including deep fungal infection, Mycobacterium infection, cutaneous granulomatous conditions, nonmelanoma cutaneous neoplasms, and trauma. Taking a thorough patient history, including potential exposures and travels; having high clinical suspicion; and being aware of classic presentation allows for identification of leishmaniasis and subsequent stratification by manifestation.⁷

Diagnosis is made by detecting Leishmania organisms or DNA using light microscopy and staining to visualize the kinetoplast in an amastigote, molecular methods, or specialized culturing.⁷ The CDC is a valuable diagnostic partner for confirmation and speciation. Specific instructions for specimen collection and transportation can be found by contacting the CDC or reading their guide.⁸ To provide prompt care and reassurance to patients, it is important to be aware of the coordination effort that may be needed to send samples, receive results, and otherwise correspond with a separate institution.

Treatment
Treatment of cutaneous leishmaniasis is indicated to decrease the risk for mucosal dissemination and clinical reactivation of lesions, accelerate healing of lesions, decrease local morbidity caused by large or persistent lesions, and decrease the reservoir of infection in places where infected humans serve as reservoir hosts. Oral treatments include ketoconazole, itraconazole, and fluconazole, recommended at doses ranging from 200 to 600 mg daily for at least 28 days. For severe, refractory, or visceral leishmaniasis, parenteral choices include pentavalent antimonials, amphotericin B deoxycholate, and pentamidine isethionate, each with known toxicity or limited data on efficacy.⁶ Pentavalent antimonials can cause life-threatening cardiotoxicity and are more difficult to administer.⁹ Furthermore, they are not approved by the US Food and Drug Administration or commercially available in the United States, with only sodium stibogluconate available through the CDC.⁶

Miltefosine is becoming a more common treatment of leishmaniasis because of its oral route, tolerability in nonpregnant patients, and commercial availability. It was approved by the US Food and Drug Administration in 2014 for cutaneous leishmaniasis due to L braziliensis, L panamensis, and Leishmania guyanensis; mucosal leishmaniasis due to L braziliensis; and visceral leishmaniasis due to Leishmania donovani in patients at least 12 years of age. For cutaneous leishmaniasis, the standard dosage of 50 mg twice daily (for patients weighing 30–44 kg) or 3 times daily (for patients weighing 45 kg or more) for 28 consecutive days has cure rates of 48% to 85% by 6 months after therapy ends. Cure is defined as epithelialization of lesions, no enlargement greater than 50% in lesions, no appearance of new lesions, and/or negative parasitology. The antileishmanial mechanism of action is unknown and likely involves interaction with lipids, inhibition of cytochrome c oxidase, and apoptosislike cell death. Miltefosine is contraindicated in pregnancy. The most common adverse reactions in patients include nausea (35.9%–41.7%), motion sickness (29.2%), headache (28.1%), and emesis (4.5%–27.5%). With the exception of headache, these adverse reactions can decrease with administration of food, fluids, and antiemetics. Potentially more serious but rarer adverse reactions include elevated serum creatinine (5%–25%) and transaminases (5%). Although our patients had mild hyperkalemia, it is not an established adverse reaction. However, renal injury has been reported.¹⁰

Conclusion

Cutaneous leishmaniasis is increasing in prevalence in the United States due to increased foreign travel. Providers should be familiar with the cutaneous presentation of leishmaniasis, even in areas of low prevalence, to limit the risk for mucocutaneous dissemination from infection with the subgenus Viannia. Prompt treatment is vital to ensuring the best prognosis, and first-line treatment with miltefosine should be strongly considered given its efficacy and tolerability.

A shift in managing symptoms for patients with relapsing-remitting multiple sclerosis (RRMS) may be in order as new research questions the efficacy of three commonly used drugs for MS-related fatigue. Results of a study from Johns Hopkins University show that amantadine, modafinil, and methylphenidate were not superior to placebo. As Dr Mark Freedman reports in this ReCAP, the study suggests that clinicians consider focusing more on patient sleep quality rather than tiredness in their evaluation of fatigue.

This study was presented during the 8th Joint Meeting of ACTRIMS-ECTRIMS, this year branded MSVirtual2020. Dr Freedman, a recognized neurologist from the University of Ottawa, shares key highlights from the online conference.

He explains the significance of new evidence that points to the potential for a selective retinoid X receptor agonist to promote remyelination in relapsing disease. He also discusses a study by researchers at the University of Melbourne that looked at data from the largest cohort of MS patients with COVID-19 and drew troubling conclusions.

Professor, Department of Neurology, University of Ottawa and The Ottawa Hospital Research Institute; Director, Multiple Sclerosis Research Unit, The Ottawa Hospital – General Campus, Ottawa, Ontario, Canada.

Mark S. Freedman, MSc, MD, has disclosed the following relevant financial relationships: Serve(d) on the advisory board, board of directors, or other similar groups for: Actelion (Janssen/Johnson & Johnson); Alexion; Atara Biotherapeutics; BayerHealthcare; BiogenIdec; Celgene; Clene Nanomedicine; GRI Bio; Hoffman La-Roche; Magenta Therapeutics; Merck Serono; MedDay; Novartis; Sanofi-Genzyme; Teva Canada Innovation. Serve(d) as a member of a speakers bureau for: Sanofi-Genzyme; EMD Serono. Received honoraria or consultation fees for: Actelion (Janssen/Johnson & Johnson); Alexion; BiogenIdec; Celgene (BMS); EMD Inc; Sanofi-Genzyme; Hoffman La-Roche; Merck Serono; Novartis; Teva Canada Innovation­. Received research or educational grants from: Sanofi-Genzyme Canada; Hoffman-La Roche; EMD Inc.

A shift in managing symptoms for patients with relapsing-remitting multiple sclerosis (RRMS) may be in order as new research questions the efficacy of three commonly used drugs for MS-related fatigue. Results of a study from Johns Hopkins University show that amantadine, modafinil, and methylphenidate were not superior to placebo. As Dr Mark Freedman reports in this ReCAP, the study suggests that clinicians consider focusing more on patient sleep quality rather than tiredness in their evaluation of fatigue.

This study was presented during the 8th Joint Meeting of ACTRIMS-ECTRIMS, this year branded MSVirtual2020. Dr Freedman, a recognized neurologist from the University of Ottawa, shares key highlights from the online conference.

He explains the significance of new evidence that points to the potential for a selective retinoid X receptor agonist to promote remyelination in relapsing disease. He also discusses a study by researchers at the University of Melbourne that looked at data from the largest cohort of MS patients with COVID-19 and drew troubling conclusions.

Professor, Department of Neurology, University of Ottawa and The Ottawa Hospital Research Institute; Director, Multiple Sclerosis Research Unit, The Ottawa Hospital – General Campus, Ottawa, Ontario, Canada.

Mark S. Freedman, MSc, MD, has disclosed the following relevant financial relationships: Serve(d) on the advisory board, board of directors, or other similar groups for: Actelion (Janssen/Johnson & Johnson); Alexion; Atara Biotherapeutics; BayerHealthcare; BiogenIdec; Celgene; Clene Nanomedicine; GRI Bio; Hoffman La-Roche; Magenta Therapeutics; Merck Serono; MedDay; Novartis; Sanofi-Genzyme; Teva Canada Innovation. Serve(d) as a member of a speakers bureau for: Sanofi-Genzyme; EMD Serono. Received honoraria or consultation fees for: Actelion (Janssen/Johnson & Johnson); Alexion; BiogenIdec; Celgene (BMS); EMD Inc; Sanofi-Genzyme; Hoffman La-Roche; Merck Serono; Novartis; Teva Canada Innovation­. Received research or educational grants from: Sanofi-Genzyme Canada; Hoffman-La Roche; EMD Inc.

A shift in managing symptoms for patients with relapsing-remitting multiple sclerosis (RRMS) may be in order as new research questions the efficacy of three commonly used drugs for MS-related fatigue. Results of a study from Johns Hopkins University show that amantadine, modafinil, and methylphenidate were not superior to placebo. As Dr Mark Freedman reports in this ReCAP, the study suggests that clinicians consider focusing more on patient sleep quality rather than tiredness in their evaluation of fatigue.

This study was presented during the 8th Joint Meeting of ACTRIMS-ECTRIMS, this year branded MSVirtual2020. Dr Freedman, a recognized neurologist from the University of Ottawa, shares key highlights from the online conference.

He explains the significance of new evidence that points to the potential for a selective retinoid X receptor agonist to promote remyelination in relapsing disease. He also discusses a study by researchers at the University of Melbourne that looked at data from the largest cohort of MS patients with COVID-19 and drew troubling conclusions.

Professor, Department of Neurology, University of Ottawa and The Ottawa Hospital Research Institute; Director, Multiple Sclerosis Research Unit, The Ottawa Hospital – General Campus, Ottawa, Ontario, Canada.

Mark S. Freedman, MSc, MD, has disclosed the following relevant financial relationships: Serve(d) on the advisory board, board of directors, or other similar groups for: Actelion (Janssen/Johnson & Johnson); Alexion; Atara Biotherapeutics; BayerHealthcare; BiogenIdec; Celgene; Clene Nanomedicine; GRI Bio; Hoffman La-Roche; Magenta Therapeutics; Merck Serono; MedDay; Novartis; Sanofi-Genzyme; Teva Canada Innovation. Serve(d) as a member of a speakers bureau for: Sanofi-Genzyme; EMD Serono. Received honoraria or consultation fees for: Actelion (Janssen/Johnson & Johnson); Alexion; BiogenIdec; Celgene (BMS); EMD Inc; Sanofi-Genzyme; Hoffman La-Roche; Merck Serono; Novartis; Teva Canada Innovation­. Received research or educational grants from: Sanofi-Genzyme Canada; Hoffman-La Roche; EMD Inc.

Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.¹ It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.² The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including tumor necrosis factor (TNF) α.³ More recently, interactions of helper T cells (T_H17) via IL-17 and IL-23 have been supported to play a major role in the pathogenesis of psoriasis.^4,5

With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.⁶ Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.⁷

Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.^8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.¹¹ Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.

Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.

METHODS

A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.

RESULTSIL-17 Inhibitors

Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).

Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al¹² reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.¹² In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.¹³ A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.¹⁴ JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.¹⁵ Common AEs for both studies included nasopharyngitis and headache.^14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.¹⁶ In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al¹⁷ demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.¹⁸ Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.^17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.¹⁹ In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.²⁰ Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.²¹ In a phase 2 study of 103 patients with psoriasis, Papp et al²² demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,²³ the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.

Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al⁹ conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.²⁴ FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.²⁵ In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.²⁶ A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.²⁷

Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.²⁸ In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.²⁹ MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.³⁰

Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.³¹ In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.³² In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.³³ A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.³⁴ An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.³⁵

Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.³⁶

We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.³⁷

Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.³⁸ In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.³⁹ In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.¹⁰ A phase 3 RCT conducted by Papp et al⁴⁰ (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al⁴¹ reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.⁴²

Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.⁴³ In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.⁴⁴ Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.⁴⁵

IL-12/IL-23 Inhibitor

Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).^46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.^66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.

IL-23 Inhibitors

Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,^50-54 9 with guselkumab,^55-63 and 2 with tildrakizumab.^64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.

COMMENT

Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.

Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.

A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.¹¹ Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.⁶⁸ If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.⁶⁸ Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.⁶⁸

Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.⁶⁹

Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.⁷⁰ Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.⁷¹ Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.

Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.

Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.¹ It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.² The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including tumor necrosis factor (TNF) α.³ More recently, interactions of helper T cells (T_H17) via IL-17 and IL-23 have been supported to play a major role in the pathogenesis of psoriasis.^4,5

With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.⁶ Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.⁷

Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.^8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.¹¹ Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.

Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.

METHODS

A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.

RESULTSIL-17 Inhibitors

Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).

Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al¹² reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.¹² In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.¹³ A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.¹⁴ JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.¹⁵ Common AEs for both studies included nasopharyngitis and headache.^14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.¹⁶ In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al¹⁷ demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.¹⁸ Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.^17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.¹⁹ In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.²⁰ Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.²¹ In a phase 2 study of 103 patients with psoriasis, Papp et al²² demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,²³ the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.

Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al⁹ conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.²⁴ FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.²⁵ In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.²⁶ A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.²⁷

Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.²⁸ In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.²⁹ MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.³⁰

Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.³¹ In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.³² In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.³³ A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.³⁴ An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.³⁵

Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.³⁶

We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.³⁷

Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.³⁸ In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.³⁹ In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.¹⁰ A phase 3 RCT conducted by Papp et al⁴⁰ (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al⁴¹ reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.⁴²

Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.⁴³ In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.⁴⁴ Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.⁴⁵

IL-12/IL-23 Inhibitor

Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).^46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.^66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.

IL-23 Inhibitors

Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,^50-54 9 with guselkumab,^55-63 and 2 with tildrakizumab.^64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.

COMMENT

Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.

Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.

A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.¹¹ Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.⁶⁸ If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.⁶⁸ Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.⁶⁸

Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.⁶⁹

Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.⁷⁰ Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.⁷¹ Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.

Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.

Psoriasis is a common chronic, multisystem, inflammatory disease with predominantly skin and joint manifestations that affects approximately 2% of the world’s population.¹ It occurs in a variety of clinical forms, from a few well-demarcated, erythematous plaques with a silvery scale to involvement of almost the entire body surface area. Beyond the debilitating physical ailments of the disease, psoriasis also may have psychosocial effects on quality of life.² The pathogenesis of psoriasis is not fully understood but represents a complex multifactorial disease with both immune-mediated and genetic components. Characterized by hyperplasia of epidermal keratinocytes, psoriasis is shown to be mediated by infiltration of T-cell lymphocytes with an increase of various inflammatory cytokines, including tumor necrosis factor (TNF) α.³ More recently, interactions of helper T cells (T_H17) via IL-17 and IL-23 have been supported to play a major role in the pathogenesis of psoriasis.^4,5

With the growing understanding of the pathophysiology of psoriasis, focused biologics have been developed to target specific cytokines implicated in the disease process and have been increasingly utilized. Tumor necrosis factor α inhibitors, including adalimumab, infliximab, and etanercept, along with the IL-12/IL-23 inhibitor ustekinumab, have been revolutionary in psoriasis treatment by providing safe and effective long-term therapy; however, there is concern of life-threatening infections with biologics because of the immunosuppressive effects and mechanisms of action.⁶ Specifically, there have been reported cases of deep fungal infections associated with TNF-α inhibitor use.⁷

Recently, the advent of IL-17 and IL-23 inhibitors has garnered notable interest in these biologics as promising treatments for psoriasis. With IL-17 and IL-23 supported to have a major role in the pathogenesis of psoriasis, targeting the cytokine is not only logical but also has proven to be effacacious.^8-10 Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. Secukinumab and ixekizumab are anti–IL-17A monoclonal antibodies, whereas brodalumab is an anti–IL-17 receptor antibody. Risankizumab, guselkumab, and tildrakizumab are IL-23 inhibitors that also have been approved by the FDA for the treatment of psoriasis. As with older biologics, there is concern over the safety of these inhibitors because of the central role of IL-17 and IL-23 in both innate and adaptive immune responses, particularly against fungi.¹¹ Therefore, use of biologics targeting IL-17 and IL-23 may increase susceptibility to deep fungal infections.

Safety data and discussion of the risk for deep fungal infections from IL-17, IL-12/IL-23, and IL-23 inhibitor use for psoriasis treatment currently are lacking. Given the knowledge gap, we sought to synthesize and review the current evidence on risks for deep fungal infections during biologic therapy in patients with psoriasis, with a focus on IL-17 inhibitor therapies.

METHODS

A PubMed search of articles indexed for MEDLINE from database inception to 2019 (1946-2019) was performed to find randomized controlled trials (RCTs), including extended trials and clinical trials, for IL-17, IL-12/IL-23, and IL-23 inhibitors approved by the FDA for psoriasis treatment. The following keywords were used: psoriasis or inflammatory disease and secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Studies were restricted to the English-language literature, and those that did not provide adequate safety data on the specific types of infections that occurred were excluded.

RESULTSIL-17 Inhibitors

Our search yielded RCTs, some including extension trials, and clinical trials of IL-17 inhibitors used for psoriatic disease and other nonpsoriatic conditions (Table).

Risk for Deep Fungal Infection With Secukinumab
The queried studies included 20 RCTs or clinical trials along with extension trials of 3746 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In a 3-year extension study of SCULPTURE, Bissonnette et al¹² reported no new safety concerns for the 340 patients with moderate to severe psoriasis treated with secukinumab. Common adverse events (AEs) included nasopharyngitis, upper respiratory tract infections, and headache, but there were no reports of deep fungal infections.¹² In a subsequent 5-year analysis of 168 patients that focused on the 300-mg fixed interval treatment with secukinumab, the safety profile remained favorable, with 0 reports of invasive fungal infections.¹³ A study (FEATURE) of 118 patients with psoriasis treated with a prefilled syringe of 300 or 150 mg of secukinumab also described an acceptable safety profile and reported no deep fungal infections.¹⁴ JUNCTURE, another study utilizing autoinjectors, also found that treatment with 300 or 150 mg of secukinumab was well tolerated in 121 patients, with no deep fungal infections.¹⁵ Common AEs for both studies included nasopharyngitis and headache.^14,15 A 24-week phase 3 study for scalp psoriasis treated with secukinumab also reported 0 deep fungal infections in 51 patients.¹⁶ In an RCT comparing secukinumab and ustekinumab for moderate to severe plaque psoriasis, Blauvelt et al¹⁷ demonstrated that the incidence of serious AEs was comparable between the 2 groups, with no reports of invasive fungal infections in the 334 patients exposed to secukinumab. The CLEAR study, which compared secukinumab and ustekinumab, also found no reported deep fungal disease in the 335 patients exposed to secukinumab.¹⁸ Secukinumab exhibited a similar safety profile to ustekinumab in both studies, with common AEs being headache and nasopharyngitis.^17,18 The GESTURE study investigated the efficacy of secukinumab in 137 patients with palmoplantar psoriasis and reported a favorable profile with no reports of deep fungal disease.¹⁹ In a subanalysis of the phase 3 study ERASURE, secukinumab was shown to have a robust and sustainable efficacy in 58 Japanese patients with moderate to severe plaque psoriasis, and there were no reports of invasive fungal infections.²⁰ Another subanalysis of 36 Taiwanese patients from the ERASURE study also had similar findings, with no dose relationship observed for AEs.²¹ In a phase 2 study of 103 patients with psoriasis, Papp et al²² demonstrated AE rates that were similar across different doses of secukinumab—3×150 mg, 3×75 mg, 3×25 mg, and 1×25 mg—and described no incidences of invasive fungal disease. In a phase 2 regimen-finding study of 337 patients conducted by Rich et al,²³ the most commonly reported AEs included nasopharyngitis, worsening psoriasis, and upper respiratory tract infections, but there were no reported deep fungal infections.

Our search also resulted in studies specific to the treatment of psoriatic arthritis (PsA) with secukinumab. McInnes et al⁹ conducted a phase 2 proof-of-concept trial for patients with PsA and reported no deep fungal infections in 28 patients exposed to 10 mg/kg of secukinumab. A 2-year follow-up with the cohort from FUTURE 1, a phase 3 clinical trial, also showed no new or unexpected safety signals in 404 patients exposed to 150 or 75 mg of secukinumab, including no reports of invasive fungal disease.²⁴ FUTURE 2, a phase 3 clinical trial, demonstrated that the most common AE was upper respiratory tract infection in the 299 patients treatedwith secukinumab, but there were no recorded invasive fungal infections.²⁵ In FUTURE 3, 277 patients were treated with secukinumab, with 14 nonserious candida infections but no observed deep fungal infections.²⁶ A study comparing secukinumab to fumaric acid esters reported that 6 of 105 patients treated with secukinumab also experienced superficial candidiasis, but there were no reports of deep fungal disease.²⁷

Secukinumab also has been used in the treatment of ankylosing spondylitis in a phase 3 RCT (MEASURE 1) in which 4 cases of superficial candidiasis were reported (0.7 cases per 100 patient-years of secukinumab) that were all resolved with standard antifungal therapy.²⁸ In MEASURE 2, a 5-year phase 3 RCT, 145 patients were treated with secukinumab for ankylosing spondylitis, with common AEs including nasopharyngitis, diarrhea, and upper respiratory tract infection, but there were no reports of any invasive fungal infections.²⁹ MEASURE 3 also demonstrated similar results in which no invasive fungal infections were observed.³⁰

Risk for Deep Fungal Infection With Ixekizumab
The queried studies included 7 RCTs or clinical trials of 3523 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 52 weeks. In UNCOVER-A, a phase 3 RCT of the pharmacokinetics and safety of ixekizumab, 204 patients were randomized to a prefilled syringe or autoinjector; 48% of patients experienced AEs, but no invasive fungal infections were observed.³¹ In an analysis of 3 phase 3 trials of ixekizumab including a total 2334 patients treated with ixekizumab from UNCOVER-1, UNCOVER-2, and UNCOVER-3, oral candidiasis frequently was reported, but no candidal infections met criteria for serious invasive infection.³² In UNCOVER-J, a 52-week phase 3 open-label trial of Japanese patients, 91 patients were treated for plaque psoriasis, erythrodermic psoriasis, or generalized pustular psoriasis using ixekizumab; the most common AEs included allergic reactions and injection-site reactions. One case of oral candidiasis was reported, but there were no reported cases of invasive fungal infections.³³ A comparison of ixekizumab vs ustekinumab from the IXORA-S trial demonstrated no substantial differences in AEs between the two, and no cases of deep fungal infections were reported. The most common AE between the 2 groups was nasopharyngitis.³⁴ An open-label extension over 4 years of a phase 2 RCT treated 211 patients with either 120 or 80 mg of ixekizumab; 87% of patients had experienced at least 1 AE, and all AEs were considered mild or moderate in severity, with no invasive fungal disease.³⁵

Our search also resulted in 1 study specific to the treatment of PsA with ixekizumab. A phase 3, 52-week study of patients treated with ixekizumab for PsA observed 2 incidences of oral candidiasis and nail candida infections, but no invasive fungal infections were reported.³⁶

We also found 1 study of ixekizumab used in the treatment of ankylosing spondylitis. COAST-V was a phase 3 RCT of patients treated for ankylosing spondylitis in which 164 patients were treated with ixekizumab; no serious AEs were recorded, including 0 deep fungal infections. The most common AEs observed were nasopharyngitis and upper respiratory tract infections.³⁷

Risk for Deep Fungal Infection With Brodalumab
The queried studies included 9 RCTs and 3 clinical trials along with extension trials of 1599 patients with psoriasis or other inflammatory conditions, with follow-up ranging from 12 to 120 weeks. In a phase 2 RCT of Japanese patients with moderate to severe plaque psoriasis, 113 patients were treated with 70, 140, or 210 mg of brodalumab, and the most common AEs were nasopharyngitis, diarrhea, and upper respiratory tract inflammation. There were no reported cases of fungal infections in the study.³⁸ In an open-label extension study of Japanese patients that evaluated the long-term clinical safety of brodalumab, 145 patients were enrolled and observed similar AEs to the RCT, with 7 patients experiencing oral candidiasis and 1 patient having skin candidiasis, but there were no observed deep fungal infections.³⁹ In AMG 827, which evaluated the efficacy and safety of brodalumab, 320 patients were treated, and only 2 serious AEs were reported, neither of which were deep fungal disease.¹⁰ A phase 3 RCT conducted by Papp et al⁴⁰ (AMAGINE-1) also treated 441 patients with moderate to severe plaque psoriasis with brodalumab and observed candida infections in 9 patients that were mild to moderate and responsive to treatment, with no patients discontinuing the study. In a 120-week open-label extension study of 181 patients, Papp et al⁴¹ reported 8% of patients experienced serious AEs, with 1 case of latent tuberculosis that led to withdrawal of treatment. A study also investigated the efficacy and safety of brodalumab in 30 patients with generalized pustular psoriasis or psoriatic erythroderma and observed 2 cases of mild candida infections that resolved with treatment. There were no reports of invasive fungal disease.⁴²

Our search also resulted in studies of brodalumab used in the treatment of PsA and nonpsoriatic diseases. In one phase 2 RCT, 113 patients with PsA were treated with 140 mg, 280 mg, or combined doses of brodalumab, with the most common AEs being nasopharyngitis, upper respiratory tract infection, and diarrhea, but there were no reports of deep fungal infection.⁴³ In a phase 1b trial of patients with methotrexate-resistant rheumatoid arthritis treated with brodalumab, common AEs reported included headache, cough, and abdominal pain, with only 1 case of oral candidiasis that was determined not to be drug related.⁴⁴ Finally, an RCT of patients with moderate to severe asthma treated 226 patients with brodalumab and reported a greater incidence of oral candidiasis in treatment groups compared with placebo (3.5% vs 0%) but saw no instances of invasive fungal infection.⁴⁵

IL-12/IL-23 Inhibitor

Risk for Deep Fungal Infection With Ustekinumab
The queried studies included 4 RCTs of 954 patients with psoriasis treated with ustekinumab (eTable).^46-49 Within these trials, there were no reported cases of serious infections involving deep fungal organisms during the stated follow-up period. The literature search also found long-term safety data from the ACCEPT and PHOENIX trials that included 5437 patients with psoriasis treated with ustekinumab.^66,67 There also were no demonstrated incidences of invasive fungal disease in these studies, with most cases of infection being common bacterial or viral infections.

IL-23 Inhibitors

Risk for Deep Fungal Infection With Risankizumab, Guselkumab, and Tildrakizumab
The queried studies included 16 RCTs or clinical trials for psoriatic patients treated with IL-23 inhibitors, including 5 with risankizumab,^50-54 9 with guselkumab,^55-63 and 2 with tildrakizumab.^64,65 Within these trials there were no observed cases of serious infections with deep fungal disease.

COMMENT

Our literature review has demonstrated that there does not appear to be an increased incidence of deep fungal infections for patients treated with IL-17, IL-12/IL-23, or IL-23 inhibitors for psoriatic disease. All of the reviewed studies found no cases of invasive fungal infections for patients with psoriasis treated with secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, or tildrakizumab. Patients with other inflammatory conditions, such as ankylosing spondylitis, rheumatoid arthritis, and asthma, also did not appear to show an increased incidence of deep fungal disease.

Although these results show promising safety data for the use of these biologic therapies in treating inflammatory conditions, caution still is warranted, as these medications still are relatively new, with FDA approvals within the last 5 years. Safety data among different study populations also cannot be derived without further investigation, and much of the available literature is limited in long-term data. More extended trials or registry data from a large, broadly representative cohort are necessary to establish the long-term safety and risk for deep fungal infections with IL-17 and especially the newer IL-23 inhibitors.

A small percentage of patients from the reviewed literature did develop superficial candidiasis. This outcome can be expected, as the central role of IL-17 and IL-23 has been recognized in immunologic protection against infections, specifically against fungi.¹¹ Because all of the fungal infections reported for patients on IL-17 inhibitors were superficial candidiasis, guides for practical management and treatment should be implemented to standardize future research and care. A proposed screening algorithm for patients on these biologic therapies involves safety monitoring, including inspection of the oral cavity, folds, and genitals, along with inquiring about symptoms such as burning, dysgeusia, and dysuria.⁶⁸ If infection is suspected, confirmation by culture, molecular method, or optimally with esophagoscopy can be performed, and appropriate treatment may be initiated.⁶⁸ Patients with candida infections of the oral cavity, folds, or genitals can be placed on topical therapy such as nystatin, amphotericin B, ciclopirox, or other azoles, while those with infections of the esophagus can be started on oral fluconazole.⁶⁸

Although there were no reported cases of deep fungal infections, the theoretical risk for developing one while on IL-17 and IL-23 inhibitors may warrant further screening prior to beginning therapy. The TNF inhibitors approved for the treatment of psoriasis currently contain a black box warning for risk for disseminated and extrapulmonary histoplasmosis, coccidioidomycosis, blastomycosis, and other invasive fungal infections, which may highlight the importance of thorough evaluation and awareness of endemic areas for patients on biologics. Prior to initiating treatment with TNF inhibitors, current suggestions involve performing a thorough examination along with keeping a high index of suspicion for invasive fungal infections in patients who live in or have traveled to endemic regions.⁶⁹

Screening for invasive fungal infections for patients on TNF inhibitors involves questioning about potential exposures, such as demolition of old buildings, bird roosts, or spelunking.⁷⁰ Serologies or antigen testing can be used routinely, but as these tests are insensitive, empiric antifungal therapy should be initiated if there is high enough clinical suspicion.⁷¹ Currently, there are no clinical guidelines regarding fungal screening and initiation of IL-17 and IL-23 inhibitors for treatment of psoriasis and other inflammatory conditions, but careful stewardship over using these effective medications should still be practiced.

Upon review of the available safety data on the use of IL-17 and IL-23 inhibitors for the treatment of psoriasis and other inflammatory conditions, there does not appear to be an increased incidence of deep fungal infections. Physicians, however, should still be cautiously optimistic in prescribing these medications, as there is a theoretical risk for infection for all patients on biologics. A high index of suspicion for patients presenting with symptoms of fungal infections should be maintained, and appropriate diagnosis and management should be initiated if they do occur.

Children should not return to sports for 14 days after exposure to COVID-19, and those with moderate symptoms should undergo an electrocardiogram before returning, according to the American Academy of Pediatrics.

The recommendations, which update the academy’s July 23 guidance, stem from new concerns that the disease can cause myocarditis, said Susannah Briskin, MD, a pediatric sports medicine specialist at Rainbow Babies and Children’s Hospital in Cleveland.

“There has been emerging evidence about cases of myocarditis occurring in athletes, including athletes who are asymptomatic with COVID-19,” she said in an interview.

The update aligns the AAP recommendations with those from the American College of Cardiologists, she added.

Recent imaging studies have turned up signs of myocarditis in athletes recovering from mild or asymptomatic cases of COVID-19 and have prompted calls for clearer guidelines about imaging studies and return to play.

Viral myocarditis poses a risk to athletes because it can lead to potentially fatal arrhythmias, Dr. Briskin said.

Although children benefit from participating in sports, these activities also put them at risk of contracting COVID-19 and spreading it to others, the guidance noted.

To balance the risks and benefits, the academy proposed guidelines that vary depending on the severity of the presentation.

In the first category are patients with a severe presentation (hypotension, arrhythmias, need for intubation or extracorporeal membrane oxygenation support, kidney or cardiac failure) or with multisystem inflammatory syndrome. Clinicians should treat these patients as though they have myocarditis. Patients should be restricted from engaging in sports and other exercise for 3-6 months, the guidance stated.

The primary care physician and “appropriate pediatric medical subspecialist, preferably in consultation with a pediatric cardiologist,” should clear them before they return to activities. In examining patients for return to play, clinicians should focus on cardiac symptoms, including chest pain, shortness of breath, fatigue, palpitations, or syncope, the guidance said.

In another category are patients with cardiac symptoms, those with concerning findings on examination, and those with moderate symptoms of COVID-19, including prolonged fever. These patients should undergo an ECG and possibly be referred to a pediatric cardiologist, the guidelines said. These symptoms must be absent for at least 14 days before these patients can return to sports, and the athletes should obtain clearance from their primary care physicians before they resume.

In a third category are patients who have been infected with SARS-CoV-2 or who have had close contact with someone who was infected but who have not themselves experienced symptoms. These athletes should refrain from sports for at least 14 days, the guidelines said.

Children who don’t fall into any of these categories should not be tested for the virus or antibodies to it before participation in sports, the academy said.

The guidelines don’t vary depending on the sport. But the academy has issued separate guidance for parents and guardians to help them evaluate the risk for COVID-19 transmission by sport.

Athletes participating in “sports that have greater amount of contact time or proximity to people would be at higher risk for contracting COVID-19,” Dr. Briskin said. “But I think that’s all fairly common sense, given the recommendations for non–sport-related activity just in terms of social distancing and masking.”

The new guidance called on sports organizers to minimize contact by, for example, modifying drills and conditioning. It recommended that athletes wear masks except during vigorous exercise or when participating in water sports, as well as in other circumstances in which the mask could become a safety hazard.

They also recommended using handwashing stations or hand sanitizer, avoiding contact with shared surfaces, and avoiding small rooms and areas with poor ventilation.

Dr. Briskin disclosed no relevant financial relationships.

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

Children should not return to sports for 14 days after exposure to COVID-19, and those with moderate symptoms should undergo an electrocardiogram before returning, according to the American Academy of Pediatrics.

The recommendations, which update the academy’s July 23 guidance, stem from new concerns that the disease can cause myocarditis, said Susannah Briskin, MD, a pediatric sports medicine specialist at Rainbow Babies and Children’s Hospital in Cleveland.

“There has been emerging evidence about cases of myocarditis occurring in athletes, including athletes who are asymptomatic with COVID-19,” she said in an interview.

The update aligns the AAP recommendations with those from the American College of Cardiologists, she added.

Recent imaging studies have turned up signs of myocarditis in athletes recovering from mild or asymptomatic cases of COVID-19 and have prompted calls for clearer guidelines about imaging studies and return to play.

Viral myocarditis poses a risk to athletes because it can lead to potentially fatal arrhythmias, Dr. Briskin said.

Although children benefit from participating in sports, these activities also put them at risk of contracting COVID-19 and spreading it to others, the guidance noted.

To balance the risks and benefits, the academy proposed guidelines that vary depending on the severity of the presentation.

In the first category are patients with a severe presentation (hypotension, arrhythmias, need for intubation or extracorporeal membrane oxygenation support, kidney or cardiac failure) or with multisystem inflammatory syndrome. Clinicians should treat these patients as though they have myocarditis. Patients should be restricted from engaging in sports and other exercise for 3-6 months, the guidance stated.

The primary care physician and “appropriate pediatric medical subspecialist, preferably in consultation with a pediatric cardiologist,” should clear them before they return to activities. In examining patients for return to play, clinicians should focus on cardiac symptoms, including chest pain, shortness of breath, fatigue, palpitations, or syncope, the guidance said.

In another category are patients with cardiac symptoms, those with concerning findings on examination, and those with moderate symptoms of COVID-19, including prolonged fever. These patients should undergo an ECG and possibly be referred to a pediatric cardiologist, the guidelines said. These symptoms must be absent for at least 14 days before these patients can return to sports, and the athletes should obtain clearance from their primary care physicians before they resume.

In a third category are patients who have been infected with SARS-CoV-2 or who have had close contact with someone who was infected but who have not themselves experienced symptoms. These athletes should refrain from sports for at least 14 days, the guidelines said.

Children who don’t fall into any of these categories should not be tested for the virus or antibodies to it before participation in sports, the academy said.

The guidelines don’t vary depending on the sport. But the academy has issued separate guidance for parents and guardians to help them evaluate the risk for COVID-19 transmission by sport.

Athletes participating in “sports that have greater amount of contact time or proximity to people would be at higher risk for contracting COVID-19,” Dr. Briskin said. “But I think that’s all fairly common sense, given the recommendations for non–sport-related activity just in terms of social distancing and masking.”

The new guidance called on sports organizers to minimize contact by, for example, modifying drills and conditioning. It recommended that athletes wear masks except during vigorous exercise or when participating in water sports, as well as in other circumstances in which the mask could become a safety hazard.

They also recommended using handwashing stations or hand sanitizer, avoiding contact with shared surfaces, and avoiding small rooms and areas with poor ventilation.

Dr. Briskin disclosed no relevant financial relationships.

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

Children should not return to sports for 14 days after exposure to COVID-19, and those with moderate symptoms should undergo an electrocardiogram before returning, according to the American Academy of Pediatrics.

The recommendations, which update the academy’s July 23 guidance, stem from new concerns that the disease can cause myocarditis, said Susannah Briskin, MD, a pediatric sports medicine specialist at Rainbow Babies and Children’s Hospital in Cleveland.

“There has been emerging evidence about cases of myocarditis occurring in athletes, including athletes who are asymptomatic with COVID-19,” she said in an interview.

The update aligns the AAP recommendations with those from the American College of Cardiologists, she added.

Recent imaging studies have turned up signs of myocarditis in athletes recovering from mild or asymptomatic cases of COVID-19 and have prompted calls for clearer guidelines about imaging studies and return to play.

Viral myocarditis poses a risk to athletes because it can lead to potentially fatal arrhythmias, Dr. Briskin said.

Although children benefit from participating in sports, these activities also put them at risk of contracting COVID-19 and spreading it to others, the guidance noted.

To balance the risks and benefits, the academy proposed guidelines that vary depending on the severity of the presentation.

In the first category are patients with a severe presentation (hypotension, arrhythmias, need for intubation or extracorporeal membrane oxygenation support, kidney or cardiac failure) or with multisystem inflammatory syndrome. Clinicians should treat these patients as though they have myocarditis. Patients should be restricted from engaging in sports and other exercise for 3-6 months, the guidance stated.

The primary care physician and “appropriate pediatric medical subspecialist, preferably in consultation with a pediatric cardiologist,” should clear them before they return to activities. In examining patients for return to play, clinicians should focus on cardiac symptoms, including chest pain, shortness of breath, fatigue, palpitations, or syncope, the guidance said.

In another category are patients with cardiac symptoms, those with concerning findings on examination, and those with moderate symptoms of COVID-19, including prolonged fever. These patients should undergo an ECG and possibly be referred to a pediatric cardiologist, the guidelines said. These symptoms must be absent for at least 14 days before these patients can return to sports, and the athletes should obtain clearance from their primary care physicians before they resume.

In a third category are patients who have been infected with SARS-CoV-2 or who have had close contact with someone who was infected but who have not themselves experienced symptoms. These athletes should refrain from sports for at least 14 days, the guidelines said.

Children who don’t fall into any of these categories should not be tested for the virus or antibodies to it before participation in sports, the academy said.

The guidelines don’t vary depending on the sport. But the academy has issued separate guidance for parents and guardians to help them evaluate the risk for COVID-19 transmission by sport.

Athletes participating in “sports that have greater amount of contact time or proximity to people would be at higher risk for contracting COVID-19,” Dr. Briskin said. “But I think that’s all fairly common sense, given the recommendations for non–sport-related activity just in terms of social distancing and masking.”

The new guidance called on sports organizers to minimize contact by, for example, modifying drills and conditioning. It recommended that athletes wear masks except during vigorous exercise or when participating in water sports, as well as in other circumstances in which the mask could become a safety hazard.

They also recommended using handwashing stations or hand sanitizer, avoiding contact with shared surfaces, and avoiding small rooms and areas with poor ventilation.

Dr. Briskin disclosed no relevant financial relationships.

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

Women are known to lag 5-10 years behind men in experiencing coronary heart disease (CHD), but new research suggests the gap narrows substantially following a myocardial infarction.

“Women lose a considerable portion, but not all, of their coronary and survival advantage – i.e., the lower event rates – after suffering a MI,” study author Sanne Peters, PhD, George Institute for Global Health, Imperial College London, said in an interview.

Previous studies of sex differences in event rates after a coronary event have produced mixed results and were primarily focused on mortality following MI. Importantly, the studies also lacked a control group without a history of CHD and, thus, were unable to provide a reference point for the disparity in event rates, she explained.

Using the MarketScan and Medicare databases, however, Dr. Peters and colleagues matched 339,890 U.S. adults hospitalized for an MI between January 2015 and December 2016 with 1,359,560 U.S. adults without a history of CHD.

Over a median 1.3 years follow-up, there were 12,518 MIs in the non-CHD group and 27,115 recurrent MIs in the MI group.

The age-standardized rate of MI per 1,000 person-years was 4.0 in women and 6.1 in men without a history of CHD, compared with 57.6 in women and 62.7 in men with a prior MI.

After multivariate adjustment, the women-to-men hazard ratio for MI was 0.64 (95% confidence interval, 0.62-0.67) in the non-CHD group and 0.94 (95% CI, 0.92-0.96) in the prior MI group, the authors reported Oct. 5 in the Journal of the American College of Cardiology

Additional results show the multivariate adjusted women-to-men hazard ratios for three other cardiovascular outcomes follow a similar pattern in the non-CHD and prior MI groups:

• CHD events: 0.53 (95% CI, 0.51-0.54) and 0.87 (95% CI, 0.85-0.89).
• Heart failure hospitalization: 0.93 (95% CI, 0.90-0.96) and 1.02 (95% CI, 1.00-1.04).
• All-cause mortality: 0.72 (95% CI, 0.71-0.73) and 0.90 (95% CI, 0.89-0.92).

“By including a control group of individuals without CHD, we demonstrated that the magnitude of the sex difference in cardiac event rates and survival is considerably smaller among those with prior MI than among those without a history of CHD,” Dr. Peters said.

Of note, the sex differences were consistent across age and race/ethnicity groups for all events, except for heart failure hospitalizations, where the adjusted hazard ratio for women vs. men age 80 years or older was 0.95 for those without a history of CHD (95% CI, 0.91-0.98) and 0.99 (95% CI, 0.96-1.02) for participants with a previous MI.

Dr. Peters said it’s not clear why the female advantage is attenuated post-MI but that one explanation is that women are less likely than men to receive guideline-recommended treatments and dosages or to adhere to prescribed therapies after MI hospitalization, which could put them at a higher risk of subsequent events and worse outcomes than men.

“Sex differences in pathophysiology of CHD and its complications may also explain, to some extent, why the rates of recurrent events are considerably more similar between the sexes than incident event rates,” she said. Compared with men, women have a higher incidence of MI with nonobstructive coronary artery disease and of heart failure with preserved ejection fraction, and evidence-based treatment options are more limited for both conditions.

“After people read this, I think the important thing to recognize is we need to push– as much as we can, with what meds we have, and what data we have – secondary prevention in these women,” Laxmi Mehta, MD, director of preventive cardiology and women’s cardiovascular health at Ohio State University, Columbus, said in an interview.

The lack of a female advantage post-MI should also elicit a “really meaningful conversation with our patients on shared decision-making of why they need to be on medications, remembering on our part to prescribe the medications, remembering to prescribe cardiac rehab, and also reminding our community we do need more data and need to investigate this further,” she said.

In an accompanying editorial, Nanette Wenger, MD, of Emory University, Atlanta, also points out that nonobstructive coronary disease is more common in women and, “yet, guideline-based therapies are those validated for obstructive coronary disease in a predominantly male population but, nonetheless, are applied for nonobstructive coronary disease.”

She advocates for aggressive evaluation and treatment for women with chest pain symptoms as well as early identification of women at risk for CHD, specifically those with metabolic syndrome, preeclampsia, hypertensive disorders of pregnancy, chronic inflammatory conditions, and high-risk race/ethnicity.

“Next, when coronary angiography is undertaken, particularly in younger women, an assiduous search for spontaneous coronary artery dissection and its appropriate management, as well as prompt and evidence-based interventions and medical therapies for an acute coronary event [are indicated],” Dr. Wenger wrote. “However, basic to improving outcomes for women is the elucidation of the optimal noninvasive techniques to identify microvascular disease, which could then enable delineation of appropriate preventive and therapeutic approaches.”

Dr. Peters is supported by a U.K. Medical Research Council Skills Development Fellowship. Dr. Mehta and Dr. Wenger disclosed no relevant financial relationships.

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

Women are known to lag 5-10 years behind men in experiencing coronary heart disease (CHD), but new research suggests the gap narrows substantially following a myocardial infarction.

“Women lose a considerable portion, but not all, of their coronary and survival advantage – i.e., the lower event rates – after suffering a MI,” study author Sanne Peters, PhD, George Institute for Global Health, Imperial College London, said in an interview.

Previous studies of sex differences in event rates after a coronary event have produced mixed results and were primarily focused on mortality following MI. Importantly, the studies also lacked a control group without a history of CHD and, thus, were unable to provide a reference point for the disparity in event rates, she explained.

Using the MarketScan and Medicare databases, however, Dr. Peters and colleagues matched 339,890 U.S. adults hospitalized for an MI between January 2015 and December 2016 with 1,359,560 U.S. adults without a history of CHD.

Over a median 1.3 years follow-up, there were 12,518 MIs in the non-CHD group and 27,115 recurrent MIs in the MI group.

The age-standardized rate of MI per 1,000 person-years was 4.0 in women and 6.1 in men without a history of CHD, compared with 57.6 in women and 62.7 in men with a prior MI.

After multivariate adjustment, the women-to-men hazard ratio for MI was 0.64 (95% confidence interval, 0.62-0.67) in the non-CHD group and 0.94 (95% CI, 0.92-0.96) in the prior MI group, the authors reported Oct. 5 in the Journal of the American College of Cardiology

Additional results show the multivariate adjusted women-to-men hazard ratios for three other cardiovascular outcomes follow a similar pattern in the non-CHD and prior MI groups:

• CHD events: 0.53 (95% CI, 0.51-0.54) and 0.87 (95% CI, 0.85-0.89).
• Heart failure hospitalization: 0.93 (95% CI, 0.90-0.96) and 1.02 (95% CI, 1.00-1.04).
• All-cause mortality: 0.72 (95% CI, 0.71-0.73) and 0.90 (95% CI, 0.89-0.92).

“By including a control group of individuals without CHD, we demonstrated that the magnitude of the sex difference in cardiac event rates and survival is considerably smaller among those with prior MI than among those without a history of CHD,” Dr. Peters said.

Of note, the sex differences were consistent across age and race/ethnicity groups for all events, except for heart failure hospitalizations, where the adjusted hazard ratio for women vs. men age 80 years or older was 0.95 for those without a history of CHD (95% CI, 0.91-0.98) and 0.99 (95% CI, 0.96-1.02) for participants with a previous MI.

Dr. Peters said it’s not clear why the female advantage is attenuated post-MI but that one explanation is that women are less likely than men to receive guideline-recommended treatments and dosages or to adhere to prescribed therapies after MI hospitalization, which could put them at a higher risk of subsequent events and worse outcomes than men.

“Sex differences in pathophysiology of CHD and its complications may also explain, to some extent, why the rates of recurrent events are considerably more similar between the sexes than incident event rates,” she said. Compared with men, women have a higher incidence of MI with nonobstructive coronary artery disease and of heart failure with preserved ejection fraction, and evidence-based treatment options are more limited for both conditions.

“After people read this, I think the important thing to recognize is we need to push– as much as we can, with what meds we have, and what data we have – secondary prevention in these women,” Laxmi Mehta, MD, director of preventive cardiology and women’s cardiovascular health at Ohio State University, Columbus, said in an interview.

The lack of a female advantage post-MI should also elicit a “really meaningful conversation with our patients on shared decision-making of why they need to be on medications, remembering on our part to prescribe the medications, remembering to prescribe cardiac rehab, and also reminding our community we do need more data and need to investigate this further,” she said.

In an accompanying editorial, Nanette Wenger, MD, of Emory University, Atlanta, also points out that nonobstructive coronary disease is more common in women and, “yet, guideline-based therapies are those validated for obstructive coronary disease in a predominantly male population but, nonetheless, are applied for nonobstructive coronary disease.”

She advocates for aggressive evaluation and treatment for women with chest pain symptoms as well as early identification of women at risk for CHD, specifically those with metabolic syndrome, preeclampsia, hypertensive disorders of pregnancy, chronic inflammatory conditions, and high-risk race/ethnicity.

“Next, when coronary angiography is undertaken, particularly in younger women, an assiduous search for spontaneous coronary artery dissection and its appropriate management, as well as prompt and evidence-based interventions and medical therapies for an acute coronary event [are indicated],” Dr. Wenger wrote. “However, basic to improving outcomes for women is the elucidation of the optimal noninvasive techniques to identify microvascular disease, which could then enable delineation of appropriate preventive and therapeutic approaches.”

Dr. Peters is supported by a U.K. Medical Research Council Skills Development Fellowship. Dr. Mehta and Dr. Wenger disclosed no relevant financial relationships.

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

Women are known to lag 5-10 years behind men in experiencing coronary heart disease (CHD), but new research suggests the gap narrows substantially following a myocardial infarction.

“Women lose a considerable portion, but not all, of their coronary and survival advantage – i.e., the lower event rates – after suffering a MI,” study author Sanne Peters, PhD, George Institute for Global Health, Imperial College London, said in an interview.

Previous studies of sex differences in event rates after a coronary event have produced mixed results and were primarily focused on mortality following MI. Importantly, the studies also lacked a control group without a history of CHD and, thus, were unable to provide a reference point for the disparity in event rates, she explained.

Using the MarketScan and Medicare databases, however, Dr. Peters and colleagues matched 339,890 U.S. adults hospitalized for an MI between January 2015 and December 2016 with 1,359,560 U.S. adults without a history of CHD.

Over a median 1.3 years follow-up, there were 12,518 MIs in the non-CHD group and 27,115 recurrent MIs in the MI group.

The age-standardized rate of MI per 1,000 person-years was 4.0 in women and 6.1 in men without a history of CHD, compared with 57.6 in women and 62.7 in men with a prior MI.

After multivariate adjustment, the women-to-men hazard ratio for MI was 0.64 (95% confidence interval, 0.62-0.67) in the non-CHD group and 0.94 (95% CI, 0.92-0.96) in the prior MI group, the authors reported Oct. 5 in the Journal of the American College of Cardiology

Additional results show the multivariate adjusted women-to-men hazard ratios for three other cardiovascular outcomes follow a similar pattern in the non-CHD and prior MI groups:

• CHD events: 0.53 (95% CI, 0.51-0.54) and 0.87 (95% CI, 0.85-0.89).
• Heart failure hospitalization: 0.93 (95% CI, 0.90-0.96) and 1.02 (95% CI, 1.00-1.04).
• All-cause mortality: 0.72 (95% CI, 0.71-0.73) and 0.90 (95% CI, 0.89-0.92).

“By including a control group of individuals without CHD, we demonstrated that the magnitude of the sex difference in cardiac event rates and survival is considerably smaller among those with prior MI than among those without a history of CHD,” Dr. Peters said.

Of note, the sex differences were consistent across age and race/ethnicity groups for all events, except for heart failure hospitalizations, where the adjusted hazard ratio for women vs. men age 80 years or older was 0.95 for those without a history of CHD (95% CI, 0.91-0.98) and 0.99 (95% CI, 0.96-1.02) for participants with a previous MI.

Dr. Peters said it’s not clear why the female advantage is attenuated post-MI but that one explanation is that women are less likely than men to receive guideline-recommended treatments and dosages or to adhere to prescribed therapies after MI hospitalization, which could put them at a higher risk of subsequent events and worse outcomes than men.

“Sex differences in pathophysiology of CHD and its complications may also explain, to some extent, why the rates of recurrent events are considerably more similar between the sexes than incident event rates,” she said. Compared with men, women have a higher incidence of MI with nonobstructive coronary artery disease and of heart failure with preserved ejection fraction, and evidence-based treatment options are more limited for both conditions.

“After people read this, I think the important thing to recognize is we need to push– as much as we can, with what meds we have, and what data we have – secondary prevention in these women,” Laxmi Mehta, MD, director of preventive cardiology and women’s cardiovascular health at Ohio State University, Columbus, said in an interview.

The lack of a female advantage post-MI should also elicit a “really meaningful conversation with our patients on shared decision-making of why they need to be on medications, remembering on our part to prescribe the medications, remembering to prescribe cardiac rehab, and also reminding our community we do need more data and need to investigate this further,” she said.

In an accompanying editorial, Nanette Wenger, MD, of Emory University, Atlanta, also points out that nonobstructive coronary disease is more common in women and, “yet, guideline-based therapies are those validated for obstructive coronary disease in a predominantly male population but, nonetheless, are applied for nonobstructive coronary disease.”

She advocates for aggressive evaluation and treatment for women with chest pain symptoms as well as early identification of women at risk for CHD, specifically those with metabolic syndrome, preeclampsia, hypertensive disorders of pregnancy, chronic inflammatory conditions, and high-risk race/ethnicity.

“Next, when coronary angiography is undertaken, particularly in younger women, an assiduous search for spontaneous coronary artery dissection and its appropriate management, as well as prompt and evidence-based interventions and medical therapies for an acute coronary event [are indicated],” Dr. Wenger wrote. “However, basic to improving outcomes for women is the elucidation of the optimal noninvasive techniques to identify microvascular disease, which could then enable delineation of appropriate preventive and therapeutic approaches.”

Dr. Peters is supported by a U.K. Medical Research Council Skills Development Fellowship. Dr. Mehta and Dr. Wenger disclosed no relevant financial relationships.

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

In relapsing-remitting multiple sclerosis (RRMS), MRI has provided a key indication of disease presence and activity. With the availability of serum neurofilament (sNfL) assays, disease activity can be correlated with sNfL levels.

Dr Tobias Derfuss, from University Hospital Basel in Basel, Switzerland, discusses emerging research reported at the ACTRIMS/ECTRIMS 2020 Virtual Meeting, focusing on the use of sNfL as a biomarker for monitoring treatment response and disease activity in RRMS.

Dr Derfuss highlights one study in which longitudinal observations showed that high levels of sNfL at baseline are associated with a high risk for gadolinium-enhancing lesions; the study authors suggest that quarterly monitoring may be adequate for surveillance of subclinical disease.

In another study, higher sNfL levels at baseline were linked to a higher risk for T2 lesions and a more pronounced brain atrophy rate, but disability progression was not correlated to baseline sNfL levels.

Finally, Dr Derfuss reports on a real-world, large cohort study supporting the value of sNfL to capture and predict disability progression independent of relapses.

Tobias J. Derfuss, MD, Professor, Head of Outpatient Clinic, Department of Neurology, University Hospital Board, Basel, Switzerland

Tobias J. Derfuss, MD, has disclosed the following relevant financial relationships:­ Received financial compensation for his activities in advisory boards, steering committees, data safety monitoring boards, and consultation for: Novartis; Merck; Biogen; Celgene; Actelion; Mitsubishi Pharma; MedDay; Roche; Sanofi Genzyme. Received research grant from: Novartis; Biogen; Roche; Swiss National Science Foundation; European Union; Swiss MS Society. Spouse is an employee of and holds stock options in: Novartis

In relapsing-remitting multiple sclerosis (RRMS), MRI has provided a key indication of disease presence and activity. With the availability of serum neurofilament (sNfL) assays, disease activity can be correlated with sNfL levels.

Dr Tobias Derfuss, from University Hospital Basel in Basel, Switzerland, discusses emerging research reported at the ACTRIMS/ECTRIMS 2020 Virtual Meeting, focusing on the use of sNfL as a biomarker for monitoring treatment response and disease activity in RRMS.

Dr Derfuss highlights one study in which longitudinal observations showed that high levels of sNfL at baseline are associated with a high risk for gadolinium-enhancing lesions; the study authors suggest that quarterly monitoring may be adequate for surveillance of subclinical disease.

In another study, higher sNfL levels at baseline were linked to a higher risk for T2 lesions and a more pronounced brain atrophy rate, but disability progression was not correlated to baseline sNfL levels.

Finally, Dr Derfuss reports on a real-world, large cohort study supporting the value of sNfL to capture and predict disability progression independent of relapses.

Tobias J. Derfuss, MD, Professor, Head of Outpatient Clinic, Department of Neurology, University Hospital Board, Basel, Switzerland

Tobias J. Derfuss, MD, has disclosed the following relevant financial relationships:­ Received financial compensation for his activities in advisory boards, steering committees, data safety monitoring boards, and consultation for: Novartis; Merck; Biogen; Celgene; Actelion; Mitsubishi Pharma; MedDay; Roche; Sanofi Genzyme. Received research grant from: Novartis; Biogen; Roche; Swiss National Science Foundation; European Union; Swiss MS Society. Spouse is an employee of and holds stock options in: Novartis

In relapsing-remitting multiple sclerosis (RRMS), MRI has provided a key indication of disease presence and activity. With the availability of serum neurofilament (sNfL) assays, disease activity can be correlated with sNfL levels.

Dr Tobias Derfuss, from University Hospital Basel in Basel, Switzerland, discusses emerging research reported at the ACTRIMS/ECTRIMS 2020 Virtual Meeting, focusing on the use of sNfL as a biomarker for monitoring treatment response and disease activity in RRMS.

Dr Derfuss highlights one study in which longitudinal observations showed that high levels of sNfL at baseline are associated with a high risk for gadolinium-enhancing lesions; the study authors suggest that quarterly monitoring may be adequate for surveillance of subclinical disease.

In another study, higher sNfL levels at baseline were linked to a higher risk for T2 lesions and a more pronounced brain atrophy rate, but disability progression was not correlated to baseline sNfL levels.

Finally, Dr Derfuss reports on a real-world, large cohort study supporting the value of sNfL to capture and predict disability progression independent of relapses.

Tobias J. Derfuss, MD, Professor, Head of Outpatient Clinic, Department of Neurology, University Hospital Board, Basel, Switzerland

Tobias J. Derfuss, MD, has disclosed the following relevant financial relationships:­ Received financial compensation for his activities in advisory boards, steering committees, data safety monitoring boards, and consultation for: Novartis; Merck; Biogen; Celgene; Actelion; Mitsubishi Pharma; MedDay; Roche; Sanofi Genzyme. Received research grant from: Novartis; Biogen; Roche; Swiss National Science Foundation; European Union; Swiss MS Society. Spouse is an employee of and holds stock options in: Novartis

Having been a reader of Pediatric News for years, I want to bring to light access-to-care issues involving COVID-19 medical facility restrictions for pediatric patients and their parents.

On March 27, 2020, I received a phone call from the Department of Human Services pleading with me to take a medically fragile child who was entering the foster care system that day. He had very specific needs, and they had no one available who could medically meet those needs. The week prior was my kids’ scheduled spring break; the week I got the call was the week that I was voluntarily furloughed from my job as a pediatric nurse practitioner so that I could stay home with my kids as their school would not be reopening for the year, and someone had to be with them. I was already home with my 3-year-old and 6-year-old, so why not add another?

Leo (name changed for privacy) came to me with a multitude of diagnoses, to say the least. Not only did he require physical, speech, and occupational therapy twice weekly, but he often had appointments with 10 different specialists at the local children’s hospital. The first few weeks he was in my care, we had almost daily visits to either therapists or specialists. Keeping up with these types of appointments in a normal world is difficult ... I was getting the crash course on how to navigate all of it in the COVID-19 world.

So now, I am the primary caregiver during the day for my two children and our medically fragile foster child who has multiple medical appointments a week. Our local children’s hospital allowed only the caregiver to accompany him to his visits. In theory this sounds great, right? Fewer people in a facility equals less exposure, less risk, and fewer COVID-19 infections.

But what about the negative consequences of these hospital policies? I have two other children I was caring for. I couldn’t take them to their grandparents’ house because people over age 65 years are at risk of having COVID-19 complications. I had been furloughed, so our income was half what it typically was. Regardless, I had to hire a babysitter each time I took our foster child to the hospital for his appointments because they would not allow my children to accompany me.

Now imagine if I were a single mom who had three kids and a lesser paying job. Schools are closed and she’s forced to work from home and homeschool her children. Or worse, she’s been laid off and living on unemployment. Do you think she is going to have the time or finances available to hire a babysitter so that she can take her medically fragile child in for his cardiology follow-up? Because not only does she have to pay the copays and whatever insurance doesn’t cover, but now she has to fork over $50 for child care. If you don’t know the answer already, it’s no, she does not have the time or the finances. So her child misses a cardiology appointment, which means that his meds weren’t increased according to his growth, which means his pulmonary hypertension is not controlled, which worsens his heart failure ... you get my drift.

Fast forward to Sept. 22, 2020. I had a cardiology appointment at our local heart hospital for myself. It’s 2020, people, I’ve been having some palpitations that I needed checked out and was going in to have a heart monitor patch placed. I had my 4-year-old son with me because he is on a hybrid schedule where we homeschool 2 days a week. We entered the building wearing masks, and I was immediately stopped by security and informed that, according to the COVID-19 policy for their hospital, children under 16 are not allowed to enter the building. After some discussion, I was ultimately refused care because my son was with me that day. Refused care because I had a masked 4-year-old with a normal temperature at my side.

These policies are not working. We are in health care. It should not matter what pandemic is on the table, we should not be refusing patients access to care based on who is by their side that day. We knew the risks when we entered our profession, and we know the proper measures to protect ourselves. Our patients also know the risks and can protect themselves accordingly.

So this is my plea to all medical facilities out there: Stop. Stop telling people their loved ones can’t accompany them to appointments. Stop telling caregivers to wait in their cars while their elderly, demented mothers have their annual physicals. Stop telling moms they need to leave their other children at home. This is now a huge access-to-care issue nationwide and it needs to stop. Excess deaths in our nation are soaring, and it’s not just because people don’t want to seek medical attention; it’s because medical facilities are making it almost impossible to seek help for many. People are dying, and it’s not only from COVID-19. This is on us as health care providers, and we need to step up to the plate and do what is right.
 

Ms. Baxendale is a nurse practitioner in Mustang, Okla. Email her at [email protected].

Having been a reader of Pediatric News for years, I want to bring to light access-to-care issues involving COVID-19 medical facility restrictions for pediatric patients and their parents.

On March 27, 2020, I received a phone call from the Department of Human Services pleading with me to take a medically fragile child who was entering the foster care system that day. He had very specific needs, and they had no one available who could medically meet those needs. The week prior was my kids’ scheduled spring break; the week I got the call was the week that I was voluntarily furloughed from my job as a pediatric nurse practitioner so that I could stay home with my kids as their school would not be reopening for the year, and someone had to be with them. I was already home with my 3-year-old and 6-year-old, so why not add another?

Leo (name changed for privacy) came to me with a multitude of diagnoses, to say the least. Not only did he require physical, speech, and occupational therapy twice weekly, but he often had appointments with 10 different specialists at the local children’s hospital. The first few weeks he was in my care, we had almost daily visits to either therapists or specialists. Keeping up with these types of appointments in a normal world is difficult ... I was getting the crash course on how to navigate all of it in the COVID-19 world.

So now, I am the primary caregiver during the day for my two children and our medically fragile foster child who has multiple medical appointments a week. Our local children’s hospital allowed only the caregiver to accompany him to his visits. In theory this sounds great, right? Fewer people in a facility equals less exposure, less risk, and fewer COVID-19 infections.

But what about the negative consequences of these hospital policies? I have two other children I was caring for. I couldn’t take them to their grandparents’ house because people over age 65 years are at risk of having COVID-19 complications. I had been furloughed, so our income was half what it typically was. Regardless, I had to hire a babysitter each time I took our foster child to the hospital for his appointments because they would not allow my children to accompany me.

Now imagine if I were a single mom who had three kids and a lesser paying job. Schools are closed and she’s forced to work from home and homeschool her children. Or worse, she’s been laid off and living on unemployment. Do you think she is going to have the time or finances available to hire a babysitter so that she can take her medically fragile child in for his cardiology follow-up? Because not only does she have to pay the copays and whatever insurance doesn’t cover, but now she has to fork over $50 for child care. If you don’t know the answer already, it’s no, she does not have the time or the finances. So her child misses a cardiology appointment, which means that his meds weren’t increased according to his growth, which means his pulmonary hypertension is not controlled, which worsens his heart failure ... you get my drift.

Fast forward to Sept. 22, 2020. I had a cardiology appointment at our local heart hospital for myself. It’s 2020, people, I’ve been having some palpitations that I needed checked out and was going in to have a heart monitor patch placed. I had my 4-year-old son with me because he is on a hybrid schedule where we homeschool 2 days a week. We entered the building wearing masks, and I was immediately stopped by security and informed that, according to the COVID-19 policy for their hospital, children under 16 are not allowed to enter the building. After some discussion, I was ultimately refused care because my son was with me that day. Refused care because I had a masked 4-year-old with a normal temperature at my side.

These policies are not working. We are in health care. It should not matter what pandemic is on the table, we should not be refusing patients access to care based on who is by their side that day. We knew the risks when we entered our profession, and we know the proper measures to protect ourselves. Our patients also know the risks and can protect themselves accordingly.

So this is my plea to all medical facilities out there: Stop. Stop telling people their loved ones can’t accompany them to appointments. Stop telling caregivers to wait in their cars while their elderly, demented mothers have their annual physicals. Stop telling moms they need to leave their other children at home. This is now a huge access-to-care issue nationwide and it needs to stop. Excess deaths in our nation are soaring, and it’s not just because people don’t want to seek medical attention; it’s because medical facilities are making it almost impossible to seek help for many. People are dying, and it’s not only from COVID-19. This is on us as health care providers, and we need to step up to the plate and do what is right.
 

Ms. Baxendale is a nurse practitioner in Mustang, Okla. Email her at [email protected].

Having been a reader of Pediatric News for years, I want to bring to light access-to-care issues involving COVID-19 medical facility restrictions for pediatric patients and their parents.

On March 27, 2020, I received a phone call from the Department of Human Services pleading with me to take a medically fragile child who was entering the foster care system that day. He had very specific needs, and they had no one available who could medically meet those needs. The week prior was my kids’ scheduled spring break; the week I got the call was the week that I was voluntarily furloughed from my job as a pediatric nurse practitioner so that I could stay home with my kids as their school would not be reopening for the year, and someone had to be with them. I was already home with my 3-year-old and 6-year-old, so why not add another?

Leo (name changed for privacy) came to me with a multitude of diagnoses, to say the least. Not only did he require physical, speech, and occupational therapy twice weekly, but he often had appointments with 10 different specialists at the local children’s hospital. The first few weeks he was in my care, we had almost daily visits to either therapists or specialists. Keeping up with these types of appointments in a normal world is difficult ... I was getting the crash course on how to navigate all of it in the COVID-19 world.

So now, I am the primary caregiver during the day for my two children and our medically fragile foster child who has multiple medical appointments a week. Our local children’s hospital allowed only the caregiver to accompany him to his visits. In theory this sounds great, right? Fewer people in a facility equals less exposure, less risk, and fewer COVID-19 infections.

But what about the negative consequences of these hospital policies? I have two other children I was caring for. I couldn’t take them to their grandparents’ house because people over age 65 years are at risk of having COVID-19 complications. I had been furloughed, so our income was half what it typically was. Regardless, I had to hire a babysitter each time I took our foster child to the hospital for his appointments because they would not allow my children to accompany me.

Now imagine if I were a single mom who had three kids and a lesser paying job. Schools are closed and she’s forced to work from home and homeschool her children. Or worse, she’s been laid off and living on unemployment. Do you think she is going to have the time or finances available to hire a babysitter so that she can take her medically fragile child in for his cardiology follow-up? Because not only does she have to pay the copays and whatever insurance doesn’t cover, but now she has to fork over $50 for child care. If you don’t know the answer already, it’s no, she does not have the time or the finances. So her child misses a cardiology appointment, which means that his meds weren’t increased according to his growth, which means his pulmonary hypertension is not controlled, which worsens his heart failure ... you get my drift.

Fast forward to Sept. 22, 2020. I had a cardiology appointment at our local heart hospital for myself. It’s 2020, people, I’ve been having some palpitations that I needed checked out and was going in to have a heart monitor patch placed. I had my 4-year-old son with me because he is on a hybrid schedule where we homeschool 2 days a week. We entered the building wearing masks, and I was immediately stopped by security and informed that, according to the COVID-19 policy for their hospital, children under 16 are not allowed to enter the building. After some discussion, I was ultimately refused care because my son was with me that day. Refused care because I had a masked 4-year-old with a normal temperature at my side.

These policies are not working. We are in health care. It should not matter what pandemic is on the table, we should not be refusing patients access to care based on who is by their side that day. We knew the risks when we entered our profession, and we know the proper measures to protect ourselves. Our patients also know the risks and can protect themselves accordingly.

So this is my plea to all medical facilities out there: Stop. Stop telling people their loved ones can’t accompany them to appointments. Stop telling caregivers to wait in their cars while their elderly, demented mothers have their annual physicals. Stop telling moms they need to leave their other children at home. This is now a huge access-to-care issue nationwide and it needs to stop. Excess deaths in our nation are soaring, and it’s not just because people don’t want to seek medical attention; it’s because medical facilities are making it almost impossible to seek help for many. People are dying, and it’s not only from COVID-19. This is on us as health care providers, and we need to step up to the plate and do what is right.
 

Ms. Baxendale is a nurse practitioner in Mustang, Okla. Email her at [email protected].

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder that is estimated to occur in 1:2500 births and to have a prevalence of 1:2000 to 1:4000.^1,2 It was first described in 1882 by Friedrich Daniel Von Recklinghausen, who identified patients and their relatives with signs of neuroectodermal abnormalities (café-au-lait macules [CALMs], axillary and inguinal freckling, and neurofibromas).

NF1 may begin insidiously in childhood and evolves as the patient ages. It is associated with intracranial, intraspinal, and intraorbital neoplasms, although other organs and tissues can also be involved.

The family physician might be the first one to recognize the signs of this condition during a well-child exam and is in a unique position to coordinate a multidisciplinary approach to care.

A mutated allele and early manifestations on the skin

NF1 has been attributed to genetic mosaicism and is classified as segmental, generalized, or (less frequently) gonadal. The disorder results from germline mutations in the NF1 tumor-suppressor gene on chromosome 17, known to codify the cytoplasmic protein called neurofibromin.³ The penetrance of NF1 is complete, which means that 100% of patients with the mutated allele will develop the disease.

Patients typically have symptoms by the third decade of life, although many will show signs of the disease in early childhood. CALMs are the earliest expression of NF1. They manifest in the first 2 years of life and are found in almost all affected patients. The lesions are well defined and measure 10 to 40 mm. They are typically light brown, although they may darken with sun exposure.

Histologically, the lesions will show macromelanosomes and high concentrations of melanin but do not represent an increased risk for malignancy.⁴ Not all isolated CALMs are a sign of NF1. While children younger than 29 months with 6 or more CALMs have a high risk for NF1 (80.4%; 95% confidence interval [CI], 74.6% to 86.2%), those who are older than 29 months with at least 1 atypical CALM or fewer than 6 CALMs have just a 0.9% (95% CI, 0% to 2.6%) risk for constitutional NF1.⁵

Freckles are also observed in 90% of patients with NF1; these tend to develop after the third year of life. The breast and trunk are the most commonly affected areas in adults. The pathophysiology is unknown, but this freckling is believed to be related to skin friction, high humidity, and ambient temperature.⁶

Continue to: Neurofibromas are benign...

Some patients show disfiguration when hundreds of neurofibromas are present.

Neurofibromas are benign subcutaneous palpable lesions that grow within peripheral nerve tissue, including spinal, subcutaneous, plexiform, or dermal encapsulated nerves. Originating in Schwann cells, they are composed of fibroblasts, mast cells, macrophages, endothelial cells, and other perineural cells. Some patients show disfiguration when hundreds of these masses are present (FIGURE). These tumors increase in number as the patient ages or during pregnancy, which is thought to be secondary to hormonal changes.⁷ They are sometimes painful and can be pruritic. Their appearance can also cause patient distress.

The diagnosis is a clinical one

Suspicion for NF1 should be high in patients presenting with the dermatologic findings described, although CALMs and freckling are not exclusive to NF1. Diagnostic criteria for NF1, which distinguish it from other conditions, were first outlined in a National Institutes of Health Consensus Development Conference Statement in 1987.⁸ The list of criteria has subsequently been expanded.

While the presence of at least 2 criteria is required for diagnosis,² NF1 should be suspected in individuals who have any of the following findings^8,9:

• the presence of at least 6 CALMs that are > 5 mm in prepubertal children and > 15 mm in adults
• 2 or more neurofibromas of any type, or at least one plexiform neurofibroma
• axillary or groin freckling
• optic pathway glioma
• 2 or more Lisch nodules (iris hamartomas seen on slit-lamp examination)
• bony dysplasia (sphenoid wing dysplasia, bowing of long bone ± pseudarthrosis)
• first-degree relative with NF1.

What you’ll see as the disease progresses

NF1 can affect a variety of systems, and potential complications of the disease are numerous and varied (see TABLE⁹). Here is some of what you may see as the patient’s disease progresses to various organ systems:

Learning disabilities and other cognitive and behavioral problems, such as attention-deficit/hyperactivity disorder, may affect up to 70% of children with NF1. Additionally, children with NF1 have visual/spatial problems, impaired visual motor integration, and language deficits.¹⁰ The etiology of cognitive impairment in NF1 is unknown.¹¹  

Continue to: Hypertension

Hypertension is common and may contribute to premature death in patients with NF1. Up to 27% of patients will have significant cardiovascular anomalies, including pulmonary valve stenosis, hypertrophic cardiomyopathy in patients with complete deletions of the NF1 gene, intracardiac neurofibromas, renal artery stenosis, coarctation of the aorta, and cerebral infarctions.¹² Renal artery stenosis occurs in approximately 2% of the NF1 population, and the diagnosis should be considered in hypertensive children, young adults, pregnant women, older individuals with refractory hypertension, and those with an abdominal bruit.¹³

Psychological issues. The disfigurement caused by neurofibromas and the uncertainty of an unpredictable disease course can cause psychological manifestations for patients with NF1. Anxiety and depression are common. Not surprisingly, patients with more severe disease report more adverse psychological effects.

Orthopedic deformities. Spinal deformities are the most common skeletal manifestation of NF1, with an incidence estimated from 10% to 25% in various studies. Bone mineral density, as measured by age- and gender-adjusted Z-scores, is significantly lower in NF1 patients than in the general population.¹⁴ Children may develop bowing of the long bones, particularly the tibia, and pseudarthrosis, a false joint in a long bone. Children with NF1 need yearly assessment of the spine. Patients with clinical evidence of scoliosis should be referred to Orthopedics for further evaluation.

Eye issues. A majority of adult patients develop neurofibroma-like nodules in the iris known as Lisch nodules. The nodules are not thought to cause any ophthalmologic complications. Patients may also develop palpebral neurofibroma, which may become large and sporadically show malignant transformation. Optic nerve glioma may cause strabismus and proptosis, and a large number of patients will also develop glaucoma and globe enlargement.¹⁵

Gastrointestinal lesions and cancer. Neurofibromas can grow in the stomach, liver, mesentery, retroperitoneum, and bowel. Adenocarcinoma developed in 23% of patients.¹⁶ Gastrointestinal tract bleeding, pseudo-obstruction, and protein-losing enteropathy also may occur.¹⁷

Continue to: Central nervous system manifestations

Central nervous system manifestations. Neurological manifestations have been observed in 55% of patients with NF1.¹⁸ These include headache, hydrocephalus, epilepsy, lacunar stroke, white matter disease, intraspinal neurofibroma, facial palsy, radiculopathy, and polyneuropathy. Tumors include optic pathway tumors, meningioma, and cerebral glioma. Glioma is the predominant tumor type in NF1 and occurs in all parts of the nervous system, with a predilection for the optic pathways, brainstem, and cerebellum.¹⁸

Malignant peripheral nerve sheath tumors. There is an 8% to 13% lifetime risk for malignant peripheral nerve sheath tumors (MPNST), predominantly in individuals between the ages of 20 and 35.^19,20 Any change in neurofibroma from soft to hard, or a rapid increase in the size, is suspicious for MPNST. Other symptoms include persistent pain lasting for longer than a month, pain that disturbs sleep, and new neurological deficits. These cancers can be hard to detect, leading to poor prognosis secondary to metastasis.^19,20 The greatest risk factors for MPNST are pain associated with a mass and the presence of cutaneous and subcutaneous neurofibromas.²¹

Treatment is symptom based, but there is a new option

Treatment is individualized to the patient’s symptoms. Neurofibromas that are disfiguring, disruptive, or malignant may be surgically removed.

In April 2020, the US Food and Drug Administration (FDA) approved selumetinib (Koselugo) for the treatment of pediatric patients (ages ≥ 2 years) with NF1 who have symptomatic, inoperable plexiform neurofibromas (PNs).²² In a clinical trial, patients received selumetinib 25 mg/m² orally twice a day until they demonstrated disease progression or experienced “unacceptable” adverse events.^22,23 The overall response rate was 66%, defined as “the percentage of patients with a complete response and those who experienced more than a 20% reduction in PN volume on MRI that was confirmed on a subsequent MRI within 3 to 6 months.”²²

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms.

Of note, all patients had a partial, not complete, response. Common adverse effects included vomiting, rash, abdominal pain, diarrhea, and nausea.²³ Selumetinib may also cause more serious adverse effects, including cardiomyopathy and ocular toxicity. Prior to treatment initiation and at regular intervals during treatment, patients should undergo cardiac and ophthalmic evaluation.^22,23 Selumetinib was granted priority review and orphan drug status by the FDA.²²

Continue to: You play a key role in ongoing monitoring

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms; optimization of quality of life; and identification and treatment of comorbidities. Family physicians are well positioned to monitor patients with NF1 for age-specific disease manifestations and potential complications.⁹ All patients require:

• an annual physical examination by a physician who is familiar with the individual and with the disease
• annual ophthalmologic examination in early childhood; less frequent examination in older children and adults
• regular blood pressure monitoring
• other studies (eg, MRI) only as indicated on the basis of clinically apparent signs or symptoms
• monitoring by an appropriate specialist if there are abnormalities of the central nervous, skeletal, or cardiovascular systems
• referral to a neurologist for any unexplained neurological signs and symptoms. Referral should be urgent if there are acute symptoms of progressive sensory disturbance, motor deficit and incoordination, or sphincter disturbances since these might indicate an intracranial lesion or spinal cord compression. Headaches on waking, morning vomiting, and altered consciousness are suggestive of raised intracranial pressure.

Children with NF1 benefit from coordinated care between the FP and a pediatrician or other specialist familiar with the disease. In addition to providing usual well care, perform regular assessment of development and school performance. Pay careful attention to the cardiovascular system (particularly blood pressure) and evaluate for scoliosis.

Young adults should be continually monitored for all complications, especially hypertension. This population requires continued education about NF1 and its possible complications and may benefit from counseling about disease inheritance. Screen for anxiety and depression; offer psychological support.

Provide adult patients with education about complications, especially malignant peripheral nerve sheath tumors and spinal cord compression.

Adults require monitoring based on patient preference and disease severity. For this population, blood pressure should be measured annually, or more frequently if the patient’s values indicate borderline hypertension. Provide education about complications, especially MPNSTs and spinal cord compression. Patients who have abnormalities of the central nervous, skeletal, or cardiovascular systems should be monitored by an appropriate specialist. If desired, the patient may be referred to a geneticist, especially if he or she expresses concern about inheritance. Cutaneous neurofibromas can be removed if they cause discomfort, although removal occasionally results in neurological deficit.

CORRESPONDENCE
T. Grant Phillips, MD, Associate Director, UPMC Altoona Family Physicians Residency, 501 Howard Avenue, Altoona, PA 16601-4899; [email protected]

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder that is estimated to occur in 1:2500 births and to have a prevalence of 1:2000 to 1:4000.^1,2 It was first described in 1882 by Friedrich Daniel Von Recklinghausen, who identified patients and their relatives with signs of neuroectodermal abnormalities (café-au-lait macules [CALMs], axillary and inguinal freckling, and neurofibromas).

NF1 may begin insidiously in childhood and evolves as the patient ages. It is associated with intracranial, intraspinal, and intraorbital neoplasms, although other organs and tissues can also be involved.

The family physician might be the first one to recognize the signs of this condition during a well-child exam and is in a unique position to coordinate a multidisciplinary approach to care.

A mutated allele and early manifestations on the skin

NF1 has been attributed to genetic mosaicism and is classified as segmental, generalized, or (less frequently) gonadal. The disorder results from germline mutations in the NF1 tumor-suppressor gene on chromosome 17, known to codify the cytoplasmic protein called neurofibromin.³ The penetrance of NF1 is complete, which means that 100% of patients with the mutated allele will develop the disease.

Patients typically have symptoms by the third decade of life, although many will show signs of the disease in early childhood. CALMs are the earliest expression of NF1. They manifest in the first 2 years of life and are found in almost all affected patients. The lesions are well defined and measure 10 to 40 mm. They are typically light brown, although they may darken with sun exposure.

Histologically, the lesions will show macromelanosomes and high concentrations of melanin but do not represent an increased risk for malignancy.⁴ Not all isolated CALMs are a sign of NF1. While children younger than 29 months with 6 or more CALMs have a high risk for NF1 (80.4%; 95% confidence interval [CI], 74.6% to 86.2%), those who are older than 29 months with at least 1 atypical CALM or fewer than 6 CALMs have just a 0.9% (95% CI, 0% to 2.6%) risk for constitutional NF1.⁵

Freckles are also observed in 90% of patients with NF1; these tend to develop after the third year of life. The breast and trunk are the most commonly affected areas in adults. The pathophysiology is unknown, but this freckling is believed to be related to skin friction, high humidity, and ambient temperature.⁶

Continue to: Neurofibromas are benign...

Some patients show disfiguration when hundreds of neurofibromas are present.

Neurofibromas are benign subcutaneous palpable lesions that grow within peripheral nerve tissue, including spinal, subcutaneous, plexiform, or dermal encapsulated nerves. Originating in Schwann cells, they are composed of fibroblasts, mast cells, macrophages, endothelial cells, and other perineural cells. Some patients show disfiguration when hundreds of these masses are present (FIGURE). These tumors increase in number as the patient ages or during pregnancy, which is thought to be secondary to hormonal changes.⁷ They are sometimes painful and can be pruritic. Their appearance can also cause patient distress.

The diagnosis is a clinical one

Suspicion for NF1 should be high in patients presenting with the dermatologic findings described, although CALMs and freckling are not exclusive to NF1. Diagnostic criteria for NF1, which distinguish it from other conditions, were first outlined in a National Institutes of Health Consensus Development Conference Statement in 1987.⁸ The list of criteria has subsequently been expanded.

While the presence of at least 2 criteria is required for diagnosis,² NF1 should be suspected in individuals who have any of the following findings^8,9:

• the presence of at least 6 CALMs that are > 5 mm in prepubertal children and > 15 mm in adults
• 2 or more neurofibromas of any type, or at least one plexiform neurofibroma
• axillary or groin freckling
• optic pathway glioma
• 2 or more Lisch nodules (iris hamartomas seen on slit-lamp examination)
• bony dysplasia (sphenoid wing dysplasia, bowing of long bone ± pseudarthrosis)
• first-degree relative with NF1.

What you’ll see as the disease progresses

NF1 can affect a variety of systems, and potential complications of the disease are numerous and varied (see TABLE⁹). Here is some of what you may see as the patient’s disease progresses to various organ systems:

Learning disabilities and other cognitive and behavioral problems, such as attention-deficit/hyperactivity disorder, may affect up to 70% of children with NF1. Additionally, children with NF1 have visual/spatial problems, impaired visual motor integration, and language deficits.¹⁰ The etiology of cognitive impairment in NF1 is unknown.¹¹  

Continue to: Hypertension

Hypertension is common and may contribute to premature death in patients with NF1. Up to 27% of patients will have significant cardiovascular anomalies, including pulmonary valve stenosis, hypertrophic cardiomyopathy in patients with complete deletions of the NF1 gene, intracardiac neurofibromas, renal artery stenosis, coarctation of the aorta, and cerebral infarctions.¹² Renal artery stenosis occurs in approximately 2% of the NF1 population, and the diagnosis should be considered in hypertensive children, young adults, pregnant women, older individuals with refractory hypertension, and those with an abdominal bruit.¹³

Psychological issues. The disfigurement caused by neurofibromas and the uncertainty of an unpredictable disease course can cause psychological manifestations for patients with NF1. Anxiety and depression are common. Not surprisingly, patients with more severe disease report more adverse psychological effects.

Orthopedic deformities. Spinal deformities are the most common skeletal manifestation of NF1, with an incidence estimated from 10% to 25% in various studies. Bone mineral density, as measured by age- and gender-adjusted Z-scores, is significantly lower in NF1 patients than in the general population.¹⁴ Children may develop bowing of the long bones, particularly the tibia, and pseudarthrosis, a false joint in a long bone. Children with NF1 need yearly assessment of the spine. Patients with clinical evidence of scoliosis should be referred to Orthopedics for further evaluation.

Eye issues. A majority of adult patients develop neurofibroma-like nodules in the iris known as Lisch nodules. The nodules are not thought to cause any ophthalmologic complications. Patients may also develop palpebral neurofibroma, which may become large and sporadically show malignant transformation. Optic nerve glioma may cause strabismus and proptosis, and a large number of patients will also develop glaucoma and globe enlargement.¹⁵

Gastrointestinal lesions and cancer. Neurofibromas can grow in the stomach, liver, mesentery, retroperitoneum, and bowel. Adenocarcinoma developed in 23% of patients.¹⁶ Gastrointestinal tract bleeding, pseudo-obstruction, and protein-losing enteropathy also may occur.¹⁷

Continue to: Central nervous system manifestations

Central nervous system manifestations. Neurological manifestations have been observed in 55% of patients with NF1.¹⁸ These include headache, hydrocephalus, epilepsy, lacunar stroke, white matter disease, intraspinal neurofibroma, facial palsy, radiculopathy, and polyneuropathy. Tumors include optic pathway tumors, meningioma, and cerebral glioma. Glioma is the predominant tumor type in NF1 and occurs in all parts of the nervous system, with a predilection for the optic pathways, brainstem, and cerebellum.¹⁸

Malignant peripheral nerve sheath tumors. There is an 8% to 13% lifetime risk for malignant peripheral nerve sheath tumors (MPNST), predominantly in individuals between the ages of 20 and 35.^19,20 Any change in neurofibroma from soft to hard, or a rapid increase in the size, is suspicious for MPNST. Other symptoms include persistent pain lasting for longer than a month, pain that disturbs sleep, and new neurological deficits. These cancers can be hard to detect, leading to poor prognosis secondary to metastasis.^19,20 The greatest risk factors for MPNST are pain associated with a mass and the presence of cutaneous and subcutaneous neurofibromas.²¹

Treatment is symptom based, but there is a new option

Treatment is individualized to the patient’s symptoms. Neurofibromas that are disfiguring, disruptive, or malignant may be surgically removed.

In April 2020, the US Food and Drug Administration (FDA) approved selumetinib (Koselugo) for the treatment of pediatric patients (ages ≥ 2 years) with NF1 who have symptomatic, inoperable plexiform neurofibromas (PNs).²² In a clinical trial, patients received selumetinib 25 mg/m² orally twice a day until they demonstrated disease progression or experienced “unacceptable” adverse events.^22,23 The overall response rate was 66%, defined as “the percentage of patients with a complete response and those who experienced more than a 20% reduction in PN volume on MRI that was confirmed on a subsequent MRI within 3 to 6 months.”²²

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms.

Of note, all patients had a partial, not complete, response. Common adverse effects included vomiting, rash, abdominal pain, diarrhea, and nausea.²³ Selumetinib may also cause more serious adverse effects, including cardiomyopathy and ocular toxicity. Prior to treatment initiation and at regular intervals during treatment, patients should undergo cardiac and ophthalmic evaluation.^22,23 Selumetinib was granted priority review and orphan drug status by the FDA.²²

Continue to: You play a key role in ongoing monitoring

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms; optimization of quality of life; and identification and treatment of comorbidities. Family physicians are well positioned to monitor patients with NF1 for age-specific disease manifestations and potential complications.⁹ All patients require:

• an annual physical examination by a physician who is familiar with the individual and with the disease
• annual ophthalmologic examination in early childhood; less frequent examination in older children and adults
• regular blood pressure monitoring
• other studies (eg, MRI) only as indicated on the basis of clinically apparent signs or symptoms
• monitoring by an appropriate specialist if there are abnormalities of the central nervous, skeletal, or cardiovascular systems
• referral to a neurologist for any unexplained neurological signs and symptoms. Referral should be urgent if there are acute symptoms of progressive sensory disturbance, motor deficit and incoordination, or sphincter disturbances since these might indicate an intracranial lesion or spinal cord compression. Headaches on waking, morning vomiting, and altered consciousness are suggestive of raised intracranial pressure.

Children with NF1 benefit from coordinated care between the FP and a pediatrician or other specialist familiar with the disease. In addition to providing usual well care, perform regular assessment of development and school performance. Pay careful attention to the cardiovascular system (particularly blood pressure) and evaluate for scoliosis.

Young adults should be continually monitored for all complications, especially hypertension. This population requires continued education about NF1 and its possible complications and may benefit from counseling about disease inheritance. Screen for anxiety and depression; offer psychological support.

Provide adult patients with education about complications, especially malignant peripheral nerve sheath tumors and spinal cord compression.

Adults require monitoring based on patient preference and disease severity. For this population, blood pressure should be measured annually, or more frequently if the patient’s values indicate borderline hypertension. Provide education about complications, especially MPNSTs and spinal cord compression. Patients who have abnormalities of the central nervous, skeletal, or cardiovascular systems should be monitored by an appropriate specialist. If desired, the patient may be referred to a geneticist, especially if he or she expresses concern about inheritance. Cutaneous neurofibromas can be removed if they cause discomfort, although removal occasionally results in neurological deficit.

CORRESPONDENCE
T. Grant Phillips, MD, Associate Director, UPMC Altoona Family Physicians Residency, 501 Howard Avenue, Altoona, PA 16601-4899; [email protected]

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder that is estimated to occur in 1:2500 births and to have a prevalence of 1:2000 to 1:4000.^1,2 It was first described in 1882 by Friedrich Daniel Von Recklinghausen, who identified patients and their relatives with signs of neuroectodermal abnormalities (café-au-lait macules [CALMs], axillary and inguinal freckling, and neurofibromas).

NF1 may begin insidiously in childhood and evolves as the patient ages. It is associated with intracranial, intraspinal, and intraorbital neoplasms, although other organs and tissues can also be involved.

The family physician might be the first one to recognize the signs of this condition during a well-child exam and is in a unique position to coordinate a multidisciplinary approach to care.

A mutated allele and early manifestations on the skin

NF1 has been attributed to genetic mosaicism and is classified as segmental, generalized, or (less frequently) gonadal. The disorder results from germline mutations in the NF1 tumor-suppressor gene on chromosome 17, known to codify the cytoplasmic protein called neurofibromin.³ The penetrance of NF1 is complete, which means that 100% of patients with the mutated allele will develop the disease.

Patients typically have symptoms by the third decade of life, although many will show signs of the disease in early childhood. CALMs are the earliest expression of NF1. They manifest in the first 2 years of life and are found in almost all affected patients. The lesions are well defined and measure 10 to 40 mm. They are typically light brown, although they may darken with sun exposure.

Histologically, the lesions will show macromelanosomes and high concentrations of melanin but do not represent an increased risk for malignancy.⁴ Not all isolated CALMs are a sign of NF1. While children younger than 29 months with 6 or more CALMs have a high risk for NF1 (80.4%; 95% confidence interval [CI], 74.6% to 86.2%), those who are older than 29 months with at least 1 atypical CALM or fewer than 6 CALMs have just a 0.9% (95% CI, 0% to 2.6%) risk for constitutional NF1.⁵

Freckles are also observed in 90% of patients with NF1; these tend to develop after the third year of life. The breast and trunk are the most commonly affected areas in adults. The pathophysiology is unknown, but this freckling is believed to be related to skin friction, high humidity, and ambient temperature.⁶

Continue to: Neurofibromas are benign...

Some patients show disfiguration when hundreds of neurofibromas are present.

Neurofibromas are benign subcutaneous palpable lesions that grow within peripheral nerve tissue, including spinal, subcutaneous, plexiform, or dermal encapsulated nerves. Originating in Schwann cells, they are composed of fibroblasts, mast cells, macrophages, endothelial cells, and other perineural cells. Some patients show disfiguration when hundreds of these masses are present (FIGURE). These tumors increase in number as the patient ages or during pregnancy, which is thought to be secondary to hormonal changes.⁷ They are sometimes painful and can be pruritic. Their appearance can also cause patient distress.

The diagnosis is a clinical one

Suspicion for NF1 should be high in patients presenting with the dermatologic findings described, although CALMs and freckling are not exclusive to NF1. Diagnostic criteria for NF1, which distinguish it from other conditions, were first outlined in a National Institutes of Health Consensus Development Conference Statement in 1987.⁸ The list of criteria has subsequently been expanded.

While the presence of at least 2 criteria is required for diagnosis,² NF1 should be suspected in individuals who have any of the following findings^8,9:

• the presence of at least 6 CALMs that are > 5 mm in prepubertal children and > 15 mm in adults
• 2 or more neurofibromas of any type, or at least one plexiform neurofibroma
• axillary or groin freckling
• optic pathway glioma
• 2 or more Lisch nodules (iris hamartomas seen on slit-lamp examination)
• bony dysplasia (sphenoid wing dysplasia, bowing of long bone ± pseudarthrosis)
• first-degree relative with NF1.

What you’ll see as the disease progresses

NF1 can affect a variety of systems, and potential complications of the disease are numerous and varied (see TABLE⁹). Here is some of what you may see as the patient’s disease progresses to various organ systems:

Learning disabilities and other cognitive and behavioral problems, such as attention-deficit/hyperactivity disorder, may affect up to 70% of children with NF1. Additionally, children with NF1 have visual/spatial problems, impaired visual motor integration, and language deficits.¹⁰ The etiology of cognitive impairment in NF1 is unknown.¹¹  

Continue to: Hypertension

Hypertension is common and may contribute to premature death in patients with NF1. Up to 27% of patients will have significant cardiovascular anomalies, including pulmonary valve stenosis, hypertrophic cardiomyopathy in patients with complete deletions of the NF1 gene, intracardiac neurofibromas, renal artery stenosis, coarctation of the aorta, and cerebral infarctions.¹² Renal artery stenosis occurs in approximately 2% of the NF1 population, and the diagnosis should be considered in hypertensive children, young adults, pregnant women, older individuals with refractory hypertension, and those with an abdominal bruit.¹³

Psychological issues. The disfigurement caused by neurofibromas and the uncertainty of an unpredictable disease course can cause psychological manifestations for patients with NF1. Anxiety and depression are common. Not surprisingly, patients with more severe disease report more adverse psychological effects.

Orthopedic deformities. Spinal deformities are the most common skeletal manifestation of NF1, with an incidence estimated from 10% to 25% in various studies. Bone mineral density, as measured by age- and gender-adjusted Z-scores, is significantly lower in NF1 patients than in the general population.¹⁴ Children may develop bowing of the long bones, particularly the tibia, and pseudarthrosis, a false joint in a long bone. Children with NF1 need yearly assessment of the spine. Patients with clinical evidence of scoliosis should be referred to Orthopedics for further evaluation.

Eye issues. A majority of adult patients develop neurofibroma-like nodules in the iris known as Lisch nodules. The nodules are not thought to cause any ophthalmologic complications. Patients may also develop palpebral neurofibroma, which may become large and sporadically show malignant transformation. Optic nerve glioma may cause strabismus and proptosis, and a large number of patients will also develop glaucoma and globe enlargement.¹⁵

Gastrointestinal lesions and cancer. Neurofibromas can grow in the stomach, liver, mesentery, retroperitoneum, and bowel. Adenocarcinoma developed in 23% of patients.¹⁶ Gastrointestinal tract bleeding, pseudo-obstruction, and protein-losing enteropathy also may occur.¹⁷

Continue to: Central nervous system manifestations

Central nervous system manifestations. Neurological manifestations have been observed in 55% of patients with NF1.¹⁸ These include headache, hydrocephalus, epilepsy, lacunar stroke, white matter disease, intraspinal neurofibroma, facial palsy, radiculopathy, and polyneuropathy. Tumors include optic pathway tumors, meningioma, and cerebral glioma. Glioma is the predominant tumor type in NF1 and occurs in all parts of the nervous system, with a predilection for the optic pathways, brainstem, and cerebellum.¹⁸

Malignant peripheral nerve sheath tumors. There is an 8% to 13% lifetime risk for malignant peripheral nerve sheath tumors (MPNST), predominantly in individuals between the ages of 20 and 35.^19,20 Any change in neurofibroma from soft to hard, or a rapid increase in the size, is suspicious for MPNST. Other symptoms include persistent pain lasting for longer than a month, pain that disturbs sleep, and new neurological deficits. These cancers can be hard to detect, leading to poor prognosis secondary to metastasis.^19,20 The greatest risk factors for MPNST are pain associated with a mass and the presence of cutaneous and subcutaneous neurofibromas.²¹

Treatment is symptom based, but there is a new option

Treatment is individualized to the patient’s symptoms. Neurofibromas that are disfiguring, disruptive, or malignant may be surgically removed.

In April 2020, the US Food and Drug Administration (FDA) approved selumetinib (Koselugo) for the treatment of pediatric patients (ages ≥ 2 years) with NF1 who have symptomatic, inoperable plexiform neurofibromas (PNs).²² In a clinical trial, patients received selumetinib 25 mg/m² orally twice a day until they demonstrated disease progression or experienced “unacceptable” adverse events.^22,23 The overall response rate was 66%, defined as “the percentage of patients with a complete response and those who experienced more than a 20% reduction in PN volume on MRI that was confirmed on a subsequent MRI within 3 to 6 months.”²²

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms.

Of note, all patients had a partial, not complete, response. Common adverse effects included vomiting, rash, abdominal pain, diarrhea, and nausea.²³ Selumetinib may also cause more serious adverse effects, including cardiomyopathy and ocular toxicity. Prior to treatment initiation and at regular intervals during treatment, patients should undergo cardiac and ophthalmic evaluation.^22,23 Selumetinib was granted priority review and orphan drug status by the FDA.²²

Continue to: You play a key role in ongoing monitoring

In light of the condition’s heterogeneity, the goals of care include early recognition and treatment of complications, especially neoplasms; optimization of quality of life; and identification and treatment of comorbidities. Family physicians are well positioned to monitor patients with NF1 for age-specific disease manifestations and potential complications.⁹ All patients require:

• an annual physical examination by a physician who is familiar with the individual and with the disease
• annual ophthalmologic examination in early childhood; less frequent examination in older children and adults
• regular blood pressure monitoring
• other studies (eg, MRI) only as indicated on the basis of clinically apparent signs or symptoms
• monitoring by an appropriate specialist if there are abnormalities of the central nervous, skeletal, or cardiovascular systems
• referral to a neurologist for any unexplained neurological signs and symptoms. Referral should be urgent if there are acute symptoms of progressive sensory disturbance, motor deficit and incoordination, or sphincter disturbances since these might indicate an intracranial lesion or spinal cord compression. Headaches on waking, morning vomiting, and altered consciousness are suggestive of raised intracranial pressure.

Children with NF1 benefit from coordinated care between the FP and a pediatrician or other specialist familiar with the disease. In addition to providing usual well care, perform regular assessment of development and school performance. Pay careful attention to the cardiovascular system (particularly blood pressure) and evaluate for scoliosis.

Young adults should be continually monitored for all complications, especially hypertension. This population requires continued education about NF1 and its possible complications and may benefit from counseling about disease inheritance. Screen for anxiety and depression; offer psychological support.

Provide adult patients with education about complications, especially malignant peripheral nerve sheath tumors and spinal cord compression.

Adults require monitoring based on patient preference and disease severity. For this population, blood pressure should be measured annually, or more frequently if the patient’s values indicate borderline hypertension. Provide education about complications, especially MPNSTs and spinal cord compression. Patients who have abnormalities of the central nervous, skeletal, or cardiovascular systems should be monitored by an appropriate specialist. If desired, the patient may be referred to a geneticist, especially if he or she expresses concern about inheritance. Cutaneous neurofibromas can be removed if they cause discomfort, although removal occasionally results in neurological deficit.

CORRESPONDENCE
T. Grant Phillips, MD, Associate Director, UPMC Altoona Family Physicians Residency, 501 Howard Avenue, Altoona, PA 16601-4899; [email protected]