Hospital Consult

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects approximately 0.1% of the US population.^1,2 Severe disease or HS flares can lead patients to seek care through the emergency department (ED), with some requiring inpatient admission. ³ Inpatient hospitalization of patients with HS has increased over the last 2 decades, and patients with HS utilize emergency and inpatient care more frequently than those with other dermatologic conditions.^4,5 Minority patients and those of lower socioeconomic status are more likely to present to the ED for HS management due to limited access to care and other existing comorbid conditions. ⁴ In a 2022 study of the Nationwide Readmissions Database, the authors looked at hospital readmission rates of patients with HS compared with those with heart failure—both patient populations with chronic debilitating conditions. Results indicated that the hospital readmission rates for patients with HS surpassed those of patients with heart failure for that year, highlighting the need for improved inpatient management of HS.⁶

Patients with HS present to the ED with severe pain, fever, wound care, or the need for surgical intervention. The ED and inpatient hospital setting are locations in which physicians may not be as familiar with the diagnosis or treatment of HS, specifically flares or severe disease. ⁷ The inpatient care setting provides access to certain resources that can be challenging to obtain in the outpatient clinical setting, such as social workers and pain specialists, but also can prove challenging in obtaining other resources for HS management, such as advanced medical therapies. Given the increase in hospital- based care for HS and lack of widespread inpatient access to dermatology and HS experts, consensus recommendations for management of HS in the acute hospital setting would be beneficial. In our study, we sought to generate a collection of expert consensus statements providers can refer to when managing patients with HS in the inpatient setting.

Methods

The study team at the Wake Forest University School of Medicine (Winston-Salem, North Carolina)(M.N., R.P., L.C.S.) developed an initial set of consensus statements based on current published HS treatment guidelines,^8,9 publications on management of inpatient HS,³ published supportive care guidelines for Stevens-Johnson syndrome, 10 and personal clinical experience in managing inpatient HS, which resulted in 50 statements organized into the following categories: overall care, wound care, genital care, pain management, infection control, medical management, surgical management, nutrition, and transitional care guidelines. This study was approved by the Wake Forest University institutional review board (IRB00084257).

Participant Recruitment—Dermatologists were identified for participation in the study based on membership in the Society of Dermatology Hospitalists and the Hidradenitis Suppurativa Foundation or authorship of publications relevant to HS or inpatient dermatology. Dermatologists from larger academic institutions with HS specialty clinics and inpatient dermatology services also were identified. Participants were invited via email and could suggest other experts for inclusion. A total of 31 dermatologists were invited to participate in the study, with 26 agreeing to participate. All participating dermatologists were practicing in the United States.

Delphi Study—In the first round of the Delphi study, the participants were sent an online survey via REDCap in which they were asked to rank the appropriateness of each of the proposed 50 guideline statements on a scale of 1 (very inappropriate) to 9 (very appropriate). Participants also were able to provide commentary and feedback on each of the statements. Survey results were analyzed using the RAND/ UCLA Appropriateness Method.¹¹ For each statement, the median rating for appropriateness, interpercentile range (IPR), IPR adjusted for symmetry, and disagreement index (DI) were calculated (DI=IPR/IPR adjusted for symmetry). The 30th and 70th percentiles were used in the DI calculation as the upper and lower limits, respectively. A median rating for appropriateness of 1.0 to 3.9 was considered “inappropriate,” 4.0 to 6.9 was considered “uncertain appropriateness,” and 7.0 to 9.0 was “appropriate.” A DI value greater than or equal to 1 indicated a lack of consensus regarding the appropriateness of the statement. Following each round, participants received a copy of their responses along with the group median rank of each statement. Statements that did not reach consensus in the first Delphi round were revised based on feedback received by the participants, and a second survey with 14 statements was sent via REDCap 2 weeks later. The RAND/UCLA Appropriateness Method also was applied to this second Delphi round. After the second survey, participants received a copy of anonymized comments regarding the consensus statements and were allowed to provide additional final commentary to be included in the discussion of these recommendations.

Results

Twenty-six dermatologists completed the first-round survey, and 24 participants completed the second-round survey. All participants self-identified as having expertise in either HS (n=22 [85%]) or inpatient dermatology (n=17 [65%]), and 13 (50%) participants self-identified as experts in both HS and inpatient dermatology. All participants, except 1, were affiliated with an academic health system with inpatient dermatology services. The average length of time in practice as a dermatologist was 10 years (median, 9 years [range, 3–27 years]).

Of the 50 initial proposed consensus statements, 26 (52%) achieved consensus after the first round; 21 statements revealed DI calculations that did not achieve consensus. Two statements achieved consensus but received median ratings for appropriateness, indicating uncertain appropriateness; because of this, 1 statement was removed and 1 was revised based on participant feedback, resulting in 13 revised statements (eTable 1). Controversial topics in the consensus process included obtaining wound cultures and meaningful culture data interpretation, use of specific biologic medications in the inpatient setting, and use of intravenous ertapenem. Participant responses to these topics are discussed in detail below. Of these secondround statements, all achieved consensus. The final set of consensus statements can be found in eTable 2.

Comment

Our Delphi consensus study combined the expertise of both dermatologists who care for patients with HS and those with inpatient dermatology experience to produce a set of recommendations for the management of HS in the hospital care setting. A strength of this study is inclusion of many national leaders in both HS and inpatient dermatology, with some participants having developed the previously published HS treatment guidelines and others having participated in inpatient dermatology Delphi studies.8-10 The expertise is further strengthened by the geographically diverse institutional representation within the United States.

The final consensus recommendations included 40 statements covering a range of patient care issues, including use of appropriate inpatient subspecialists (care team), supportive care measures (wound care, pain control, genital care), disease-oriented treatment (medical management, surgical management), inpatient complications (infection control, nutrition), and successful transition back to outpatient management (transitional care). These recommendations are meant to serve as a resource for providers to consider when taking care of inpatient HS flares, recognizing that the complexity and individual circumstances of each patient are unique.

Delphi Consensus Recommendations Compared to Prior Guidelines—Several recommendations in the current study align with the previously published North American clinical management guidelines for HS.^8,9 Our recommendations agree with prior guidelines on the importance of disease staging and pain assessment using validated assessment tools as well as screening for HS comorbidities. There also is agreement in the potential benefit of involving pain specialists in the development of a comprehensive pain management plan. The inpatient care setting provides a unique opportunity to engage multiple specialists and collaborate on patient care in a timely manner. Our recommendations regarding surgical care also align with established guidelines in recommending incision and drainage as an acute bedside procedure best utilized for symptom relief in inflamed abscesses and relegating most other surgical management to the outpatient setting. Wound care recommendations also are similar, with our expert participants agreeing on individualizing dressing choices based on wound characteristics. A benefit of inpatient wound care is access to skilled nursing for dressing changes and potentially improved access to more sophisticated dressing materials. Our recommendations differ from the prior guidelines in our focus on severe HS, HS flares, and HS complications, which constitute the majority of inpatient disease management. We provide additional guidance on management of secondary infections, perianal fistulous disease, and importantly transitional care to optimize discharge planning.

Differing Opinions in Our Analysis—Despite the success of our Delphi consensus process, there were some differing opinions regarding certain aspects of inpatient HS management, which is to be expected given the lack of strong evidence-based research to support some of the recommended practices. There were differing opinions on the utility of wound culture data, with some participants feeling culture data could help with antibiotic susceptibility and resistance patterns, while others felt wound cultures represent bacterial colonization or biofilm formation.

Initial consensus statements in the first Delphi round were created for individual biologic medications but did not achieve consensus, and feedback on the use of biologics in the inpatient environment was mixed, largely due to logistic and insurance issues. Many participants felt biologic medication cost, difficulty obtaining inpatient reimbursement, health care resource utilization, and availability of biologics in different hospital systems prevented recommending the use of specific biologics during hospitalization. The one exception was in the case of a hospitalized patient who was already receiving infliximab for HS: there was consensus on ensuring the patient dosing was maximized, if appropriate, to 10 mg/kg.12 Ertapenem use also was controversial, with some participants using it as a bridge therapy to either outpatient biologic use or surgery, while others felt it was onerous and difficult to establish reliable access to secure intravenous administration and regular dosing once the patient left the inpatient setting.¹³ Others said they have experienced objections from infectious disease colleagues on the use of intravenous antibiotics, citing antibiotic stewardship concerns.

Patient Care in the Inpatient Setting—Prior literature suggests patients admitted as inpatients for HS tend to be of lower socioeconomic status and are admitted to larger urban teaching hospitals.^14,15 Patients with lower socioeconomic status have increased difficulty accessing health care resources; therefore, inpatient admission serves as an opportunity to provide a holistic HS assessment and coordinate resources for chronic outpatient management.

Study Limitations—This Delphi consensus study has some limitations. The existing literature on inpatient management of HS is limited, challenging our ability to assess the extent to which these published recommendations are already being implemented. Additionally, the study included HS and inpatient dermatology experts from the United States, which means the recommendations may not be generalizable to other countries. Most participants practiced dermatology at large tertiary care academic medical centers, which may limit the ability to implement recommendations in all US inpatient care settings such as small community-based hospitals; however, many of the supportive care guidelines such as pain control, wound care, nutritional support, and social work should be achievable in most inpatient care settings.

Conclusion

Given the increase in inpatient and ED health care utilization for HS, there is an urgent need for expert consensus recommendations on inpatient management of this unique patient population, which requires complex multidisciplinary care. Our recommendations are a resource for providers to utilize and potentially improve the standard of care we provide these patients.

Acknowledgment—We thank the Wake Forest University Clinical and Translational Science Institute (Winston- Salem, North Carolina) for providing statistical help.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects approximately 0.1% of the US population.^1,2 Severe disease or HS flares can lead patients to seek care through the emergency department (ED), with some requiring inpatient admission. ³ Inpatient hospitalization of patients with HS has increased over the last 2 decades, and patients with HS utilize emergency and inpatient care more frequently than those with other dermatologic conditions.^4,5 Minority patients and those of lower socioeconomic status are more likely to present to the ED for HS management due to limited access to care and other existing comorbid conditions. ⁴ In a 2022 study of the Nationwide Readmissions Database, the authors looked at hospital readmission rates of patients with HS compared with those with heart failure—both patient populations with chronic debilitating conditions. Results indicated that the hospital readmission rates for patients with HS surpassed those of patients with heart failure for that year, highlighting the need for improved inpatient management of HS.⁶

Patients with HS present to the ED with severe pain, fever, wound care, or the need for surgical intervention. The ED and inpatient hospital setting are locations in which physicians may not be as familiar with the diagnosis or treatment of HS, specifically flares or severe disease. ⁷ The inpatient care setting provides access to certain resources that can be challenging to obtain in the outpatient clinical setting, such as social workers and pain specialists, but also can prove challenging in obtaining other resources for HS management, such as advanced medical therapies. Given the increase in hospital- based care for HS and lack of widespread inpatient access to dermatology and HS experts, consensus recommendations for management of HS in the acute hospital setting would be beneficial. In our study, we sought to generate a collection of expert consensus statements providers can refer to when managing patients with HS in the inpatient setting.

Methods

The study team at the Wake Forest University School of Medicine (Winston-Salem, North Carolina)(M.N., R.P., L.C.S.) developed an initial set of consensus statements based on current published HS treatment guidelines,^8,9 publications on management of inpatient HS,³ published supportive care guidelines for Stevens-Johnson syndrome, 10 and personal clinical experience in managing inpatient HS, which resulted in 50 statements organized into the following categories: overall care, wound care, genital care, pain management, infection control, medical management, surgical management, nutrition, and transitional care guidelines. This study was approved by the Wake Forest University institutional review board (IRB00084257).

Participant Recruitment—Dermatologists were identified for participation in the study based on membership in the Society of Dermatology Hospitalists and the Hidradenitis Suppurativa Foundation or authorship of publications relevant to HS or inpatient dermatology. Dermatologists from larger academic institutions with HS specialty clinics and inpatient dermatology services also were identified. Participants were invited via email and could suggest other experts for inclusion. A total of 31 dermatologists were invited to participate in the study, with 26 agreeing to participate. All participating dermatologists were practicing in the United States.

Delphi Study—In the first round of the Delphi study, the participants were sent an online survey via REDCap in which they were asked to rank the appropriateness of each of the proposed 50 guideline statements on a scale of 1 (very inappropriate) to 9 (very appropriate). Participants also were able to provide commentary and feedback on each of the statements. Survey results were analyzed using the RAND/ UCLA Appropriateness Method.¹¹ For each statement, the median rating for appropriateness, interpercentile range (IPR), IPR adjusted for symmetry, and disagreement index (DI) were calculated (DI=IPR/IPR adjusted for symmetry). The 30th and 70th percentiles were used in the DI calculation as the upper and lower limits, respectively. A median rating for appropriateness of 1.0 to 3.9 was considered “inappropriate,” 4.0 to 6.9 was considered “uncertain appropriateness,” and 7.0 to 9.0 was “appropriate.” A DI value greater than or equal to 1 indicated a lack of consensus regarding the appropriateness of the statement. Following each round, participants received a copy of their responses along with the group median rank of each statement. Statements that did not reach consensus in the first Delphi round were revised based on feedback received by the participants, and a second survey with 14 statements was sent via REDCap 2 weeks later. The RAND/UCLA Appropriateness Method also was applied to this second Delphi round. After the second survey, participants received a copy of anonymized comments regarding the consensus statements and were allowed to provide additional final commentary to be included in the discussion of these recommendations.

Results

Twenty-six dermatologists completed the first-round survey, and 24 participants completed the second-round survey. All participants self-identified as having expertise in either HS (n=22 [85%]) or inpatient dermatology (n=17 [65%]), and 13 (50%) participants self-identified as experts in both HS and inpatient dermatology. All participants, except 1, were affiliated with an academic health system with inpatient dermatology services. The average length of time in practice as a dermatologist was 10 years (median, 9 years [range, 3–27 years]).

Of the 50 initial proposed consensus statements, 26 (52%) achieved consensus after the first round; 21 statements revealed DI calculations that did not achieve consensus. Two statements achieved consensus but received median ratings for appropriateness, indicating uncertain appropriateness; because of this, 1 statement was removed and 1 was revised based on participant feedback, resulting in 13 revised statements (eTable 1). Controversial topics in the consensus process included obtaining wound cultures and meaningful culture data interpretation, use of specific biologic medications in the inpatient setting, and use of intravenous ertapenem. Participant responses to these topics are discussed in detail below. Of these secondround statements, all achieved consensus. The final set of consensus statements can be found in eTable 2.

Comment

Our Delphi consensus study combined the expertise of both dermatologists who care for patients with HS and those with inpatient dermatology experience to produce a set of recommendations for the management of HS in the hospital care setting. A strength of this study is inclusion of many national leaders in both HS and inpatient dermatology, with some participants having developed the previously published HS treatment guidelines and others having participated in inpatient dermatology Delphi studies.8-10 The expertise is further strengthened by the geographically diverse institutional representation within the United States.

The final consensus recommendations included 40 statements covering a range of patient care issues, including use of appropriate inpatient subspecialists (care team), supportive care measures (wound care, pain control, genital care), disease-oriented treatment (medical management, surgical management), inpatient complications (infection control, nutrition), and successful transition back to outpatient management (transitional care). These recommendations are meant to serve as a resource for providers to consider when taking care of inpatient HS flares, recognizing that the complexity and individual circumstances of each patient are unique.

Delphi Consensus Recommendations Compared to Prior Guidelines—Several recommendations in the current study align with the previously published North American clinical management guidelines for HS.^8,9 Our recommendations agree with prior guidelines on the importance of disease staging and pain assessment using validated assessment tools as well as screening for HS comorbidities. There also is agreement in the potential benefit of involving pain specialists in the development of a comprehensive pain management plan. The inpatient care setting provides a unique opportunity to engage multiple specialists and collaborate on patient care in a timely manner. Our recommendations regarding surgical care also align with established guidelines in recommending incision and drainage as an acute bedside procedure best utilized for symptom relief in inflamed abscesses and relegating most other surgical management to the outpatient setting. Wound care recommendations also are similar, with our expert participants agreeing on individualizing dressing choices based on wound characteristics. A benefit of inpatient wound care is access to skilled nursing for dressing changes and potentially improved access to more sophisticated dressing materials. Our recommendations differ from the prior guidelines in our focus on severe HS, HS flares, and HS complications, which constitute the majority of inpatient disease management. We provide additional guidance on management of secondary infections, perianal fistulous disease, and importantly transitional care to optimize discharge planning.

Differing Opinions in Our Analysis—Despite the success of our Delphi consensus process, there were some differing opinions regarding certain aspects of inpatient HS management, which is to be expected given the lack of strong evidence-based research to support some of the recommended practices. There were differing opinions on the utility of wound culture data, with some participants feeling culture data could help with antibiotic susceptibility and resistance patterns, while others felt wound cultures represent bacterial colonization or biofilm formation.

Initial consensus statements in the first Delphi round were created for individual biologic medications but did not achieve consensus, and feedback on the use of biologics in the inpatient environment was mixed, largely due to logistic and insurance issues. Many participants felt biologic medication cost, difficulty obtaining inpatient reimbursement, health care resource utilization, and availability of biologics in different hospital systems prevented recommending the use of specific biologics during hospitalization. The one exception was in the case of a hospitalized patient who was already receiving infliximab for HS: there was consensus on ensuring the patient dosing was maximized, if appropriate, to 10 mg/kg.12 Ertapenem use also was controversial, with some participants using it as a bridge therapy to either outpatient biologic use or surgery, while others felt it was onerous and difficult to establish reliable access to secure intravenous administration and regular dosing once the patient left the inpatient setting.¹³ Others said they have experienced objections from infectious disease colleagues on the use of intravenous antibiotics, citing antibiotic stewardship concerns.

Patient Care in the Inpatient Setting—Prior literature suggests patients admitted as inpatients for HS tend to be of lower socioeconomic status and are admitted to larger urban teaching hospitals.^14,15 Patients with lower socioeconomic status have increased difficulty accessing health care resources; therefore, inpatient admission serves as an opportunity to provide a holistic HS assessment and coordinate resources for chronic outpatient management.

Study Limitations—This Delphi consensus study has some limitations. The existing literature on inpatient management of HS is limited, challenging our ability to assess the extent to which these published recommendations are already being implemented. Additionally, the study included HS and inpatient dermatology experts from the United States, which means the recommendations may not be generalizable to other countries. Most participants practiced dermatology at large tertiary care academic medical centers, which may limit the ability to implement recommendations in all US inpatient care settings such as small community-based hospitals; however, many of the supportive care guidelines such as pain control, wound care, nutritional support, and social work should be achievable in most inpatient care settings.

Conclusion

Given the increase in inpatient and ED health care utilization for HS, there is an urgent need for expert consensus recommendations on inpatient management of this unique patient population, which requires complex multidisciplinary care. Our recommendations are a resource for providers to utilize and potentially improve the standard of care we provide these patients.

Acknowledgment—We thank the Wake Forest University Clinical and Translational Science Institute (Winston- Salem, North Carolina) for providing statistical help.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects approximately 0.1% of the US population.^1,2 Severe disease or HS flares can lead patients to seek care through the emergency department (ED), with some requiring inpatient admission. ³ Inpatient hospitalization of patients with HS has increased over the last 2 decades, and patients with HS utilize emergency and inpatient care more frequently than those with other dermatologic conditions.^4,5 Minority patients and those of lower socioeconomic status are more likely to present to the ED for HS management due to limited access to care and other existing comorbid conditions. ⁴ In a 2022 study of the Nationwide Readmissions Database, the authors looked at hospital readmission rates of patients with HS compared with those with heart failure—both patient populations with chronic debilitating conditions. Results indicated that the hospital readmission rates for patients with HS surpassed those of patients with heart failure for that year, highlighting the need for improved inpatient management of HS.⁶

Patients with HS present to the ED with severe pain, fever, wound care, or the need for surgical intervention. The ED and inpatient hospital setting are locations in which physicians may not be as familiar with the diagnosis or treatment of HS, specifically flares or severe disease. ⁷ The inpatient care setting provides access to certain resources that can be challenging to obtain in the outpatient clinical setting, such as social workers and pain specialists, but also can prove challenging in obtaining other resources for HS management, such as advanced medical therapies. Given the increase in hospital- based care for HS and lack of widespread inpatient access to dermatology and HS experts, consensus recommendations for management of HS in the acute hospital setting would be beneficial. In our study, we sought to generate a collection of expert consensus statements providers can refer to when managing patients with HS in the inpatient setting.

Methods

The study team at the Wake Forest University School of Medicine (Winston-Salem, North Carolina)(M.N., R.P., L.C.S.) developed an initial set of consensus statements based on current published HS treatment guidelines,^8,9 publications on management of inpatient HS,³ published supportive care guidelines for Stevens-Johnson syndrome, 10 and personal clinical experience in managing inpatient HS, which resulted in 50 statements organized into the following categories: overall care, wound care, genital care, pain management, infection control, medical management, surgical management, nutrition, and transitional care guidelines. This study was approved by the Wake Forest University institutional review board (IRB00084257).

Participant Recruitment—Dermatologists were identified for participation in the study based on membership in the Society of Dermatology Hospitalists and the Hidradenitis Suppurativa Foundation or authorship of publications relevant to HS or inpatient dermatology. Dermatologists from larger academic institutions with HS specialty clinics and inpatient dermatology services also were identified. Participants were invited via email and could suggest other experts for inclusion. A total of 31 dermatologists were invited to participate in the study, with 26 agreeing to participate. All participating dermatologists were practicing in the United States.

Delphi Study—In the first round of the Delphi study, the participants were sent an online survey via REDCap in which they were asked to rank the appropriateness of each of the proposed 50 guideline statements on a scale of 1 (very inappropriate) to 9 (very appropriate). Participants also were able to provide commentary and feedback on each of the statements. Survey results were analyzed using the RAND/ UCLA Appropriateness Method.¹¹ For each statement, the median rating for appropriateness, interpercentile range (IPR), IPR adjusted for symmetry, and disagreement index (DI) were calculated (DI=IPR/IPR adjusted for symmetry). The 30th and 70th percentiles were used in the DI calculation as the upper and lower limits, respectively. A median rating for appropriateness of 1.0 to 3.9 was considered “inappropriate,” 4.0 to 6.9 was considered “uncertain appropriateness,” and 7.0 to 9.0 was “appropriate.” A DI value greater than or equal to 1 indicated a lack of consensus regarding the appropriateness of the statement. Following each round, participants received a copy of their responses along with the group median rank of each statement. Statements that did not reach consensus in the first Delphi round were revised based on feedback received by the participants, and a second survey with 14 statements was sent via REDCap 2 weeks later. The RAND/UCLA Appropriateness Method also was applied to this second Delphi round. After the second survey, participants received a copy of anonymized comments regarding the consensus statements and were allowed to provide additional final commentary to be included in the discussion of these recommendations.

Results

Twenty-six dermatologists completed the first-round survey, and 24 participants completed the second-round survey. All participants self-identified as having expertise in either HS (n=22 [85%]) or inpatient dermatology (n=17 [65%]), and 13 (50%) participants self-identified as experts in both HS and inpatient dermatology. All participants, except 1, were affiliated with an academic health system with inpatient dermatology services. The average length of time in practice as a dermatologist was 10 years (median, 9 years [range, 3–27 years]).

Of the 50 initial proposed consensus statements, 26 (52%) achieved consensus after the first round; 21 statements revealed DI calculations that did not achieve consensus. Two statements achieved consensus but received median ratings for appropriateness, indicating uncertain appropriateness; because of this, 1 statement was removed and 1 was revised based on participant feedback, resulting in 13 revised statements (eTable 1). Controversial topics in the consensus process included obtaining wound cultures and meaningful culture data interpretation, use of specific biologic medications in the inpatient setting, and use of intravenous ertapenem. Participant responses to these topics are discussed in detail below. Of these secondround statements, all achieved consensus. The final set of consensus statements can be found in eTable 2.

Comment

Our Delphi consensus study combined the expertise of both dermatologists who care for patients with HS and those with inpatient dermatology experience to produce a set of recommendations for the management of HS in the hospital care setting. A strength of this study is inclusion of many national leaders in both HS and inpatient dermatology, with some participants having developed the previously published HS treatment guidelines and others having participated in inpatient dermatology Delphi studies.8-10 The expertise is further strengthened by the geographically diverse institutional representation within the United States.

The final consensus recommendations included 40 statements covering a range of patient care issues, including use of appropriate inpatient subspecialists (care team), supportive care measures (wound care, pain control, genital care), disease-oriented treatment (medical management, surgical management), inpatient complications (infection control, nutrition), and successful transition back to outpatient management (transitional care). These recommendations are meant to serve as a resource for providers to consider when taking care of inpatient HS flares, recognizing that the complexity and individual circumstances of each patient are unique.

Delphi Consensus Recommendations Compared to Prior Guidelines—Several recommendations in the current study align with the previously published North American clinical management guidelines for HS.^8,9 Our recommendations agree with prior guidelines on the importance of disease staging and pain assessment using validated assessment tools as well as screening for HS comorbidities. There also is agreement in the potential benefit of involving pain specialists in the development of a comprehensive pain management plan. The inpatient care setting provides a unique opportunity to engage multiple specialists and collaborate on patient care in a timely manner. Our recommendations regarding surgical care also align with established guidelines in recommending incision and drainage as an acute bedside procedure best utilized for symptom relief in inflamed abscesses and relegating most other surgical management to the outpatient setting. Wound care recommendations also are similar, with our expert participants agreeing on individualizing dressing choices based on wound characteristics. A benefit of inpatient wound care is access to skilled nursing for dressing changes and potentially improved access to more sophisticated dressing materials. Our recommendations differ from the prior guidelines in our focus on severe HS, HS flares, and HS complications, which constitute the majority of inpatient disease management. We provide additional guidance on management of secondary infections, perianal fistulous disease, and importantly transitional care to optimize discharge planning.

Differing Opinions in Our Analysis—Despite the success of our Delphi consensus process, there were some differing opinions regarding certain aspects of inpatient HS management, which is to be expected given the lack of strong evidence-based research to support some of the recommended practices. There were differing opinions on the utility of wound culture data, with some participants feeling culture data could help with antibiotic susceptibility and resistance patterns, while others felt wound cultures represent bacterial colonization or biofilm formation.

Initial consensus statements in the first Delphi round were created for individual biologic medications but did not achieve consensus, and feedback on the use of biologics in the inpatient environment was mixed, largely due to logistic and insurance issues. Many participants felt biologic medication cost, difficulty obtaining inpatient reimbursement, health care resource utilization, and availability of biologics in different hospital systems prevented recommending the use of specific biologics during hospitalization. The one exception was in the case of a hospitalized patient who was already receiving infliximab for HS: there was consensus on ensuring the patient dosing was maximized, if appropriate, to 10 mg/kg.12 Ertapenem use also was controversial, with some participants using it as a bridge therapy to either outpatient biologic use or surgery, while others felt it was onerous and difficult to establish reliable access to secure intravenous administration and regular dosing once the patient left the inpatient setting.¹³ Others said they have experienced objections from infectious disease colleagues on the use of intravenous antibiotics, citing antibiotic stewardship concerns.

Patient Care in the Inpatient Setting—Prior literature suggests patients admitted as inpatients for HS tend to be of lower socioeconomic status and are admitted to larger urban teaching hospitals.^14,15 Patients with lower socioeconomic status have increased difficulty accessing health care resources; therefore, inpatient admission serves as an opportunity to provide a holistic HS assessment and coordinate resources for chronic outpatient management.

Study Limitations—This Delphi consensus study has some limitations. The existing literature on inpatient management of HS is limited, challenging our ability to assess the extent to which these published recommendations are already being implemented. Additionally, the study included HS and inpatient dermatology experts from the United States, which means the recommendations may not be generalizable to other countries. Most participants practiced dermatology at large tertiary care academic medical centers, which may limit the ability to implement recommendations in all US inpatient care settings such as small community-based hospitals; however, many of the supportive care guidelines such as pain control, wound care, nutritional support, and social work should be achievable in most inpatient care settings.

Conclusion

Given the increase in inpatient and ED health care utilization for HS, there is an urgent need for expert consensus recommendations on inpatient management of this unique patient population, which requires complex multidisciplinary care. Our recommendations are a resource for providers to utilize and potentially improve the standard of care we provide these patients.

Acknowledgment—We thank the Wake Forest University Clinical and Translational Science Institute (Winston- Salem, North Carolina) for providing statistical help.

Dermatologic conditions affect approximately one-third of individuals in the United States.^1,2 Nearly 1 in 4 physician office visits in the United States are for skin conditions, and less than one-third of these visits are with dermatologists. Although many of these patients may prefer to see a dermatologist for their concerns, they may not be able to access specialist care.³ The limited supply and urban-focused distribution of dermatologists along with reduced acceptance of state-funded insurance plans and long appointment wait times all pose considerable challenges to individuals seeking dermatologic care.² Electronic consultations (e-consults) have emerged as a promising solution to overcoming these barriers while providing high-quality dermatologic care to a large diverse patient population.^2,4 Although e-consults can be of service to all dermatology patients, this modality may be especially beneficial to underserved populations, such as the uninsured and Medicaid patients—groups that historically have experienced limited access to dermatology care due to the low reimbursement rates and high administrative burdens accompanying care delivery.⁴ This limited access leads to inequity in care, as timely access to dermatology is associated with improved diagnostic accuracy and disease outcomes.³ E-consult implementation can facilitate timely access for these underserved populations and bypass additional barriers to care such as lack of transportation or time off work. Prior e-consult studies have demonstrated relatively high numbers of Medicaid patients utilizing e-consult services.^3,5

Although in-person visits remain the gold standard for diagnosis and treatment of dermatologic conditions, e-consults placed by primary care providers (PCPs) can improve access and help triage patients who require in-person dermatology visits.⁶ In this study, we conducted a retrospective chart review to characterize the e-consults requested of the dermatology department at a large tertiary care medical center in Winston-Salem, North Carolina.

Methods

The electronic health record (EHR) of Atrium Health Wake Forest Baptist (Winston-Salem, North Carolina) was screened for eligible patients from January 1, 2020, to May 31, 2021. Patients—both adult (aged ≥18 years) and pediatric (aged <18 years)—were included if they underwent a dermatology e-consult within this time frame. Provider notes in the medical records were reviewed to determine the nature of the lesion, how long the dermatologist took to complete the e-consult, whether an in-person appointment was recommended, and whether the patient was seen by dermatology within 90 days of the e-consult. Institutional review board approval was obtained.

For each e-consult, the PCP obtained clinical photographs of the lesion in question either through the EHR mobile application or by having patients upload their own photographs directly to their medical records. The referring PCP then completed a brief template regarding the patient’s clinical question and medical history and then sent the completed information to the consulting dermatologist’s EHR inbox. From there, the dermatologist could view the clinical question, documented photographs, and patient medical record to create a brief consult note with recommendations. The note was then sent back via EHR to the PCP to follow up with the patient. Patients were not charged for the e-consult.

CT113003107_eTable.jpg

Results

Two hundred fifty-four dermatology e-consults were requested by providers at the study center (eTable), which included 252 unique patients (2 patients had 2 separate e-consults regarding different clinical questions). The median time for completion of the e-consult—from submission of the PCP’s e-consult request to dermatologist completion—was 0.37 days. Fifty-six patients (22.0%) were recommended for an in-person appointment (Figure), 33 (58.9%) of whom ultimately scheduled the in-person appointment, and the median length of time between the completion of the e-consult and the in-person appointment was 16.5 days. The remaining 198 patients (78.0%) were not triaged to receive an in-person appointment following the e-consult,but 2 patients (8.7%) were ultimately seen in-person anyway via other referral pathways, with a median length of 33 days between e-consult completion and the in-person appointment. One hundred seventy-six patients (69.8%) avoided an in-person dermatology visit, although 38 (21.6%) of those patients were fewer than 90 days out from their e-consults at the time of data collection. The 254 e-consults included patients from 50 different zip codes, 49 (98.0%) of which were in North Carolina.

Salisbury_Figure.jpg

Comment

An e-consult is an asynchronous telehealth modality through which PCPs can request specialty evaluation to provide diagnostic and therapeutic guidance, facilitate PCP-specialist coordination of care, and increase access to specialty care with reduced wait times.^7,8 Increased care access is especially important, as specialty referral can decrease overall health care expenditure; however, the demand for specialists often exceeds the availability.⁸ Our e-consult program drastically reduced the time from patients’ initial presentation at their PCP’s office to dermatologist recommendations for treatment or need for in-person dermatology follow-up.

In our analysis, patients were of different racial, ethnic, and socioeconomic backgrounds and lived across a variety of zip codes, predominantly in central and western North Carolina. Almost three-quarters of the patients resided in zip codes where the average income was less than the North Carolina median household income ($66,196).⁹ Additionally, 82 patients (32.3%) were uninsured or on Medicaid (eTable). These economically disadvantaged patient populations historically have had limited access to dermatologic care.⁴ One study showed that privately insured individuals were accepted as new patients by dermatologists 91% of the time compared to a 29.8% acceptance rate for publicly insured individuals.¹⁰ Uninsured and Medicaid patients also have to wait 34% longer for an appointment compared to individuals with Medicare or private insurance.² Considering these patients may already be at an economic disadvantage when it comes to seeing and paying for dermatologic services, e-consults may reduce patient travel and appointment expenses while increasing access to specialty care. Based on a 2020 study, each e-consult generates an estimated savings of $80 out-of-pocket per patient per avoided in-person visit.¹¹

In our study, the most common condition for an e-consult in both adult and pediatric patients was rash, which is consistent with prior e-consult studies.^5,11 We found that most e-consult patients were not recommended for an in-person dermatology visit, and for those who were recommended to have an in-person visit, the wait time was reduced (Figure). These results corroborate that e-consults may be used as an important triage tool for determining whether a specialist appointment is indicated as well as a public health tool, as timely evaluation is associated with better dermatologic health care outcomes.³ However, the number of patients who did not present for an in-person appointment in our study may be overestimated, as 38 patients’ (21.6%) e-consults were conducted fewer than 90 days before our data collection. Although none of these patients had been seen in person, it is possible they requested an in-person visit after their medical records were reviewed for this study. Additionally, it is possible patients sought care from outside providers not documented in the EHR.

With regard to the payment model for the e-consult program, Atrium Health Wake Forest Baptist initially piloted the e-consult system through a partnership with the American Academy of Medical Colleges’ Project CORE: Coordinating Optimal Referral Experiences (https://www.aamc.org/what-we-do/mission-areas/health-care/project-core). Grant funding through Project CORE allowed both the referring PCP and the specialist completing the e-consult to each receive approximately 0.5 relative value units in payment for each consult completed. Based on early adoption successes, the institution has created additional internal funding to support the continued expansion of the e-consult system and is incentivized to continue funding, as proper utilization of e-consults improves patient access to timely specialist care, avoids no-shows or last-minute cancellations for specialist appointments, and decreases back-door access to specialist care through the emergency department and urgent care facilities.⁵ Although 0.5 relative value units is not equivalent compensation to an in-person office visit, our study showed that e-consults can be completed much more quickly and efficiently and do not utilize nursing staff or other office resources.

Conclusion

E-consults are an effective telehealth modality that can increase patients’ access to dermatologic specialty care. Patients who typically are underrepresented in dermatology practices especially may benefit from increased accessibility, and all patients requiring in-person visits may benefit from reduced appointment wait times. The savings generated by in-person appointment avoidance reduce overall health care expenditure as well as the burden of individual expenses. The short turnaround time for e-consults also allows PCPs to better manage dermatologic issues in a timely manner. Integrating and expanding e-consult programs into everyday practice would extend specialty care to broader populations and help reduce barriers to access to dermatologic care.

Acknowledgments—The authors thank the Wake Forest University School of Medicine Department of Medical Education and Department of Dermatology (Winston-Salem, North Carolina) for their contributions to this research study as well as the Wake Forest Clinical and Translational Science Institute (Winston-Salem, North Carolina) for their help extracting EHR data.

Dermatologic conditions affect approximately one-third of individuals in the United States.^1,2 Nearly 1 in 4 physician office visits in the United States are for skin conditions, and less than one-third of these visits are with dermatologists. Although many of these patients may prefer to see a dermatologist for their concerns, they may not be able to access specialist care.³ The limited supply and urban-focused distribution of dermatologists along with reduced acceptance of state-funded insurance plans and long appointment wait times all pose considerable challenges to individuals seeking dermatologic care.² Electronic consultations (e-consults) have emerged as a promising solution to overcoming these barriers while providing high-quality dermatologic care to a large diverse patient population.^2,4 Although e-consults can be of service to all dermatology patients, this modality may be especially beneficial to underserved populations, such as the uninsured and Medicaid patients—groups that historically have experienced limited access to dermatology care due to the low reimbursement rates and high administrative burdens accompanying care delivery.⁴ This limited access leads to inequity in care, as timely access to dermatology is associated with improved diagnostic accuracy and disease outcomes.³ E-consult implementation can facilitate timely access for these underserved populations and bypass additional barriers to care such as lack of transportation or time off work. Prior e-consult studies have demonstrated relatively high numbers of Medicaid patients utilizing e-consult services.^3,5

Although in-person visits remain the gold standard for diagnosis and treatment of dermatologic conditions, e-consults placed by primary care providers (PCPs) can improve access and help triage patients who require in-person dermatology visits.⁶ In this study, we conducted a retrospective chart review to characterize the e-consults requested of the dermatology department at a large tertiary care medical center in Winston-Salem, North Carolina.

Methods

The electronic health record (EHR) of Atrium Health Wake Forest Baptist (Winston-Salem, North Carolina) was screened for eligible patients from January 1, 2020, to May 31, 2021. Patients—both adult (aged ≥18 years) and pediatric (aged <18 years)—were included if they underwent a dermatology e-consult within this time frame. Provider notes in the medical records were reviewed to determine the nature of the lesion, how long the dermatologist took to complete the e-consult, whether an in-person appointment was recommended, and whether the patient was seen by dermatology within 90 days of the e-consult. Institutional review board approval was obtained.

For each e-consult, the PCP obtained clinical photographs of the lesion in question either through the EHR mobile application or by having patients upload their own photographs directly to their medical records. The referring PCP then completed a brief template regarding the patient’s clinical question and medical history and then sent the completed information to the consulting dermatologist’s EHR inbox. From there, the dermatologist could view the clinical question, documented photographs, and patient medical record to create a brief consult note with recommendations. The note was then sent back via EHR to the PCP to follow up with the patient. Patients were not charged for the e-consult.

CT113003107_eTable.jpg

Results

Two hundred fifty-four dermatology e-consults were requested by providers at the study center (eTable), which included 252 unique patients (2 patients had 2 separate e-consults regarding different clinical questions). The median time for completion of the e-consult—from submission of the PCP’s e-consult request to dermatologist completion—was 0.37 days. Fifty-six patients (22.0%) were recommended for an in-person appointment (Figure), 33 (58.9%) of whom ultimately scheduled the in-person appointment, and the median length of time between the completion of the e-consult and the in-person appointment was 16.5 days. The remaining 198 patients (78.0%) were not triaged to receive an in-person appointment following the e-consult,but 2 patients (8.7%) were ultimately seen in-person anyway via other referral pathways, with a median length of 33 days between e-consult completion and the in-person appointment. One hundred seventy-six patients (69.8%) avoided an in-person dermatology visit, although 38 (21.6%) of those patients were fewer than 90 days out from their e-consults at the time of data collection. The 254 e-consults included patients from 50 different zip codes, 49 (98.0%) of which were in North Carolina.

Salisbury_Figure.jpg

Comment

An e-consult is an asynchronous telehealth modality through which PCPs can request specialty evaluation to provide diagnostic and therapeutic guidance, facilitate PCP-specialist coordination of care, and increase access to specialty care with reduced wait times.^7,8 Increased care access is especially important, as specialty referral can decrease overall health care expenditure; however, the demand for specialists often exceeds the availability.⁸ Our e-consult program drastically reduced the time from patients’ initial presentation at their PCP’s office to dermatologist recommendations for treatment or need for in-person dermatology follow-up.

In our analysis, patients were of different racial, ethnic, and socioeconomic backgrounds and lived across a variety of zip codes, predominantly in central and western North Carolina. Almost three-quarters of the patients resided in zip codes where the average income was less than the North Carolina median household income ($66,196).⁹ Additionally, 82 patients (32.3%) were uninsured or on Medicaid (eTable). These economically disadvantaged patient populations historically have had limited access to dermatologic care.⁴ One study showed that privately insured individuals were accepted as new patients by dermatologists 91% of the time compared to a 29.8% acceptance rate for publicly insured individuals.¹⁰ Uninsured and Medicaid patients also have to wait 34% longer for an appointment compared to individuals with Medicare or private insurance.² Considering these patients may already be at an economic disadvantage when it comes to seeing and paying for dermatologic services, e-consults may reduce patient travel and appointment expenses while increasing access to specialty care. Based on a 2020 study, each e-consult generates an estimated savings of $80 out-of-pocket per patient per avoided in-person visit.¹¹

In our study, the most common condition for an e-consult in both adult and pediatric patients was rash, which is consistent with prior e-consult studies.^5,11 We found that most e-consult patients were not recommended for an in-person dermatology visit, and for those who were recommended to have an in-person visit, the wait time was reduced (Figure). These results corroborate that e-consults may be used as an important triage tool for determining whether a specialist appointment is indicated as well as a public health tool, as timely evaluation is associated with better dermatologic health care outcomes.³ However, the number of patients who did not present for an in-person appointment in our study may be overestimated, as 38 patients’ (21.6%) e-consults were conducted fewer than 90 days before our data collection. Although none of these patients had been seen in person, it is possible they requested an in-person visit after their medical records were reviewed for this study. Additionally, it is possible patients sought care from outside providers not documented in the EHR.

With regard to the payment model for the e-consult program, Atrium Health Wake Forest Baptist initially piloted the e-consult system through a partnership with the American Academy of Medical Colleges’ Project CORE: Coordinating Optimal Referral Experiences (https://www.aamc.org/what-we-do/mission-areas/health-care/project-core). Grant funding through Project CORE allowed both the referring PCP and the specialist completing the e-consult to each receive approximately 0.5 relative value units in payment for each consult completed. Based on early adoption successes, the institution has created additional internal funding to support the continued expansion of the e-consult system and is incentivized to continue funding, as proper utilization of e-consults improves patient access to timely specialist care, avoids no-shows or last-minute cancellations for specialist appointments, and decreases back-door access to specialist care through the emergency department and urgent care facilities.⁵ Although 0.5 relative value units is not equivalent compensation to an in-person office visit, our study showed that e-consults can be completed much more quickly and efficiently and do not utilize nursing staff or other office resources.

Conclusion

E-consults are an effective telehealth modality that can increase patients’ access to dermatologic specialty care. Patients who typically are underrepresented in dermatology practices especially may benefit from increased accessibility, and all patients requiring in-person visits may benefit from reduced appointment wait times. The savings generated by in-person appointment avoidance reduce overall health care expenditure as well as the burden of individual expenses. The short turnaround time for e-consults also allows PCPs to better manage dermatologic issues in a timely manner. Integrating and expanding e-consult programs into everyday practice would extend specialty care to broader populations and help reduce barriers to access to dermatologic care.

Acknowledgments—The authors thank the Wake Forest University School of Medicine Department of Medical Education and Department of Dermatology (Winston-Salem, North Carolina) for their contributions to this research study as well as the Wake Forest Clinical and Translational Science Institute (Winston-Salem, North Carolina) for their help extracting EHR data.

Dermatologic conditions affect approximately one-third of individuals in the United States.^1,2 Nearly 1 in 4 physician office visits in the United States are for skin conditions, and less than one-third of these visits are with dermatologists. Although many of these patients may prefer to see a dermatologist for their concerns, they may not be able to access specialist care.³ The limited supply and urban-focused distribution of dermatologists along with reduced acceptance of state-funded insurance plans and long appointment wait times all pose considerable challenges to individuals seeking dermatologic care.² Electronic consultations (e-consults) have emerged as a promising solution to overcoming these barriers while providing high-quality dermatologic care to a large diverse patient population.^2,4 Although e-consults can be of service to all dermatology patients, this modality may be especially beneficial to underserved populations, such as the uninsured and Medicaid patients—groups that historically have experienced limited access to dermatology care due to the low reimbursement rates and high administrative burdens accompanying care delivery.⁴ This limited access leads to inequity in care, as timely access to dermatology is associated with improved diagnostic accuracy and disease outcomes.³ E-consult implementation can facilitate timely access for these underserved populations and bypass additional barriers to care such as lack of transportation or time off work. Prior e-consult studies have demonstrated relatively high numbers of Medicaid patients utilizing e-consult services.^3,5

Although in-person visits remain the gold standard for diagnosis and treatment of dermatologic conditions, e-consults placed by primary care providers (PCPs) can improve access and help triage patients who require in-person dermatology visits.⁶ In this study, we conducted a retrospective chart review to characterize the e-consults requested of the dermatology department at a large tertiary care medical center in Winston-Salem, North Carolina.

Methods

The electronic health record (EHR) of Atrium Health Wake Forest Baptist (Winston-Salem, North Carolina) was screened for eligible patients from January 1, 2020, to May 31, 2021. Patients—both adult (aged ≥18 years) and pediatric (aged <18 years)—were included if they underwent a dermatology e-consult within this time frame. Provider notes in the medical records were reviewed to determine the nature of the lesion, how long the dermatologist took to complete the e-consult, whether an in-person appointment was recommended, and whether the patient was seen by dermatology within 90 days of the e-consult. Institutional review board approval was obtained.

For each e-consult, the PCP obtained clinical photographs of the lesion in question either through the EHR mobile application or by having patients upload their own photographs directly to their medical records. The referring PCP then completed a brief template regarding the patient’s clinical question and medical history and then sent the completed information to the consulting dermatologist’s EHR inbox. From there, the dermatologist could view the clinical question, documented photographs, and patient medical record to create a brief consult note with recommendations. The note was then sent back via EHR to the PCP to follow up with the patient. Patients were not charged for the e-consult.

CT113003107_eTable.jpg

Results

Two hundred fifty-four dermatology e-consults were requested by providers at the study center (eTable), which included 252 unique patients (2 patients had 2 separate e-consults regarding different clinical questions). The median time for completion of the e-consult—from submission of the PCP’s e-consult request to dermatologist completion—was 0.37 days. Fifty-six patients (22.0%) were recommended for an in-person appointment (Figure), 33 (58.9%) of whom ultimately scheduled the in-person appointment, and the median length of time between the completion of the e-consult and the in-person appointment was 16.5 days. The remaining 198 patients (78.0%) were not triaged to receive an in-person appointment following the e-consult,but 2 patients (8.7%) were ultimately seen in-person anyway via other referral pathways, with a median length of 33 days between e-consult completion and the in-person appointment. One hundred seventy-six patients (69.8%) avoided an in-person dermatology visit, although 38 (21.6%) of those patients were fewer than 90 days out from their e-consults at the time of data collection. The 254 e-consults included patients from 50 different zip codes, 49 (98.0%) of which were in North Carolina.

Salisbury_Figure.jpg

Comment

An e-consult is an asynchronous telehealth modality through which PCPs can request specialty evaluation to provide diagnostic and therapeutic guidance, facilitate PCP-specialist coordination of care, and increase access to specialty care with reduced wait times.^7,8 Increased care access is especially important, as specialty referral can decrease overall health care expenditure; however, the demand for specialists often exceeds the availability.⁸ Our e-consult program drastically reduced the time from patients’ initial presentation at their PCP’s office to dermatologist recommendations for treatment or need for in-person dermatology follow-up.

In our analysis, patients were of different racial, ethnic, and socioeconomic backgrounds and lived across a variety of zip codes, predominantly in central and western North Carolina. Almost three-quarters of the patients resided in zip codes where the average income was less than the North Carolina median household income ($66,196).⁹ Additionally, 82 patients (32.3%) were uninsured or on Medicaid (eTable). These economically disadvantaged patient populations historically have had limited access to dermatologic care.⁴ One study showed that privately insured individuals were accepted as new patients by dermatologists 91% of the time compared to a 29.8% acceptance rate for publicly insured individuals.¹⁰ Uninsured and Medicaid patients also have to wait 34% longer for an appointment compared to individuals with Medicare or private insurance.² Considering these patients may already be at an economic disadvantage when it comes to seeing and paying for dermatologic services, e-consults may reduce patient travel and appointment expenses while increasing access to specialty care. Based on a 2020 study, each e-consult generates an estimated savings of $80 out-of-pocket per patient per avoided in-person visit.¹¹

In our study, the most common condition for an e-consult in both adult and pediatric patients was rash, which is consistent with prior e-consult studies.^5,11 We found that most e-consult patients were not recommended for an in-person dermatology visit, and for those who were recommended to have an in-person visit, the wait time was reduced (Figure). These results corroborate that e-consults may be used as an important triage tool for determining whether a specialist appointment is indicated as well as a public health tool, as timely evaluation is associated with better dermatologic health care outcomes.³ However, the number of patients who did not present for an in-person appointment in our study may be overestimated, as 38 patients’ (21.6%) e-consults were conducted fewer than 90 days before our data collection. Although none of these patients had been seen in person, it is possible they requested an in-person visit after their medical records were reviewed for this study. Additionally, it is possible patients sought care from outside providers not documented in the EHR.

With regard to the payment model for the e-consult program, Atrium Health Wake Forest Baptist initially piloted the e-consult system through a partnership with the American Academy of Medical Colleges’ Project CORE: Coordinating Optimal Referral Experiences (https://www.aamc.org/what-we-do/mission-areas/health-care/project-core). Grant funding through Project CORE allowed both the referring PCP and the specialist completing the e-consult to each receive approximately 0.5 relative value units in payment for each consult completed. Based on early adoption successes, the institution has created additional internal funding to support the continued expansion of the e-consult system and is incentivized to continue funding, as proper utilization of e-consults improves patient access to timely specialist care, avoids no-shows or last-minute cancellations for specialist appointments, and decreases back-door access to specialist care through the emergency department and urgent care facilities.⁵ Although 0.5 relative value units is not equivalent compensation to an in-person office visit, our study showed that e-consults can be completed much more quickly and efficiently and do not utilize nursing staff or other office resources.

Conclusion

E-consults are an effective telehealth modality that can increase patients’ access to dermatologic specialty care. Patients who typically are underrepresented in dermatology practices especially may benefit from increased accessibility, and all patients requiring in-person visits may benefit from reduced appointment wait times. The savings generated by in-person appointment avoidance reduce overall health care expenditure as well as the burden of individual expenses. The short turnaround time for e-consults also allows PCPs to better manage dermatologic issues in a timely manner. Integrating and expanding e-consult programs into everyday practice would extend specialty care to broader populations and help reduce barriers to access to dermatologic care.

Acknowledgments—The authors thank the Wake Forest University School of Medicine Department of Medical Education and Department of Dermatology (Winston-Salem, North Carolina) for their contributions to this research study as well as the Wake Forest Clinical and Translational Science Institute (Winston-Salem, North Carolina) for their help extracting EHR data.

Dermatologists improve the diagnostic accuracy and quality of care of patients in the hospital setting. They help shorten the length of stay, improve outpatient follow-up, and reduce the rate of hospital readmission.¹ Medicare beneficiaries hospitalized with skin conditions at institutions with a dermatology hospitalist—a provider with a specialty interest in inpatient dermatology—have 24% lower odds of risk-adjusted 30-day mortality and 12% lower odds of risk-adjusted 30-day readmissions.²

In the last year, research among the dermatology hospitalist community has actively contributed to our understanding of challenging inpatient skin diseases and has identified new ways in which dermatologists can contribute to the care of hospitalized patients. In this review, we highlight 4 areas of focus from the published literature in 2022-2023—severe cutaneous adverse reactions, supportive oncodermatology, cost of inpatient services, and teledermatology.

Severe Cutaneous Adverse Reactions: Old and New

Severe cutaneous adverse reactions to medications frequently are encountered in the inpatient setting. Dermatology hospitalists are well positioned to phenotype these reactions, drawing insights that aid in identifying, characterizing, risk stratifying, and managing these conditions, which have considerable morbidity and mortality.

A recent 20-year retrospective review of cases of acute generalized exanthematous pustulosis (N=340) across 10 academic systems—the largest to date—improves our understanding of the features of this rare entity.³ The authors found that acute generalized exanthematous pustulosis most often is triggered by β-lactam and other antibiotics (75.5%) and is accompanied by fever (49.7%), neutrophilia (85.1%), and eosinophilia (52.1%). Kidney and liver involvement occur in less than 10% of cases, and mortality rates are low but not zero, with an all-cause 30-day mortality rate of 3.5%.³

In a multi-institutional retrospective study of 68 patients diagnosed with DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome, Sharma et al⁴ developed a scoring system to identify those at greatest risk for DRESS recurrence. Variables associated with recurrence including younger age, female sex, and features considered atypical for DRESS syndrome—nonmorbilliform rash; absence of facial edema; antinuclear antibody positivity; medication class other than antibiotic, antigout, or antiseizure—were used to develop a “ReDRESS” score. This predictive model had a sensitivity of 73% and specificity of 83% for predicting DRESS recurrence.⁴

Another case series characterized SCoRCH (sudden conjunctivitis, lymphopenia, sunburnlike rash, and hemodynamic changes), a newly described hypersensitivity reaction to trimethoprim-sulfamethoxazole.⁵ The onset of this reaction typically occurs 4 to 11 days after initiation of trimethoprim-sulfamethoxazole but can occur as quickly as 1 day following re-exposure. Patients are systemically ill with fever, hypotension, tachycardia, acute renal insufficiency, and transaminitis, and they have a diffuse sunburnlike erythema without scale, facial edema, and conjunctivitis. It is thought this distinct hypersensitivity reaction may be mediated by IL-6, which has a role in triggering a sepsislike physiology, with vasodilation, hypotension, and edema.⁵

A systematic review and meta-analysis found that sulfonamides remain the most prominent cause of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).⁶ A case-control study described SJS/TEN presentations triggered by Mycoplasma, advocating for routine Mycoplasma screening, especially in patients without a clear medication culprit. Mycoplasma-induced cases carried statistically lower rates of mortality (0%) compared with medication-induced cases (22.5%).⁷ Another prospective open-label study evaluated SJS/TEN management by randomizing 25 patients to receive either combination therapy with methylprednisolone plus a tumor necrosis factor α inhibitor or methylprednisolone alone.⁸ Anti–tumor necrosis factor therapy was associated with a shorter length of initial steroid treatment and duration of the acute stage, hospitalization, and time to re-epithelialization⁸; however, as in a prior randomized unblinded trial,⁹ there was no difference in mortality between the 2 groups.

There is limited high-quality evidence to support the use of any systemic immunomodulator to decrease SJS/TEN–related mortality.¹⁰ A Cochrane systematic review highlighted the many limitations of the available data due to variations in presentation, assessment, and management.¹¹ Because SJS/TEN is rare, powering studies based on mortality is infeasible; the authors calculated that 2872 participants were needed to detect a 50% mortality reduction among those with SCORTEN (severity-of-illness score for TEN) scores of 0 to 1.¹¹ Therefore, collaborative efforts using appropriate outcomes measures (eg, time to re-epithelialization, length of hospital stay), standardized terminology and dosing regimens, and adaptive trial designs are needed. Consensus-derived assessment and treatment protocols could help account for variation, ensure consistency in treatment, and enable head-to-head comparisons. Members of the Society of Dermatology Hospitalists are working on efforts to standardize terminology and validate outcomes measures needed for future studies.¹²

Supportive Oncodermatology: A New Frontier

With the advent of immune checkpoint inhibitors (ICIs) for a growing number of cancers, dermatologists have become critical to identifying and managing cutaneous immune-related adverse events (cirAEs). Recent findings have demonstrated that dermatology input improves patient outcomes, not only regarding the treatment of dermatoses but also by augmenting cancer-related survival. One group found that patients with cirAEs who were evaluated by a dermatologist had improved progression-free (hazard ratio, 0.69; 95% CI, 0.54-0.87; P=.002) and overall survival rates (hazard ratio, 0.62; 95% CI, 0.45-0.84; P=.002), controlling for cirAE severity, age, sex, cancer type, and ICI subtype. Patients who were under the care of a dermatologist also were more likely to resume ICI therapy following an interruption (odds ratio, 10.52; 95% CI, 5.15-21.48; P<.001).¹³ Dermatologists help to optimize skin-directed and targeted therapies, such as dupilumab, minimizing exposure to systemic immunosuppression in these complex patients.¹⁴

Supportive oncodermatologists also have made important observations on how cirAEs relate to other adverse events and prognosis. A review of 628 patients found that almost half of those with cirAEs had co-occurring noncutaneous immune-related adverse events, most commonly pulmonary. Psoriasiform eruptions were most frequently associated with noncutaneous immune-related adverse events, and cutaneous reactions frequently preceded the development of systemic manifestations, serving as a clinical biomarker to provide prognostic information.¹⁵ A review of 95 patients found that spongiotic and lichenoid interface reactions were associated with decreased mortality rates, whereas vacuolar interface and perivascular dermatitis were associated with increased mortality.¹⁶

As with severe cutaneous adverse events, dermatology input has been critical for accurately phenotyping and risk stratifying these novel reactions. The dermatologist’s skill set is necessary for optimizing skin-directed and targeted therapies while minimizing systemic immunosuppression, thereby improving patient outcomes with respect to rash, cancer response, and survival.

The Cost of Inpatient Skin Disease

Hospitalizations account for approximately half of all health care expenditures, and hospital readmission, seen as a measure of the quality of health care delivery, can double this cost.¹⁷ Identifying and developing protocols for addressing patients with complex chronic inflammatory disorders is one strategy for improving outcomes and reducing financial burden. Inpatient dermatologists have identified hidradenitis suppurativa as one disease that can benefit from early intervention by dermatologists in the hospital, with its 30-day (17.8%) and 180-day (48.6%) readmission rates being comparable to those of heart failure.¹⁸

Following an index emergency department (ED) visit, 17.2% (3484/20,269) of patients with HS have at least 1 return ED visit within 30 days, while only 2.4% (483/20,269) have a dermatology visit within the same time frame.¹⁹ Understanding the risk factors for hospital readmission and ED utilization, including severity of illness, the presence of medical comorbidities, health coverage under Medicaid, and receipt of opioids, can allow dermatologists to anticipate those at greatest risk.¹⁹ Opportunities exist for cross-specialty interventions to anticipate and address modifiable risk factors. Shorter time to dermatology outpatient follow-up leads to improved clinic attendance and may help reduce ED utilization and hospital readmission.²⁰

Teledermatology: Leveraging Inpatient Expertise

Although the benefit of inpatient dermatologic care is substantial, access to that care is finite. Following the COVID-19 pandemic, there is an increased acceptance of telemedicine and the long-term role it can play in leveraging dermatologic expertise, including meeting the increasing demand for inpatient dermatology care in rural and resource-poor communities.²¹

Recent studies conducted by dermatology hospitalists have illustrated the value of asynchronous store-and-forward technology in settings lacking access to consultative dermatology.^22,23 Stephens et al²² found that expanding provider-to-provider electronic consultation (e-consultation) capacity to an inpatient rehabilitation facility resulted in completed consultations within 1.5 days compared with a 7- to 14-day wait time for patients attending an in-person urgent access dermatology clinic. In another study, the implementation of asynchronous dermatology e-consultations for immunobullous diseases, vasculitis, and herpes zoster resulted in a change in diagnosis 86% of the time, accompanied by at least 1 new systemic or topical therapy recommendation.²³

Researchers also identified ways in which teledermatology can be inelegant and proposed specific supplemental data to aid in diagnosis. A review of 126 inpatient e-consultations demonstrated limitations related to the diagnosis of skin and soft-tissue infections. In two-thirds to three-quarters of cases, potentially useful descriptive information was missing, and in 70% (88/126), images were not appropriately focused. The authors developed a detailed checklist to help primary medical teams focus their differential diagnoses.²⁴ A recent pilot study found that supplementation of clinical information with a standardized questionnaire and thermal images improved the accuracy of cellulitis diagnosis. Using this method, there was no difference in accuracy between dermatology hospitalists and other board-certified dermatologists, supporting the notion that any dermatologist can fulfill this need successfully, even without specific inpatient experience.²⁵ Due to the high incidence and cost of cellulitis and related hospital admissions,²⁶ such an intervention could have a considerable financial and patient safety impact.

Final Thoughts

This last year brought many changes to the health care landscape, the recession of a global pandemic, and an increasingly complex health care delivery system. Inpatient dermatologists met these challenges by providing high-quality dermatologic care and practice-modifying research in the areas of severe cutaneous adverse reactions, supportive oncodermatology, hospital readmission, telemedicine, and more, demonstrating the value of dermatologic expertise in the hospital setting.

Dermatologists improve the diagnostic accuracy and quality of care of patients in the hospital setting. They help shorten the length of stay, improve outpatient follow-up, and reduce the rate of hospital readmission.¹ Medicare beneficiaries hospitalized with skin conditions at institutions with a dermatology hospitalist—a provider with a specialty interest in inpatient dermatology—have 24% lower odds of risk-adjusted 30-day mortality and 12% lower odds of risk-adjusted 30-day readmissions.²

In the last year, research among the dermatology hospitalist community has actively contributed to our understanding of challenging inpatient skin diseases and has identified new ways in which dermatologists can contribute to the care of hospitalized patients. In this review, we highlight 4 areas of focus from the published literature in 2022-2023—severe cutaneous adverse reactions, supportive oncodermatology, cost of inpatient services, and teledermatology.

Severe Cutaneous Adverse Reactions: Old and New

Severe cutaneous adverse reactions to medications frequently are encountered in the inpatient setting. Dermatology hospitalists are well positioned to phenotype these reactions, drawing insights that aid in identifying, characterizing, risk stratifying, and managing these conditions, which have considerable morbidity and mortality.

A recent 20-year retrospective review of cases of acute generalized exanthematous pustulosis (N=340) across 10 academic systems—the largest to date—improves our understanding of the features of this rare entity.³ The authors found that acute generalized exanthematous pustulosis most often is triggered by β-lactam and other antibiotics (75.5%) and is accompanied by fever (49.7%), neutrophilia (85.1%), and eosinophilia (52.1%). Kidney and liver involvement occur in less than 10% of cases, and mortality rates are low but not zero, with an all-cause 30-day mortality rate of 3.5%.³

In a multi-institutional retrospective study of 68 patients diagnosed with DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome, Sharma et al⁴ developed a scoring system to identify those at greatest risk for DRESS recurrence. Variables associated with recurrence including younger age, female sex, and features considered atypical for DRESS syndrome—nonmorbilliform rash; absence of facial edema; antinuclear antibody positivity; medication class other than antibiotic, antigout, or antiseizure—were used to develop a “ReDRESS” score. This predictive model had a sensitivity of 73% and specificity of 83% for predicting DRESS recurrence.⁴

Another case series characterized SCoRCH (sudden conjunctivitis, lymphopenia, sunburnlike rash, and hemodynamic changes), a newly described hypersensitivity reaction to trimethoprim-sulfamethoxazole.⁵ The onset of this reaction typically occurs 4 to 11 days after initiation of trimethoprim-sulfamethoxazole but can occur as quickly as 1 day following re-exposure. Patients are systemically ill with fever, hypotension, tachycardia, acute renal insufficiency, and transaminitis, and they have a diffuse sunburnlike erythema without scale, facial edema, and conjunctivitis. It is thought this distinct hypersensitivity reaction may be mediated by IL-6, which has a role in triggering a sepsislike physiology, with vasodilation, hypotension, and edema.⁵

A systematic review and meta-analysis found that sulfonamides remain the most prominent cause of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).⁶ A case-control study described SJS/TEN presentations triggered by Mycoplasma, advocating for routine Mycoplasma screening, especially in patients without a clear medication culprit. Mycoplasma-induced cases carried statistically lower rates of mortality (0%) compared with medication-induced cases (22.5%).⁷ Another prospective open-label study evaluated SJS/TEN management by randomizing 25 patients to receive either combination therapy with methylprednisolone plus a tumor necrosis factor α inhibitor or methylprednisolone alone.⁸ Anti–tumor necrosis factor therapy was associated with a shorter length of initial steroid treatment and duration of the acute stage, hospitalization, and time to re-epithelialization⁸; however, as in a prior randomized unblinded trial,⁹ there was no difference in mortality between the 2 groups.

There is limited high-quality evidence to support the use of any systemic immunomodulator to decrease SJS/TEN–related mortality.¹⁰ A Cochrane systematic review highlighted the many limitations of the available data due to variations in presentation, assessment, and management.¹¹ Because SJS/TEN is rare, powering studies based on mortality is infeasible; the authors calculated that 2872 participants were needed to detect a 50% mortality reduction among those with SCORTEN (severity-of-illness score for TEN) scores of 0 to 1.¹¹ Therefore, collaborative efforts using appropriate outcomes measures (eg, time to re-epithelialization, length of hospital stay), standardized terminology and dosing regimens, and adaptive trial designs are needed. Consensus-derived assessment and treatment protocols could help account for variation, ensure consistency in treatment, and enable head-to-head comparisons. Members of the Society of Dermatology Hospitalists are working on efforts to standardize terminology and validate outcomes measures needed for future studies.¹²

Supportive Oncodermatology: A New Frontier

With the advent of immune checkpoint inhibitors (ICIs) for a growing number of cancers, dermatologists have become critical to identifying and managing cutaneous immune-related adverse events (cirAEs). Recent findings have demonstrated that dermatology input improves patient outcomes, not only regarding the treatment of dermatoses but also by augmenting cancer-related survival. One group found that patients with cirAEs who were evaluated by a dermatologist had improved progression-free (hazard ratio, 0.69; 95% CI, 0.54-0.87; P=.002) and overall survival rates (hazard ratio, 0.62; 95% CI, 0.45-0.84; P=.002), controlling for cirAE severity, age, sex, cancer type, and ICI subtype. Patients who were under the care of a dermatologist also were more likely to resume ICI therapy following an interruption (odds ratio, 10.52; 95% CI, 5.15-21.48; P<.001).¹³ Dermatologists help to optimize skin-directed and targeted therapies, such as dupilumab, minimizing exposure to systemic immunosuppression in these complex patients.¹⁴

Supportive oncodermatologists also have made important observations on how cirAEs relate to other adverse events and prognosis. A review of 628 patients found that almost half of those with cirAEs had co-occurring noncutaneous immune-related adverse events, most commonly pulmonary. Psoriasiform eruptions were most frequently associated with noncutaneous immune-related adverse events, and cutaneous reactions frequently preceded the development of systemic manifestations, serving as a clinical biomarker to provide prognostic information.¹⁵ A review of 95 patients found that spongiotic and lichenoid interface reactions were associated with decreased mortality rates, whereas vacuolar interface and perivascular dermatitis were associated with increased mortality.¹⁶

As with severe cutaneous adverse events, dermatology input has been critical for accurately phenotyping and risk stratifying these novel reactions. The dermatologist’s skill set is necessary for optimizing skin-directed and targeted therapies while minimizing systemic immunosuppression, thereby improving patient outcomes with respect to rash, cancer response, and survival.

The Cost of Inpatient Skin Disease

Hospitalizations account for approximately half of all health care expenditures, and hospital readmission, seen as a measure of the quality of health care delivery, can double this cost.¹⁷ Identifying and developing protocols for addressing patients with complex chronic inflammatory disorders is one strategy for improving outcomes and reducing financial burden. Inpatient dermatologists have identified hidradenitis suppurativa as one disease that can benefit from early intervention by dermatologists in the hospital, with its 30-day (17.8%) and 180-day (48.6%) readmission rates being comparable to those of heart failure.¹⁸

Following an index emergency department (ED) visit, 17.2% (3484/20,269) of patients with HS have at least 1 return ED visit within 30 days, while only 2.4% (483/20,269) have a dermatology visit within the same time frame.¹⁹ Understanding the risk factors for hospital readmission and ED utilization, including severity of illness, the presence of medical comorbidities, health coverage under Medicaid, and receipt of opioids, can allow dermatologists to anticipate those at greatest risk.¹⁹ Opportunities exist for cross-specialty interventions to anticipate and address modifiable risk factors. Shorter time to dermatology outpatient follow-up leads to improved clinic attendance and may help reduce ED utilization and hospital readmission.²⁰

Teledermatology: Leveraging Inpatient Expertise

Although the benefit of inpatient dermatologic care is substantial, access to that care is finite. Following the COVID-19 pandemic, there is an increased acceptance of telemedicine and the long-term role it can play in leveraging dermatologic expertise, including meeting the increasing demand for inpatient dermatology care in rural and resource-poor communities.²¹

Recent studies conducted by dermatology hospitalists have illustrated the value of asynchronous store-and-forward technology in settings lacking access to consultative dermatology.^22,23 Stephens et al²² found that expanding provider-to-provider electronic consultation (e-consultation) capacity to an inpatient rehabilitation facility resulted in completed consultations within 1.5 days compared with a 7- to 14-day wait time for patients attending an in-person urgent access dermatology clinic. In another study, the implementation of asynchronous dermatology e-consultations for immunobullous diseases, vasculitis, and herpes zoster resulted in a change in diagnosis 86% of the time, accompanied by at least 1 new systemic or topical therapy recommendation.²³

Researchers also identified ways in which teledermatology can be inelegant and proposed specific supplemental data to aid in diagnosis. A review of 126 inpatient e-consultations demonstrated limitations related to the diagnosis of skin and soft-tissue infections. In two-thirds to three-quarters of cases, potentially useful descriptive information was missing, and in 70% (88/126), images were not appropriately focused. The authors developed a detailed checklist to help primary medical teams focus their differential diagnoses.²⁴ A recent pilot study found that supplementation of clinical information with a standardized questionnaire and thermal images improved the accuracy of cellulitis diagnosis. Using this method, there was no difference in accuracy between dermatology hospitalists and other board-certified dermatologists, supporting the notion that any dermatologist can fulfill this need successfully, even without specific inpatient experience.²⁵ Due to the high incidence and cost of cellulitis and related hospital admissions,²⁶ such an intervention could have a considerable financial and patient safety impact.

Final Thoughts

This last year brought many changes to the health care landscape, the recession of a global pandemic, and an increasingly complex health care delivery system. Inpatient dermatologists met these challenges by providing high-quality dermatologic care and practice-modifying research in the areas of severe cutaneous adverse reactions, supportive oncodermatology, hospital readmission, telemedicine, and more, demonstrating the value of dermatologic expertise in the hospital setting.

Dermatologists improve the diagnostic accuracy and quality of care of patients in the hospital setting. They help shorten the length of stay, improve outpatient follow-up, and reduce the rate of hospital readmission.¹ Medicare beneficiaries hospitalized with skin conditions at institutions with a dermatology hospitalist—a provider with a specialty interest in inpatient dermatology—have 24% lower odds of risk-adjusted 30-day mortality and 12% lower odds of risk-adjusted 30-day readmissions.²

In the last year, research among the dermatology hospitalist community has actively contributed to our understanding of challenging inpatient skin diseases and has identified new ways in which dermatologists can contribute to the care of hospitalized patients. In this review, we highlight 4 areas of focus from the published literature in 2022-2023—severe cutaneous adverse reactions, supportive oncodermatology, cost of inpatient services, and teledermatology.

Severe Cutaneous Adverse Reactions: Old and New

Severe cutaneous adverse reactions to medications frequently are encountered in the inpatient setting. Dermatology hospitalists are well positioned to phenotype these reactions, drawing insights that aid in identifying, characterizing, risk stratifying, and managing these conditions, which have considerable morbidity and mortality.

A recent 20-year retrospective review of cases of acute generalized exanthematous pustulosis (N=340) across 10 academic systems—the largest to date—improves our understanding of the features of this rare entity.³ The authors found that acute generalized exanthematous pustulosis most often is triggered by β-lactam and other antibiotics (75.5%) and is accompanied by fever (49.7%), neutrophilia (85.1%), and eosinophilia (52.1%). Kidney and liver involvement occur in less than 10% of cases, and mortality rates are low but not zero, with an all-cause 30-day mortality rate of 3.5%.³

In a multi-institutional retrospective study of 68 patients diagnosed with DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome, Sharma et al⁴ developed a scoring system to identify those at greatest risk for DRESS recurrence. Variables associated with recurrence including younger age, female sex, and features considered atypical for DRESS syndrome—nonmorbilliform rash; absence of facial edema; antinuclear antibody positivity; medication class other than antibiotic, antigout, or antiseizure—were used to develop a “ReDRESS” score. This predictive model had a sensitivity of 73% and specificity of 83% for predicting DRESS recurrence.⁴

Another case series characterized SCoRCH (sudden conjunctivitis, lymphopenia, sunburnlike rash, and hemodynamic changes), a newly described hypersensitivity reaction to trimethoprim-sulfamethoxazole.⁵ The onset of this reaction typically occurs 4 to 11 days after initiation of trimethoprim-sulfamethoxazole but can occur as quickly as 1 day following re-exposure. Patients are systemically ill with fever, hypotension, tachycardia, acute renal insufficiency, and transaminitis, and they have a diffuse sunburnlike erythema without scale, facial edema, and conjunctivitis. It is thought this distinct hypersensitivity reaction may be mediated by IL-6, which has a role in triggering a sepsislike physiology, with vasodilation, hypotension, and edema.⁵

A systematic review and meta-analysis found that sulfonamides remain the most prominent cause of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).⁶ A case-control study described SJS/TEN presentations triggered by Mycoplasma, advocating for routine Mycoplasma screening, especially in patients without a clear medication culprit. Mycoplasma-induced cases carried statistically lower rates of mortality (0%) compared with medication-induced cases (22.5%).⁷ Another prospective open-label study evaluated SJS/TEN management by randomizing 25 patients to receive either combination therapy with methylprednisolone plus a tumor necrosis factor α inhibitor or methylprednisolone alone.⁸ Anti–tumor necrosis factor therapy was associated with a shorter length of initial steroid treatment and duration of the acute stage, hospitalization, and time to re-epithelialization⁸; however, as in a prior randomized unblinded trial,⁹ there was no difference in mortality between the 2 groups.

There is limited high-quality evidence to support the use of any systemic immunomodulator to decrease SJS/TEN–related mortality.¹⁰ A Cochrane systematic review highlighted the many limitations of the available data due to variations in presentation, assessment, and management.¹¹ Because SJS/TEN is rare, powering studies based on mortality is infeasible; the authors calculated that 2872 participants were needed to detect a 50% mortality reduction among those with SCORTEN (severity-of-illness score for TEN) scores of 0 to 1.¹¹ Therefore, collaborative efforts using appropriate outcomes measures (eg, time to re-epithelialization, length of hospital stay), standardized terminology and dosing regimens, and adaptive trial designs are needed. Consensus-derived assessment and treatment protocols could help account for variation, ensure consistency in treatment, and enable head-to-head comparisons. Members of the Society of Dermatology Hospitalists are working on efforts to standardize terminology and validate outcomes measures needed for future studies.¹²

Supportive Oncodermatology: A New Frontier

With the advent of immune checkpoint inhibitors (ICIs) for a growing number of cancers, dermatologists have become critical to identifying and managing cutaneous immune-related adverse events (cirAEs). Recent findings have demonstrated that dermatology input improves patient outcomes, not only regarding the treatment of dermatoses but also by augmenting cancer-related survival. One group found that patients with cirAEs who were evaluated by a dermatologist had improved progression-free (hazard ratio, 0.69; 95% CI, 0.54-0.87; P=.002) and overall survival rates (hazard ratio, 0.62; 95% CI, 0.45-0.84; P=.002), controlling for cirAE severity, age, sex, cancer type, and ICI subtype. Patients who were under the care of a dermatologist also were more likely to resume ICI therapy following an interruption (odds ratio, 10.52; 95% CI, 5.15-21.48; P<.001).¹³ Dermatologists help to optimize skin-directed and targeted therapies, such as dupilumab, minimizing exposure to systemic immunosuppression in these complex patients.¹⁴

Supportive oncodermatologists also have made important observations on how cirAEs relate to other adverse events and prognosis. A review of 628 patients found that almost half of those with cirAEs had co-occurring noncutaneous immune-related adverse events, most commonly pulmonary. Psoriasiform eruptions were most frequently associated with noncutaneous immune-related adverse events, and cutaneous reactions frequently preceded the development of systemic manifestations, serving as a clinical biomarker to provide prognostic information.¹⁵ A review of 95 patients found that spongiotic and lichenoid interface reactions were associated with decreased mortality rates, whereas vacuolar interface and perivascular dermatitis were associated with increased mortality.¹⁶

As with severe cutaneous adverse events, dermatology input has been critical for accurately phenotyping and risk stratifying these novel reactions. The dermatologist’s skill set is necessary for optimizing skin-directed and targeted therapies while minimizing systemic immunosuppression, thereby improving patient outcomes with respect to rash, cancer response, and survival.

The Cost of Inpatient Skin Disease

Hospitalizations account for approximately half of all health care expenditures, and hospital readmission, seen as a measure of the quality of health care delivery, can double this cost.¹⁷ Identifying and developing protocols for addressing patients with complex chronic inflammatory disorders is one strategy for improving outcomes and reducing financial burden. Inpatient dermatologists have identified hidradenitis suppurativa as one disease that can benefit from early intervention by dermatologists in the hospital, with its 30-day (17.8%) and 180-day (48.6%) readmission rates being comparable to those of heart failure.¹⁸

Following an index emergency department (ED) visit, 17.2% (3484/20,269) of patients with HS have at least 1 return ED visit within 30 days, while only 2.4% (483/20,269) have a dermatology visit within the same time frame.¹⁹ Understanding the risk factors for hospital readmission and ED utilization, including severity of illness, the presence of medical comorbidities, health coverage under Medicaid, and receipt of opioids, can allow dermatologists to anticipate those at greatest risk.¹⁹ Opportunities exist for cross-specialty interventions to anticipate and address modifiable risk factors. Shorter time to dermatology outpatient follow-up leads to improved clinic attendance and may help reduce ED utilization and hospital readmission.²⁰

Teledermatology: Leveraging Inpatient Expertise

Although the benefit of inpatient dermatologic care is substantial, access to that care is finite. Following the COVID-19 pandemic, there is an increased acceptance of telemedicine and the long-term role it can play in leveraging dermatologic expertise, including meeting the increasing demand for inpatient dermatology care in rural and resource-poor communities.²¹

Recent studies conducted by dermatology hospitalists have illustrated the value of asynchronous store-and-forward technology in settings lacking access to consultative dermatology.^22,23 Stephens et al²² found that expanding provider-to-provider electronic consultation (e-consultation) capacity to an inpatient rehabilitation facility resulted in completed consultations within 1.5 days compared with a 7- to 14-day wait time for patients attending an in-person urgent access dermatology clinic. In another study, the implementation of asynchronous dermatology e-consultations for immunobullous diseases, vasculitis, and herpes zoster resulted in a change in diagnosis 86% of the time, accompanied by at least 1 new systemic or topical therapy recommendation.²³

Researchers also identified ways in which teledermatology can be inelegant and proposed specific supplemental data to aid in diagnosis. A review of 126 inpatient e-consultations demonstrated limitations related to the diagnosis of skin and soft-tissue infections. In two-thirds to three-quarters of cases, potentially useful descriptive information was missing, and in 70% (88/126), images were not appropriately focused. The authors developed a detailed checklist to help primary medical teams focus their differential diagnoses.²⁴ A recent pilot study found that supplementation of clinical information with a standardized questionnaire and thermal images improved the accuracy of cellulitis diagnosis. Using this method, there was no difference in accuracy between dermatology hospitalists and other board-certified dermatologists, supporting the notion that any dermatologist can fulfill this need successfully, even without specific inpatient experience.²⁵ Due to the high incidence and cost of cellulitis and related hospital admissions,²⁶ such an intervention could have a considerable financial and patient safety impact.

Final Thoughts

This last year brought many changes to the health care landscape, the recession of a global pandemic, and an increasingly complex health care delivery system. Inpatient dermatologists met these challenges by providing high-quality dermatologic care and practice-modifying research in the areas of severe cutaneous adverse reactions, supportive oncodermatology, hospital readmission, telemedicine, and more, demonstrating the value of dermatologic expertise in the hospital setting.

Palliative care (PC) is a field of medicine that focuses on improving quality of life by managing physical symptoms as well as mental and spiritual well-being in patients with severe illnesses.^1,2 Despite cases of severe dermatologic disease, the use of PC in the field of dermatology is limited, often leaving patients with a range of unmet needs.^2,3 In one study that explored PC in patients with melanoma, only one-third of patients with advanced melanoma had a PC consultation.⁴ Reasons behind the lack of utilization of PC in dermatology include time constraints and limited training in addressing the complex psychosocial needs of patients with severe dermatologic illnesses.¹ We conducted a retrospective, cross-sectional, single-institution study of specific inpatient dermatology consultations over a 5-year period to describe PC utilization among patients who were hospitalized with select severe dermatologic diseases.

Methods

A retrospective, cross-sectional study of inpatient dermatology consultations over a 5-year period (October 2016 to October 2021) was performed at Atrium Health Wake Forest Baptist Medical Center (Winston-Salem, North Carolina). Patients’ medical records were reviewed if they had one of the following diseases: bullous pemphigoid, calciphylaxis, cutaneous T-cell lymphoma (CTCL), drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, erythrodermic psoriasis, graft-vs-host disease, pemphigus vulgaris (PV), purpura fulminans, pyoderma gangrenosum, and Stevens-Johnson syndrome/toxic epidermal necrolysis. These diseases were selected for inclusion because they have been associated with a documented increase in inpatient mortality and have been described in the published literature on PC in dermatology.² This study was reviewed and approved by the Wake Forest University institutional review board.

Use of PC consultative services along with other associated consultative care (ie, recreation therapy [RT], acute pain management, pastoral care) was assessed for each patient. Recreation therapy included specific interventions such as music therapy, arts/craft therapy, pet therapy, and other services with the goal of improving patient cognitive, emotional, and social function. For patients with a completed PC consultation, goals for PC intervention were recorded.

Results

The total study sample included 193 inpatient dermatology consultations. The mean age of the patients was 58.9 years (range, 2–100 years); 66.8% (129/193) were White and 28.5% (55/193) were Black (Table). Palliative care was consulted in 5.7% of cases, with consultations being requested by the primary care team. Reasons for PC consultation included assessment of the patient’s goals of care (4.1% [8/193]), pain management (3.6% [7/193]), non–pain symptom management (2.6% [5/193]), psychosocial support (1.6% [3/193]), and transitions of care (1.0% [2/193]). The average length of patients’ hospital stay prior to PC consultation was 11.5 days(range, 1–32 days). Acute pain management was the reason for consultation in 15.0% of cases (29/193), RT in 21.8% (42/193), and pastoral care in 13.5% (26/193) of cases. Patients with calciphylaxis received the most PC and pain consultations, but fewer than half received these services. Patients with calciphylaxis, PV, purpura fulminans, and CTCL received a higher percentage of PC consultations than the overall cohort, while patients with calciphylaxis, DRESS syndrome, PV, and pyoderma gangrenosum received relatively more pain consultations than the overall cohort (Figure).

CT112001023_Table.jpg

Comment

Clinical practice guidelines for quality PC stress the importance of specialists being familiar with these services and the ability to involve PC as part of the treatment plan to achieve better care for patients with serious illnesses.⁵ Our results demonstrated low rates of PC consultation services for dermatology patients, which supports the existing literature and suggests that PC may be highly underutilized in inpatient settings for patients with serious skin diseases. Use of PC was infrequent and was initiated relatively late in the course of hospital admission, which can negatively impact a patient’s well-being and care experience and can increase the care burden on their caregivers and families.²

Moumen.jpg

Our results suggest a discrepancy in the frequency of formal PC and other palliative consultative services used for dermatologic diseases, with non-PC services including RT, acute pain management, and pastoral care more likely to be utilized. Impacting this finding may be that RT, pastoral care, and acute pain management are provided by nonphysician providers at our institution, not attending faculty staffing PC services. Patients with calciphylaxis were more likely to have PC consultations, potentially due to medicine providers’ familiarity with its morbidity and mortality, as it is commonly associated with end-stage renal disease. Similarly, internal medicine providers may be more familiar with pain classically associated with PG and PV and may be more likely to engage pain experts. Some diseases with notable morbidity and potential mortality were underrepresented including SJS/TEN, erythrodermic psoriasis, CTCL, and GVHD.

Limitations of our study included examination of data from a single institution, as well as the small sample sizes in specific subgroups, which prevented us from making comparisons between diseases. The cross-sectional design also limited our ability to control for confounding variables.

Conclusion

We urge dermatology consultation services to advocate for patients with serious skin diseases andinclude PC consultation as part of their recommendations to primary care teams. Further research should characterize the specific needs of patients that may be addressed by PC services and explore ways dermatologists and others can identify and provide specialty care to hospitalized patients.

Palliative care (PC) is a field of medicine that focuses on improving quality of life by managing physical symptoms as well as mental and spiritual well-being in patients with severe illnesses.^1,2 Despite cases of severe dermatologic disease, the use of PC in the field of dermatology is limited, often leaving patients with a range of unmet needs.^2,3 In one study that explored PC in patients with melanoma, only one-third of patients with advanced melanoma had a PC consultation.⁴ Reasons behind the lack of utilization of PC in dermatology include time constraints and limited training in addressing the complex psychosocial needs of patients with severe dermatologic illnesses.¹ We conducted a retrospective, cross-sectional, single-institution study of specific inpatient dermatology consultations over a 5-year period to describe PC utilization among patients who were hospitalized with select severe dermatologic diseases.

Methods

A retrospective, cross-sectional study of inpatient dermatology consultations over a 5-year period (October 2016 to October 2021) was performed at Atrium Health Wake Forest Baptist Medical Center (Winston-Salem, North Carolina). Patients’ medical records were reviewed if they had one of the following diseases: bullous pemphigoid, calciphylaxis, cutaneous T-cell lymphoma (CTCL), drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, erythrodermic psoriasis, graft-vs-host disease, pemphigus vulgaris (PV), purpura fulminans, pyoderma gangrenosum, and Stevens-Johnson syndrome/toxic epidermal necrolysis. These diseases were selected for inclusion because they have been associated with a documented increase in inpatient mortality and have been described in the published literature on PC in dermatology.² This study was reviewed and approved by the Wake Forest University institutional review board.

Use of PC consultative services along with other associated consultative care (ie, recreation therapy [RT], acute pain management, pastoral care) was assessed for each patient. Recreation therapy included specific interventions such as music therapy, arts/craft therapy, pet therapy, and other services with the goal of improving patient cognitive, emotional, and social function. For patients with a completed PC consultation, goals for PC intervention were recorded.

Results

The total study sample included 193 inpatient dermatology consultations. The mean age of the patients was 58.9 years (range, 2–100 years); 66.8% (129/193) were White and 28.5% (55/193) were Black (Table). Palliative care was consulted in 5.7% of cases, with consultations being requested by the primary care team. Reasons for PC consultation included assessment of the patient’s goals of care (4.1% [8/193]), pain management (3.6% [7/193]), non–pain symptom management (2.6% [5/193]), psychosocial support (1.6% [3/193]), and transitions of care (1.0% [2/193]). The average length of patients’ hospital stay prior to PC consultation was 11.5 days(range, 1–32 days). Acute pain management was the reason for consultation in 15.0% of cases (29/193), RT in 21.8% (42/193), and pastoral care in 13.5% (26/193) of cases. Patients with calciphylaxis received the most PC and pain consultations, but fewer than half received these services. Patients with calciphylaxis, PV, purpura fulminans, and CTCL received a higher percentage of PC consultations than the overall cohort, while patients with calciphylaxis, DRESS syndrome, PV, and pyoderma gangrenosum received relatively more pain consultations than the overall cohort (Figure).

CT112001023_Table.jpg

Comment

Clinical practice guidelines for quality PC stress the importance of specialists being familiar with these services and the ability to involve PC as part of the treatment plan to achieve better care for patients with serious illnesses.⁵ Our results demonstrated low rates of PC consultation services for dermatology patients, which supports the existing literature and suggests that PC may be highly underutilized in inpatient settings for patients with serious skin diseases. Use of PC was infrequent and was initiated relatively late in the course of hospital admission, which can negatively impact a patient’s well-being and care experience and can increase the care burden on their caregivers and families.²

Moumen.jpg

Our results suggest a discrepancy in the frequency of formal PC and other palliative consultative services used for dermatologic diseases, with non-PC services including RT, acute pain management, and pastoral care more likely to be utilized. Impacting this finding may be that RT, pastoral care, and acute pain management are provided by nonphysician providers at our institution, not attending faculty staffing PC services. Patients with calciphylaxis were more likely to have PC consultations, potentially due to medicine providers’ familiarity with its morbidity and mortality, as it is commonly associated with end-stage renal disease. Similarly, internal medicine providers may be more familiar with pain classically associated with PG and PV and may be more likely to engage pain experts. Some diseases with notable morbidity and potential mortality were underrepresented including SJS/TEN, erythrodermic psoriasis, CTCL, and GVHD.

Limitations of our study included examination of data from a single institution, as well as the small sample sizes in specific subgroups, which prevented us from making comparisons between diseases. The cross-sectional design also limited our ability to control for confounding variables.

Conclusion

We urge dermatology consultation services to advocate for patients with serious skin diseases andinclude PC consultation as part of their recommendations to primary care teams. Further research should characterize the specific needs of patients that may be addressed by PC services and explore ways dermatologists and others can identify and provide specialty care to hospitalized patients.

Palliative care (PC) is a field of medicine that focuses on improving quality of life by managing physical symptoms as well as mental and spiritual well-being in patients with severe illnesses.^1,2 Despite cases of severe dermatologic disease, the use of PC in the field of dermatology is limited, often leaving patients with a range of unmet needs.^2,3 In one study that explored PC in patients with melanoma, only one-third of patients with advanced melanoma had a PC consultation.⁴ Reasons behind the lack of utilization of PC in dermatology include time constraints and limited training in addressing the complex psychosocial needs of patients with severe dermatologic illnesses.¹ We conducted a retrospective, cross-sectional, single-institution study of specific inpatient dermatology consultations over a 5-year period to describe PC utilization among patients who were hospitalized with select severe dermatologic diseases.

Methods

A retrospective, cross-sectional study of inpatient dermatology consultations over a 5-year period (October 2016 to October 2021) was performed at Atrium Health Wake Forest Baptist Medical Center (Winston-Salem, North Carolina). Patients’ medical records were reviewed if they had one of the following diseases: bullous pemphigoid, calciphylaxis, cutaneous T-cell lymphoma (CTCL), drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, erythrodermic psoriasis, graft-vs-host disease, pemphigus vulgaris (PV), purpura fulminans, pyoderma gangrenosum, and Stevens-Johnson syndrome/toxic epidermal necrolysis. These diseases were selected for inclusion because they have been associated with a documented increase in inpatient mortality and have been described in the published literature on PC in dermatology.² This study was reviewed and approved by the Wake Forest University institutional review board.

Use of PC consultative services along with other associated consultative care (ie, recreation therapy [RT], acute pain management, pastoral care) was assessed for each patient. Recreation therapy included specific interventions such as music therapy, arts/craft therapy, pet therapy, and other services with the goal of improving patient cognitive, emotional, and social function. For patients with a completed PC consultation, goals for PC intervention were recorded.

Results

The total study sample included 193 inpatient dermatology consultations. The mean age of the patients was 58.9 years (range, 2–100 years); 66.8% (129/193) were White and 28.5% (55/193) were Black (Table). Palliative care was consulted in 5.7% of cases, with consultations being requested by the primary care team. Reasons for PC consultation included assessment of the patient’s goals of care (4.1% [8/193]), pain management (3.6% [7/193]), non–pain symptom management (2.6% [5/193]), psychosocial support (1.6% [3/193]), and transitions of care (1.0% [2/193]). The average length of patients’ hospital stay prior to PC consultation was 11.5 days(range, 1–32 days). Acute pain management was the reason for consultation in 15.0% of cases (29/193), RT in 21.8% (42/193), and pastoral care in 13.5% (26/193) of cases. Patients with calciphylaxis received the most PC and pain consultations, but fewer than half received these services. Patients with calciphylaxis, PV, purpura fulminans, and CTCL received a higher percentage of PC consultations than the overall cohort, while patients with calciphylaxis, DRESS syndrome, PV, and pyoderma gangrenosum received relatively more pain consultations than the overall cohort (Figure).

CT112001023_Table.jpg

Comment

Clinical practice guidelines for quality PC stress the importance of specialists being familiar with these services and the ability to involve PC as part of the treatment plan to achieve better care for patients with serious illnesses.⁵ Our results demonstrated low rates of PC consultation services for dermatology patients, which supports the existing literature and suggests that PC may be highly underutilized in inpatient settings for patients with serious skin diseases. Use of PC was infrequent and was initiated relatively late in the course of hospital admission, which can negatively impact a patient’s well-being and care experience and can increase the care burden on their caregivers and families.²

Moumen.jpg

Our results suggest a discrepancy in the frequency of formal PC and other palliative consultative services used for dermatologic diseases, with non-PC services including RT, acute pain management, and pastoral care more likely to be utilized. Impacting this finding may be that RT, pastoral care, and acute pain management are provided by nonphysician providers at our institution, not attending faculty staffing PC services. Patients with calciphylaxis were more likely to have PC consultations, potentially due to medicine providers’ familiarity with its morbidity and mortality, as it is commonly associated with end-stage renal disease. Similarly, internal medicine providers may be more familiar with pain classically associated with PG and PV and may be more likely to engage pain experts. Some diseases with notable morbidity and potential mortality were underrepresented including SJS/TEN, erythrodermic psoriasis, CTCL, and GVHD.

Limitations of our study included examination of data from a single institution, as well as the small sample sizes in specific subgroups, which prevented us from making comparisons between diseases. The cross-sectional design also limited our ability to control for confounding variables.

Conclusion

We urge dermatology consultation services to advocate for patients with serious skin diseases andinclude PC consultation as part of their recommendations to primary care teams. Further research should characterize the specific needs of patients that may be addressed by PC services and explore ways dermatologists and others can identify and provide specialty care to hospitalized patients.

Epidermal growth factor receptor (EGFR) inhibitors cause numerous cutaneous adverse events (AEs), including papulopustular eruptions, paronychia, acral fissures, xerosis, alopecia, and trichomegaly.¹ Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is an uncommon type IV hypersensitivity reaction reported most commonly in association with β-lactam antibiotics and other medications.² Treatment of SDRIFE generally involves withdrawing the inciting medication; however, in SDRIFE secondary to oncologic therapies, medication withdrawal may not be feasible or desirable. We present 2 cases of SDRIFE secondary to EGFR inhibitors in which treatment was continued alongside supportive skin-directed therapies. We also review the literature.

Case Reports

Patient 1—A 65-year-old man with stage IV non–small cell lung cancer presented to the dermatology clinic with an eruption of 2 months’ duration that began in the periumbilical area and spread to the perianal area within 2 weeks of starting treatment with lazertinib and amivantamab. Physical examination was notable for Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 periumbilical erythema and erosions as well as symmetric red-brown patches with linear erosions in the gluteal cleft (Figure 1) and Grade 2 facial papulopustular rash. Herpes simplex virus polymerase chain reaction and bacterial culture were negative. A skin biopsy from the left buttock revealed dermal edema and a perivascular lymphocytic infiltrate compatible with SDRIFE. Triamcinolone ointment 0.1% twice daily was initiated, then uptitrated to betamethasone ointment 0.05% twice daily with moderate improvement. The patient had a treatment interruption due to malignancy complications, at which time his skin improved, with recurrence of the eruption after treatment re-initiation. He resumed skin-directed treatment and was maintained on betamethasone ointment 0.05% and tacrolimus ointment 0.1% twice daily on alternating days. This treatment was continued for 4 months before the patient died from complications of the malignancy.

Lewis_1.jpg

Patient 2—A 68-year-old woman with stage IV lung adenocarcinoma presented to the dermatology clinic with a rash of 3 weeks’ duration. Treatment with osimertinib was initiated 8 months prior to presentation, and there were no recent medication changes. Physical examination revealed CTCAE Grade 2 erythematous patches in the inguinal folds (Figure 2A), inframammary folds (Figure 2B), and on the nasal tip, as well as Grade 2 paronychia. The patient was managed with hydrocortisone cream 1% twice daily, and osimertinib was continued. At follow-up 4 weeks later, the erythema had faded to hyperpigmentation in affected areas with resolution of symptoms. No further treatment was required.

CT111001018_Fig2_AB.jpg

Comment

Supportive oncodermatologists and dermatology hospitalists should be aware of SDRIFE as an uncommon but increasingly recognized cutaneous AE of EGFR inhibitors. Other cases of SDRIFE secondary to EGFR inhibition are described in the Table.^2-5 Although SDRIFE typically is treated by discontinuation of the offending agent, in all reported cases of EGFR inhibitor–associated SDRIFE the rash was CTCAE Grade 2, meaning that it did not interfere with instrumental activities of daily living. In 5 of 6 cases, EGFR therapy was continued while skin-directed therapies were used for symptom management.

CT111001018_Table.jpg

Presentation of SDRIFE—Symmetrical drug-related intertriginous and flexural exanthema is characterized by a symmetric, sharply demarcated erythema in the inguinal, gluteal, or perianal area with at least 1 other flexural localization involved in the absence of systemic signs. It is observed most frequently at initial exposure or re-exposure to a medication. Onset typically is within a few hours to a few days after exposure to a medication.⁶ Interestingly, in this case series, half of reported SDRIFE cases developed 8 months or more after EGFR inhibitor initiation.

Pathophysiology of SDRIFE—The mechanism of SDRIFE has not been clearly elucidated; it generally is accepted to be a delayed-type hypersensitivity drug reaction, though other proposed pathophysiologic mechanisms for the distribution of SDRIFE include recall phenomenon or predisposing anatomic factors such as temperature, humidity, and apocrine or eccrine gland density.^6,7 Epidermal growth factor receptor plays a critical role in regulating differentiation and proliferation of epidermal keratinocytes, hair follicles, and the sweat gland apparatus. Additionally, it has been hypothesized that EGFR inhibitor use may affect the microflora of the skin and that EGFR inhibitors directly affect the immune system, as demonstrated in an experiment showing EGFR inhibitor–treated mice had enhanced skin inflammation and contact hypersensitivity responses.⁸ How these disparate mechanisms may interact to produce SDRIFE and the reason for the notably delayed presentation of SDRIFE in half of the cases we reviewed is not known. Other delayed cutaneous AEs of EGFR inhibitor therapy, such as paronychia, are thought to be secondary to development of skin fragility and decreased keratinocyte proliferation with secondary infection.¹ It is conceivable that a combination of proliferative, immunologic, and microbiome-related factors may each be playing a role in EGFR inhibitor–related SDRIFE.

Dermatology Inpatient Considerations—As seen in our cases, dermatologists can play a valuable role in diagnosing, grading, and managing cutaneous AEs associated with the administration of oncologic therapies. The array of cutaneous AEs has grown as cancer treatment options have expanded from conventional antimetabolite agents to kinase inhibitors and immune checkpoint inhibitors. Dermatologists may play an important role in differentiating the etiology of a skin finding (eg, infectious vs inflammatory) and can identify serious or dose-limiting reactions, such as Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS). If cutaneous AEs appear to occur secondary to administration of a chemotherapeutic agent, use of the National Cancer Institute CTCAE should be employed. For certain AEs (eg, alopecia, acneiform rashes, bullous dermatitis), specific grading has been developed based on a combination of body surface area involved, psychosocial impact, symptoms, and other associated morbidity.⁹

In management of chemotherapy-associated cutaneous AEs, dermatologists are likely to be the members of the health care team most comfortable with prescribing high-potency anti-inflammatory topical medications. Dermatologic consultation for management of cutaneous AEs has been shown to both reduce the need for systemic immunosuppression and limit interruptions in oncologic treatment.¹⁰

Conclusion

Epidermal growth factor receptor inhibitors commonly are prescribed for colorectal cancer, non–small cell lung cancer, and squamous cell carcinoma of the head and neck. They are associated with a variety of cutaneous AEs, including acneiform eruptions, paronychia, and xerosis, which rarely necessitate stopping EGFR inhibitor therapy. Our cases support an approach to managing EGFR inhibitor–related SDRIFE that does not involve discontinuation of the offending agent. Further studies are needed on the best supportive topical and systemic regimens for EGFR inhibitor–associated SDRIFE.

Epidermal growth factor receptor (EGFR) inhibitors cause numerous cutaneous adverse events (AEs), including papulopustular eruptions, paronychia, acral fissures, xerosis, alopecia, and trichomegaly.¹ Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is an uncommon type IV hypersensitivity reaction reported most commonly in association with β-lactam antibiotics and other medications.² Treatment of SDRIFE generally involves withdrawing the inciting medication; however, in SDRIFE secondary to oncologic therapies, medication withdrawal may not be feasible or desirable. We present 2 cases of SDRIFE secondary to EGFR inhibitors in which treatment was continued alongside supportive skin-directed therapies. We also review the literature.

Case Reports

Patient 1—A 65-year-old man with stage IV non–small cell lung cancer presented to the dermatology clinic with an eruption of 2 months’ duration that began in the periumbilical area and spread to the perianal area within 2 weeks of starting treatment with lazertinib and amivantamab. Physical examination was notable for Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 periumbilical erythema and erosions as well as symmetric red-brown patches with linear erosions in the gluteal cleft (Figure 1) and Grade 2 facial papulopustular rash. Herpes simplex virus polymerase chain reaction and bacterial culture were negative. A skin biopsy from the left buttock revealed dermal edema and a perivascular lymphocytic infiltrate compatible with SDRIFE. Triamcinolone ointment 0.1% twice daily was initiated, then uptitrated to betamethasone ointment 0.05% twice daily with moderate improvement. The patient had a treatment interruption due to malignancy complications, at which time his skin improved, with recurrence of the eruption after treatment re-initiation. He resumed skin-directed treatment and was maintained on betamethasone ointment 0.05% and tacrolimus ointment 0.1% twice daily on alternating days. This treatment was continued for 4 months before the patient died from complications of the malignancy.

Lewis_1.jpg

Patient 2—A 68-year-old woman with stage IV lung adenocarcinoma presented to the dermatology clinic with a rash of 3 weeks’ duration. Treatment with osimertinib was initiated 8 months prior to presentation, and there were no recent medication changes. Physical examination revealed CTCAE Grade 2 erythematous patches in the inguinal folds (Figure 2A), inframammary folds (Figure 2B), and on the nasal tip, as well as Grade 2 paronychia. The patient was managed with hydrocortisone cream 1% twice daily, and osimertinib was continued. At follow-up 4 weeks later, the erythema had faded to hyperpigmentation in affected areas with resolution of symptoms. No further treatment was required.

CT111001018_Fig2_AB.jpg

Comment

Supportive oncodermatologists and dermatology hospitalists should be aware of SDRIFE as an uncommon but increasingly recognized cutaneous AE of EGFR inhibitors. Other cases of SDRIFE secondary to EGFR inhibition are described in the Table.^2-5 Although SDRIFE typically is treated by discontinuation of the offending agent, in all reported cases of EGFR inhibitor–associated SDRIFE the rash was CTCAE Grade 2, meaning that it did not interfere with instrumental activities of daily living. In 5 of 6 cases, EGFR therapy was continued while skin-directed therapies were used for symptom management.

CT111001018_Table.jpg

Presentation of SDRIFE—Symmetrical drug-related intertriginous and flexural exanthema is characterized by a symmetric, sharply demarcated erythema in the inguinal, gluteal, or perianal area with at least 1 other flexural localization involved in the absence of systemic signs. It is observed most frequently at initial exposure or re-exposure to a medication. Onset typically is within a few hours to a few days after exposure to a medication.⁶ Interestingly, in this case series, half of reported SDRIFE cases developed 8 months or more after EGFR inhibitor initiation.

Pathophysiology of SDRIFE—The mechanism of SDRIFE has not been clearly elucidated; it generally is accepted to be a delayed-type hypersensitivity drug reaction, though other proposed pathophysiologic mechanisms for the distribution of SDRIFE include recall phenomenon or predisposing anatomic factors such as temperature, humidity, and apocrine or eccrine gland density.^6,7 Epidermal growth factor receptor plays a critical role in regulating differentiation and proliferation of epidermal keratinocytes, hair follicles, and the sweat gland apparatus. Additionally, it has been hypothesized that EGFR inhibitor use may affect the microflora of the skin and that EGFR inhibitors directly affect the immune system, as demonstrated in an experiment showing EGFR inhibitor–treated mice had enhanced skin inflammation and contact hypersensitivity responses.⁸ How these disparate mechanisms may interact to produce SDRIFE and the reason for the notably delayed presentation of SDRIFE in half of the cases we reviewed is not known. Other delayed cutaneous AEs of EGFR inhibitor therapy, such as paronychia, are thought to be secondary to development of skin fragility and decreased keratinocyte proliferation with secondary infection.¹ It is conceivable that a combination of proliferative, immunologic, and microbiome-related factors may each be playing a role in EGFR inhibitor–related SDRIFE.

Dermatology Inpatient Considerations—As seen in our cases, dermatologists can play a valuable role in diagnosing, grading, and managing cutaneous AEs associated with the administration of oncologic therapies. The array of cutaneous AEs has grown as cancer treatment options have expanded from conventional antimetabolite agents to kinase inhibitors and immune checkpoint inhibitors. Dermatologists may play an important role in differentiating the etiology of a skin finding (eg, infectious vs inflammatory) and can identify serious or dose-limiting reactions, such as Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS). If cutaneous AEs appear to occur secondary to administration of a chemotherapeutic agent, use of the National Cancer Institute CTCAE should be employed. For certain AEs (eg, alopecia, acneiform rashes, bullous dermatitis), specific grading has been developed based on a combination of body surface area involved, psychosocial impact, symptoms, and other associated morbidity.⁹

In management of chemotherapy-associated cutaneous AEs, dermatologists are likely to be the members of the health care team most comfortable with prescribing high-potency anti-inflammatory topical medications. Dermatologic consultation for management of cutaneous AEs has been shown to both reduce the need for systemic immunosuppression and limit interruptions in oncologic treatment.¹⁰

Conclusion

Epidermal growth factor receptor inhibitors commonly are prescribed for colorectal cancer, non–small cell lung cancer, and squamous cell carcinoma of the head and neck. They are associated with a variety of cutaneous AEs, including acneiform eruptions, paronychia, and xerosis, which rarely necessitate stopping EGFR inhibitor therapy. Our cases support an approach to managing EGFR inhibitor–related SDRIFE that does not involve discontinuation of the offending agent. Further studies are needed on the best supportive topical and systemic regimens for EGFR inhibitor–associated SDRIFE.

Epidermal growth factor receptor (EGFR) inhibitors cause numerous cutaneous adverse events (AEs), including papulopustular eruptions, paronychia, acral fissures, xerosis, alopecia, and trichomegaly.¹ Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is an uncommon type IV hypersensitivity reaction reported most commonly in association with β-lactam antibiotics and other medications.² Treatment of SDRIFE generally involves withdrawing the inciting medication; however, in SDRIFE secondary to oncologic therapies, medication withdrawal may not be feasible or desirable. We present 2 cases of SDRIFE secondary to EGFR inhibitors in which treatment was continued alongside supportive skin-directed therapies. We also review the literature.

Case Reports

Patient 1—A 65-year-old man with stage IV non–small cell lung cancer presented to the dermatology clinic with an eruption of 2 months’ duration that began in the periumbilical area and spread to the perianal area within 2 weeks of starting treatment with lazertinib and amivantamab. Physical examination was notable for Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 periumbilical erythema and erosions as well as symmetric red-brown patches with linear erosions in the gluteal cleft (Figure 1) and Grade 2 facial papulopustular rash. Herpes simplex virus polymerase chain reaction and bacterial culture were negative. A skin biopsy from the left buttock revealed dermal edema and a perivascular lymphocytic infiltrate compatible with SDRIFE. Triamcinolone ointment 0.1% twice daily was initiated, then uptitrated to betamethasone ointment 0.05% twice daily with moderate improvement. The patient had a treatment interruption due to malignancy complications, at which time his skin improved, with recurrence of the eruption after treatment re-initiation. He resumed skin-directed treatment and was maintained on betamethasone ointment 0.05% and tacrolimus ointment 0.1% twice daily on alternating days. This treatment was continued for 4 months before the patient died from complications of the malignancy.

Lewis_1.jpg

Patient 2—A 68-year-old woman with stage IV lung adenocarcinoma presented to the dermatology clinic with a rash of 3 weeks’ duration. Treatment with osimertinib was initiated 8 months prior to presentation, and there were no recent medication changes. Physical examination revealed CTCAE Grade 2 erythematous patches in the inguinal folds (Figure 2A), inframammary folds (Figure 2B), and on the nasal tip, as well as Grade 2 paronychia. The patient was managed with hydrocortisone cream 1% twice daily, and osimertinib was continued. At follow-up 4 weeks later, the erythema had faded to hyperpigmentation in affected areas with resolution of symptoms. No further treatment was required.

CT111001018_Fig2_AB.jpg

Comment

Supportive oncodermatologists and dermatology hospitalists should be aware of SDRIFE as an uncommon but increasingly recognized cutaneous AE of EGFR inhibitors. Other cases of SDRIFE secondary to EGFR inhibition are described in the Table.^2-5 Although SDRIFE typically is treated by discontinuation of the offending agent, in all reported cases of EGFR inhibitor–associated SDRIFE the rash was CTCAE Grade 2, meaning that it did not interfere with instrumental activities of daily living. In 5 of 6 cases, EGFR therapy was continued while skin-directed therapies were used for symptom management.

CT111001018_Table.jpg

Presentation of SDRIFE—Symmetrical drug-related intertriginous and flexural exanthema is characterized by a symmetric, sharply demarcated erythema in the inguinal, gluteal, or perianal area with at least 1 other flexural localization involved in the absence of systemic signs. It is observed most frequently at initial exposure or re-exposure to a medication. Onset typically is within a few hours to a few days after exposure to a medication.⁶ Interestingly, in this case series, half of reported SDRIFE cases developed 8 months or more after EGFR inhibitor initiation.

Pathophysiology of SDRIFE—The mechanism of SDRIFE has not been clearly elucidated; it generally is accepted to be a delayed-type hypersensitivity drug reaction, though other proposed pathophysiologic mechanisms for the distribution of SDRIFE include recall phenomenon or predisposing anatomic factors such as temperature, humidity, and apocrine or eccrine gland density.^6,7 Epidermal growth factor receptor plays a critical role in regulating differentiation and proliferation of epidermal keratinocytes, hair follicles, and the sweat gland apparatus. Additionally, it has been hypothesized that EGFR inhibitor use may affect the microflora of the skin and that EGFR inhibitors directly affect the immune system, as demonstrated in an experiment showing EGFR inhibitor–treated mice had enhanced skin inflammation and contact hypersensitivity responses.⁸ How these disparate mechanisms may interact to produce SDRIFE and the reason for the notably delayed presentation of SDRIFE in half of the cases we reviewed is not known. Other delayed cutaneous AEs of EGFR inhibitor therapy, such as paronychia, are thought to be secondary to development of skin fragility and decreased keratinocyte proliferation with secondary infection.¹ It is conceivable that a combination of proliferative, immunologic, and microbiome-related factors may each be playing a role in EGFR inhibitor–related SDRIFE.

Dermatology Inpatient Considerations—As seen in our cases, dermatologists can play a valuable role in diagnosing, grading, and managing cutaneous AEs associated with the administration of oncologic therapies. The array of cutaneous AEs has grown as cancer treatment options have expanded from conventional antimetabolite agents to kinase inhibitors and immune checkpoint inhibitors. Dermatologists may play an important role in differentiating the etiology of a skin finding (eg, infectious vs inflammatory) and can identify serious or dose-limiting reactions, such as Stevens-Johnson syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS). If cutaneous AEs appear to occur secondary to administration of a chemotherapeutic agent, use of the National Cancer Institute CTCAE should be employed. For certain AEs (eg, alopecia, acneiform rashes, bullous dermatitis), specific grading has been developed based on a combination of body surface area involved, psychosocial impact, symptoms, and other associated morbidity.⁹

In management of chemotherapy-associated cutaneous AEs, dermatologists are likely to be the members of the health care team most comfortable with prescribing high-potency anti-inflammatory topical medications. Dermatologic consultation for management of cutaneous AEs has been shown to both reduce the need for systemic immunosuppression and limit interruptions in oncologic treatment.¹⁰

Conclusion

Epidermal growth factor receptor inhibitors commonly are prescribed for colorectal cancer, non–small cell lung cancer, and squamous cell carcinoma of the head and neck. They are associated with a variety of cutaneous AEs, including acneiform eruptions, paronychia, and xerosis, which rarely necessitate stopping EGFR inhibitor therapy. Our cases support an approach to managing EGFR inhibitor–related SDRIFE that does not involve discontinuation of the offending agent. Further studies are needed on the best supportive topical and systemic regimens for EGFR inhibitor–associated SDRIFE.

Cellulitis is an infection of the skin and skin-associated structures characterized by redness, warmth, swelling, and pain of the affected area. Cellulitis most commonly occurs in middle-aged and older adults and frequently affects the lower extremities.¹ Serious complications of cellulitis such as bacteremia, metastatic infection, and sepsis are rare, and most cases of cellulitis in patients with normal vital signs and mental status can be managed with outpatient treatment.²

Diagnosis of cellulitis can be confounded by a number of similarly presenting conditions collectively known as pseudocellulitis, such as venous stasis dermatitis and deep vein thrombosis.¹ Misdiagnosis of cellulitis is common, with rates exceeding 30% among hospitalized patients initially diagnosed with cellulitis.^3,4 Dermatology or infectious disease assessment is considered the diagnostic gold standard for cellulitis^4,5 but is not always readily available, especially in resource-constrained settings.

Most cases of uncomplicated cellulitis can be managed with outpatient treatment, especially because serious complications are rare. Frequent misdiagnosis leads to repeat or unnecessary hospitalization and antibiosis. Exceptions necessitating hospitalization usually are predicated on signs of systemic infection, severe immunocompromised states, or failure of prior outpatient therapy.⁶ Such presentations can be distinguished by corresponding notable historical or examination factors, such as vital sign abnormalities suggesting systemic infection or history of malignancy leading to an immunocompromised state.

We sought to evaluate factors leading to the diagnosis of cellulitis in a cohort of patients with uncomplicated presentations receiving dermatology consultation to emphasize findings indicative of cellulitis in the absence of clinical or historical factors suggestive of other conditions necessitating hospitalization, such as systemic infection.

Methods

Study Participants—A prospective cohort study of patients presenting to an emergency department (ED) between October 2012 and January 2017 at an urban academic medical center in Boston, Massachusetts, was conducted with approval of study design and procedures by the relevant institutional review board. Patients older than 18 years were eligible for inclusion if given an initial diagnosis of cellulitis by an ED physician. Patients were excluded if incarcerated, pregnant, or unable to provide informed consent. Other exclusion criteria includedinfections overlying temporary or permanent indwelling hardware, animal or human bites, or sites of recent surgery (within the prior 4 weeks); preceding antibiotic treatment for more than 24 hours; or clinical or radiographic evidence of complications requiring alternative management such as osteomyelitis or abscess. Patients presenting with an elevated heart rate (>100 beats per minute) or body temperature (>100.5 °F [38.1 °C]) also were excluded. Eligible patients were enrolled upon providing written informed consent, and no remuneration was offered for participation.

Dermatology Consultation Intervention—A random subset of enrolled patients received dermatology consultation within 24 hours of presentation. Consultation consisted of a patient interview and physical examination with care recommendations to relevant ED and inpatient teams. Consultations confirmed the presence or absence of cellulitis as the primary outcome and also noted the presence of any pseudocellulitis diagnoses either occurring concomitantly with or mimicking cellulitis as a secondary outcome.

Statistical Analysis—Patient characteristics were analyzed to identify factors independently associated with the diagnosis of cellulitis in cases affecting the lower extremities. Factors were recorded with categorical variables reported as counts and percentages and continuous variables as means and standard deviations. Univariate analyses between categorical variables or discretized continuous variables and cellulitis diagnosis were conducted via Fisher exact test to identify a preliminary set of potential risk factors. Continuous variables were discretized at multiple incremental values with the discretization most significantly associated with cellulitis diagnosis selected as a preliminary risk factor. Multivariate analyses involved using any objective preliminary factor meeting a significance threshold of P<.1 in univariate comparisons in a multivariate logistic regression model for prediction of cellulitis diagnosis with corresponding calculation of odds ratios with confidence intervals and receiver operating characteristic. Factors with confidence intervals that excluded 1 were considered significant independent predictors of cellulitis. Analyses were performed using Python version 3.8 (Python Software Foundation).

Of 1359 patients screened for eligibility, 104 patients with presumed lower extremity cellulitis undergoing dermatology consultation were included in this study (Figure). The mean patient age (SD) was 60.4 (19.2) years, and 63.5% of patients were male. In the study population, 63 (60.6%) patients received a final diagnosis of cellulitis. The most common pseudocellulitis diagnosis identified was venous stasis dermatitis, which occurred in 12 (11.5%) patients with concomitant cellulitis and in 12 (11.5%) patients mimicking cellulitis (Table).

Chand_figure.jpg

Univariate comparisons revealed a diverse set of historical, examination, and laboratory factors associated with cellulitis diagnosis. Diagnosis of cellulitis was associated with unilateral presentation, recent trauma to the affected site, and history of cellulitis or onychomycosis. Diagnosis of cellulitis also was associated with elevated white blood cell count, absolute neutrophil count, C-reactive protein, body mass index, hematocrit, and platelet count; age less than 75 years; and lower serum sodium and serum chloride levels. These were the independent factors included in the multivariate analysis, which consisted of a logistic regression model for prediction of cellulitis (eTable).

CT110003122_Table.jpg

Multivariate logistic regression on all preliminary factors significantly associated with cellulitis diagnosis in univariate comparisons demonstrated leukocytosis, which was defined as having a white blood cell count exceeding 11,000/μL, unilateral presentation, history of onychomycosis, and trauma to the affected site as significant independent predictors of cellulitis diagnosis; history of cellulitis approached significance (eTable). Unilateral presentation and leukocytosis were the strongest predictors; having either of these factors had a sensitivity of 93.7% and a negative predictive value of 76.5%.

CT110003122_eTable.jpg

Comment

Importance of Identifying Pseudocellulitis—Successful diagnosis of cellulitis can be confounded by pseudocellulitis that can present concomitantly with or in lieu of cellulitis itself. Although cellulitis mostly affects the lower extremities in adults, pseudocellulitis also was common in this study population of patients with suspected lower extremity cellulitis, occurring both as a mimicker and concomitantly with cellulitis with substantial frequency. Notably, among patients with both venous stasis dermatitis and cellulitis diagnosed, most patients (n=10/12; 83.3%) had unilateral presentations of cellulitis as evidenced by signs and symptoms more notably affecting one lower extremity than the other. These findings suggest that certain pseudocellulitis diagnoses may predispose patients to cellulitis by disrupting the skin barrier, leading to bacterial infiltration; however, these pseudocellulitis diagnoses typically affect both lower extremities equally,¹ and asymmetric involvement suggests the presence of overlying cellulitis. Furthermore, the most common pseudocellulitis entities found, such as venous stasis dermatitis, hematoma, and eczema, do not benefit from antibiotic treatment and require alternative therapy.¹ Successful discrimination of these pseudocellulitis entities is critical to bolster proper antibiotic stewardship and discourage unnecessary hospitalization.

Independent Predictors of Cellulitis—Unilateral presentation and leukocytosis each emerged as strong independent predictors of cellulitis diagnosis in this study. Having either of these factors furthermore demonstrated high sensitivity and negative predictive value for cellulitis diagnosis. Other notable risk factors were history of onychomycosis, cellulitis, and trauma to the affected site. Prior studies have identified similar historical factors as predisposing patients to cellulitis.^7-9 Interestingly, warmth of the affected area on physical examination emerged as strongly associated with cellulitis but was not included in the final predictive model because of its subjective determination. These factors may be especially important in diagnosing cellulitis in patients without concerning vital signs and with concomitant or prior pseudocellulitis.

Study Limitations—This study was limited to patients with uncomplicated presentations to emphasize discrimination of factors associated with cellulitis in the absence of suggestive signs of infection, such as vital sign abnormalities. Signs such as fever and tachypnea have been previously correlated to outpatient treatment failure and necessity for hospitalization.^10-12 This study instead focused on patients without concerning vital signs to reduce confounding by such factors in more severe presentations that heighten suspicion for infection and increase likelihood of additional treatment measures. For such patients, suggestive historical factors, such as those discovered in this study, should be considered instead. Interestingly, increased age did not emerge as a significant predictor in this population in contrast to other predictive models that included patients with vital sign abnormalities. Notably, older patients tend to have more variable vital signs, especially in response to physiologic stressors such as infection.¹³ As such, age may serve as a proxy for vital sign abnormalities to some degree in such predictive models, leading to heightened suspicion for infection in older patients. This study demonstrated that in the absence of concerning vital signs, historical rather than demographic factors are more predictive of cellulitis.

Conclusion

Unilateral presentation and leukocytosis emerged as strong independent predictors of lower extremity cellulitis in patients with uncomplicated presentations. Having either of these factors had a sensitivity of 93.7% and a negative predictive value of 76.5%. Other factors such as history of cellulitis, onychomycosis, and recent trauma to the affected site emerged as additional predictors. These historical, examination, and laboratory characteristics may be especially useful for successful diagnosis of cellulitis in varied practice settings, including outpatient clinics and EDs.

Cellulitis is an infection of the skin and skin-associated structures characterized by redness, warmth, swelling, and pain of the affected area. Cellulitis most commonly occurs in middle-aged and older adults and frequently affects the lower extremities.¹ Serious complications of cellulitis such as bacteremia, metastatic infection, and sepsis are rare, and most cases of cellulitis in patients with normal vital signs and mental status can be managed with outpatient treatment.²

Diagnosis of cellulitis can be confounded by a number of similarly presenting conditions collectively known as pseudocellulitis, such as venous stasis dermatitis and deep vein thrombosis.¹ Misdiagnosis of cellulitis is common, with rates exceeding 30% among hospitalized patients initially diagnosed with cellulitis.^3,4 Dermatology or infectious disease assessment is considered the diagnostic gold standard for cellulitis^4,5 but is not always readily available, especially in resource-constrained settings.

Most cases of uncomplicated cellulitis can be managed with outpatient treatment, especially because serious complications are rare. Frequent misdiagnosis leads to repeat or unnecessary hospitalization and antibiosis. Exceptions necessitating hospitalization usually are predicated on signs of systemic infection, severe immunocompromised states, or failure of prior outpatient therapy.⁶ Such presentations can be distinguished by corresponding notable historical or examination factors, such as vital sign abnormalities suggesting systemic infection or history of malignancy leading to an immunocompromised state.

We sought to evaluate factors leading to the diagnosis of cellulitis in a cohort of patients with uncomplicated presentations receiving dermatology consultation to emphasize findings indicative of cellulitis in the absence of clinical or historical factors suggestive of other conditions necessitating hospitalization, such as systemic infection.

Methods

Study Participants—A prospective cohort study of patients presenting to an emergency department (ED) between October 2012 and January 2017 at an urban academic medical center in Boston, Massachusetts, was conducted with approval of study design and procedures by the relevant institutional review board. Patients older than 18 years were eligible for inclusion if given an initial diagnosis of cellulitis by an ED physician. Patients were excluded if incarcerated, pregnant, or unable to provide informed consent. Other exclusion criteria includedinfections overlying temporary or permanent indwelling hardware, animal or human bites, or sites of recent surgery (within the prior 4 weeks); preceding antibiotic treatment for more than 24 hours; or clinical or radiographic evidence of complications requiring alternative management such as osteomyelitis or abscess. Patients presenting with an elevated heart rate (>100 beats per minute) or body temperature (>100.5 °F [38.1 °C]) also were excluded. Eligible patients were enrolled upon providing written informed consent, and no remuneration was offered for participation.

Dermatology Consultation Intervention—A random subset of enrolled patients received dermatology consultation within 24 hours of presentation. Consultation consisted of a patient interview and physical examination with care recommendations to relevant ED and inpatient teams. Consultations confirmed the presence or absence of cellulitis as the primary outcome and also noted the presence of any pseudocellulitis diagnoses either occurring concomitantly with or mimicking cellulitis as a secondary outcome.

Statistical Analysis—Patient characteristics were analyzed to identify factors independently associated with the diagnosis of cellulitis in cases affecting the lower extremities. Factors were recorded with categorical variables reported as counts and percentages and continuous variables as means and standard deviations. Univariate analyses between categorical variables or discretized continuous variables and cellulitis diagnosis were conducted via Fisher exact test to identify a preliminary set of potential risk factors. Continuous variables were discretized at multiple incremental values with the discretization most significantly associated with cellulitis diagnosis selected as a preliminary risk factor. Multivariate analyses involved using any objective preliminary factor meeting a significance threshold of P<.1 in univariate comparisons in a multivariate logistic regression model for prediction of cellulitis diagnosis with corresponding calculation of odds ratios with confidence intervals and receiver operating characteristic. Factors with confidence intervals that excluded 1 were considered significant independent predictors of cellulitis. Analyses were performed using Python version 3.8 (Python Software Foundation).

Of 1359 patients screened for eligibility, 104 patients with presumed lower extremity cellulitis undergoing dermatology consultation were included in this study (Figure). The mean patient age (SD) was 60.4 (19.2) years, and 63.5% of patients were male. In the study population, 63 (60.6%) patients received a final diagnosis of cellulitis. The most common pseudocellulitis diagnosis identified was venous stasis dermatitis, which occurred in 12 (11.5%) patients with concomitant cellulitis and in 12 (11.5%) patients mimicking cellulitis (Table).

Chand_figure.jpg

Univariate comparisons revealed a diverse set of historical, examination, and laboratory factors associated with cellulitis diagnosis. Diagnosis of cellulitis was associated with unilateral presentation, recent trauma to the affected site, and history of cellulitis or onychomycosis. Diagnosis of cellulitis also was associated with elevated white blood cell count, absolute neutrophil count, C-reactive protein, body mass index, hematocrit, and platelet count; age less than 75 years; and lower serum sodium and serum chloride levels. These were the independent factors included in the multivariate analysis, which consisted of a logistic regression model for prediction of cellulitis (eTable).

CT110003122_Table.jpg

Multivariate logistic regression on all preliminary factors significantly associated with cellulitis diagnosis in univariate comparisons demonstrated leukocytosis, which was defined as having a white blood cell count exceeding 11,000/μL, unilateral presentation, history of onychomycosis, and trauma to the affected site as significant independent predictors of cellulitis diagnosis; history of cellulitis approached significance (eTable). Unilateral presentation and leukocytosis were the strongest predictors; having either of these factors had a sensitivity of 93.7% and a negative predictive value of 76.5%.

CT110003122_eTable.jpg

Comment

Importance of Identifying Pseudocellulitis—Successful diagnosis of cellulitis can be confounded by pseudocellulitis that can present concomitantly with or in lieu of cellulitis itself. Although cellulitis mostly affects the lower extremities in adults, pseudocellulitis also was common in this study population of patients with suspected lower extremity cellulitis, occurring both as a mimicker and concomitantly with cellulitis with substantial frequency. Notably, among patients with both venous stasis dermatitis and cellulitis diagnosed, most patients (n=10/12; 83.3%) had unilateral presentations of cellulitis as evidenced by signs and symptoms more notably affecting one lower extremity than the other. These findings suggest that certain pseudocellulitis diagnoses may predispose patients to cellulitis by disrupting the skin barrier, leading to bacterial infiltration; however, these pseudocellulitis diagnoses typically affect both lower extremities equally,¹ and asymmetric involvement suggests the presence of overlying cellulitis. Furthermore, the most common pseudocellulitis entities found, such as venous stasis dermatitis, hematoma, and eczema, do not benefit from antibiotic treatment and require alternative therapy.¹ Successful discrimination of these pseudocellulitis entities is critical to bolster proper antibiotic stewardship and discourage unnecessary hospitalization.

Independent Predictors of Cellulitis—Unilateral presentation and leukocytosis each emerged as strong independent predictors of cellulitis diagnosis in this study. Having either of these factors furthermore demonstrated high sensitivity and negative predictive value for cellulitis diagnosis. Other notable risk factors were history of onychomycosis, cellulitis, and trauma to the affected site. Prior studies have identified similar historical factors as predisposing patients to cellulitis.^7-9 Interestingly, warmth of the affected area on physical examination emerged as strongly associated with cellulitis but was not included in the final predictive model because of its subjective determination. These factors may be especially important in diagnosing cellulitis in patients without concerning vital signs and with concomitant or prior pseudocellulitis.

Study Limitations—This study was limited to patients with uncomplicated presentations to emphasize discrimination of factors associated with cellulitis in the absence of suggestive signs of infection, such as vital sign abnormalities. Signs such as fever and tachypnea have been previously correlated to outpatient treatment failure and necessity for hospitalization.^10-12 This study instead focused on patients without concerning vital signs to reduce confounding by such factors in more severe presentations that heighten suspicion for infection and increase likelihood of additional treatment measures. For such patients, suggestive historical factors, such as those discovered in this study, should be considered instead. Interestingly, increased age did not emerge as a significant predictor in this population in contrast to other predictive models that included patients with vital sign abnormalities. Notably, older patients tend to have more variable vital signs, especially in response to physiologic stressors such as infection.¹³ As such, age may serve as a proxy for vital sign abnormalities to some degree in such predictive models, leading to heightened suspicion for infection in older patients. This study demonstrated that in the absence of concerning vital signs, historical rather than demographic factors are more predictive of cellulitis.

Conclusion

Unilateral presentation and leukocytosis emerged as strong independent predictors of lower extremity cellulitis in patients with uncomplicated presentations. Having either of these factors had a sensitivity of 93.7% and a negative predictive value of 76.5%. Other factors such as history of cellulitis, onychomycosis, and recent trauma to the affected site emerged as additional predictors. These historical, examination, and laboratory characteristics may be especially useful for successful diagnosis of cellulitis in varied practice settings, including outpatient clinics and EDs.

Cellulitis is an infection of the skin and skin-associated structures characterized by redness, warmth, swelling, and pain of the affected area. Cellulitis most commonly occurs in middle-aged and older adults and frequently affects the lower extremities.¹ Serious complications of cellulitis such as bacteremia, metastatic infection, and sepsis are rare, and most cases of cellulitis in patients with normal vital signs and mental status can be managed with outpatient treatment.²

Diagnosis of cellulitis can be confounded by a number of similarly presenting conditions collectively known as pseudocellulitis, such as venous stasis dermatitis and deep vein thrombosis.¹ Misdiagnosis of cellulitis is common, with rates exceeding 30% among hospitalized patients initially diagnosed with cellulitis.^3,4 Dermatology or infectious disease assessment is considered the diagnostic gold standard for cellulitis^4,5 but is not always readily available, especially in resource-constrained settings.

Most cases of uncomplicated cellulitis can be managed with outpatient treatment, especially because serious complications are rare. Frequent misdiagnosis leads to repeat or unnecessary hospitalization and antibiosis. Exceptions necessitating hospitalization usually are predicated on signs of systemic infection, severe immunocompromised states, or failure of prior outpatient therapy.⁶ Such presentations can be distinguished by corresponding notable historical or examination factors, such as vital sign abnormalities suggesting systemic infection or history of malignancy leading to an immunocompromised state.

We sought to evaluate factors leading to the diagnosis of cellulitis in a cohort of patients with uncomplicated presentations receiving dermatology consultation to emphasize findings indicative of cellulitis in the absence of clinical or historical factors suggestive of other conditions necessitating hospitalization, such as systemic infection.

Methods

Study Participants—A prospective cohort study of patients presenting to an emergency department (ED) between October 2012 and January 2017 at an urban academic medical center in Boston, Massachusetts, was conducted with approval of study design and procedures by the relevant institutional review board. Patients older than 18 years were eligible for inclusion if given an initial diagnosis of cellulitis by an ED physician. Patients were excluded if incarcerated, pregnant, or unable to provide informed consent. Other exclusion criteria includedinfections overlying temporary or permanent indwelling hardware, animal or human bites, or sites of recent surgery (within the prior 4 weeks); preceding antibiotic treatment for more than 24 hours; or clinical or radiographic evidence of complications requiring alternative management such as osteomyelitis or abscess. Patients presenting with an elevated heart rate (>100 beats per minute) or body temperature (>100.5 °F [38.1 °C]) also were excluded. Eligible patients were enrolled upon providing written informed consent, and no remuneration was offered for participation.

Dermatology Consultation Intervention—A random subset of enrolled patients received dermatology consultation within 24 hours of presentation. Consultation consisted of a patient interview and physical examination with care recommendations to relevant ED and inpatient teams. Consultations confirmed the presence or absence of cellulitis as the primary outcome and also noted the presence of any pseudocellulitis diagnoses either occurring concomitantly with or mimicking cellulitis as a secondary outcome.

Statistical Analysis—Patient characteristics were analyzed to identify factors independently associated with the diagnosis of cellulitis in cases affecting the lower extremities. Factors were recorded with categorical variables reported as counts and percentages and continuous variables as means and standard deviations. Univariate analyses between categorical variables or discretized continuous variables and cellulitis diagnosis were conducted via Fisher exact test to identify a preliminary set of potential risk factors. Continuous variables were discretized at multiple incremental values with the discretization most significantly associated with cellulitis diagnosis selected as a preliminary risk factor. Multivariate analyses involved using any objective preliminary factor meeting a significance threshold of P<.1 in univariate comparisons in a multivariate logistic regression model for prediction of cellulitis diagnosis with corresponding calculation of odds ratios with confidence intervals and receiver operating characteristic. Factors with confidence intervals that excluded 1 were considered significant independent predictors of cellulitis. Analyses were performed using Python version 3.8 (Python Software Foundation).

Of 1359 patients screened for eligibility, 104 patients with presumed lower extremity cellulitis undergoing dermatology consultation were included in this study (Figure). The mean patient age (SD) was 60.4 (19.2) years, and 63.5% of patients were male. In the study population, 63 (60.6%) patients received a final diagnosis of cellulitis. The most common pseudocellulitis diagnosis identified was venous stasis dermatitis, which occurred in 12 (11.5%) patients with concomitant cellulitis and in 12 (11.5%) patients mimicking cellulitis (Table).

Chand_figure.jpg

Univariate comparisons revealed a diverse set of historical, examination, and laboratory factors associated with cellulitis diagnosis. Diagnosis of cellulitis was associated with unilateral presentation, recent trauma to the affected site, and history of cellulitis or onychomycosis. Diagnosis of cellulitis also was associated with elevated white blood cell count, absolute neutrophil count, C-reactive protein, body mass index, hematocrit, and platelet count; age less than 75 years; and lower serum sodium and serum chloride levels. These were the independent factors included in the multivariate analysis, which consisted of a logistic regression model for prediction of cellulitis (eTable).

CT110003122_Table.jpg

Multivariate logistic regression on all preliminary factors significantly associated with cellulitis diagnosis in univariate comparisons demonstrated leukocytosis, which was defined as having a white blood cell count exceeding 11,000/μL, unilateral presentation, history of onychomycosis, and trauma to the affected site as significant independent predictors of cellulitis diagnosis; history of cellulitis approached significance (eTable). Unilateral presentation and leukocytosis were the strongest predictors; having either of these factors had a sensitivity of 93.7% and a negative predictive value of 76.5%.

CT110003122_eTable.jpg

Comment

Importance of Identifying Pseudocellulitis—Successful diagnosis of cellulitis can be confounded by pseudocellulitis that can present concomitantly with or in lieu of cellulitis itself. Although cellulitis mostly affects the lower extremities in adults, pseudocellulitis also was common in this study population of patients with suspected lower extremity cellulitis, occurring both as a mimicker and concomitantly with cellulitis with substantial frequency. Notably, among patients with both venous stasis dermatitis and cellulitis diagnosed, most patients (n=10/12; 83.3%) had unilateral presentations of cellulitis as evidenced by signs and symptoms more notably affecting one lower extremity than the other. These findings suggest that certain pseudocellulitis diagnoses may predispose patients to cellulitis by disrupting the skin barrier, leading to bacterial infiltration; however, these pseudocellulitis diagnoses typically affect both lower extremities equally,¹ and asymmetric involvement suggests the presence of overlying cellulitis. Furthermore, the most common pseudocellulitis entities found, such as venous stasis dermatitis, hematoma, and eczema, do not benefit from antibiotic treatment and require alternative therapy.¹ Successful discrimination of these pseudocellulitis entities is critical to bolster proper antibiotic stewardship and discourage unnecessary hospitalization.

Independent Predictors of Cellulitis—Unilateral presentation and leukocytosis each emerged as strong independent predictors of cellulitis diagnosis in this study. Having either of these factors furthermore demonstrated high sensitivity and negative predictive value for cellulitis diagnosis. Other notable risk factors were history of onychomycosis, cellulitis, and trauma to the affected site. Prior studies have identified similar historical factors as predisposing patients to cellulitis.^7-9 Interestingly, warmth of the affected area on physical examination emerged as strongly associated with cellulitis but was not included in the final predictive model because of its subjective determination. These factors may be especially important in diagnosing cellulitis in patients without concerning vital signs and with concomitant or prior pseudocellulitis.

Study Limitations—This study was limited to patients with uncomplicated presentations to emphasize discrimination of factors associated with cellulitis in the absence of suggestive signs of infection, such as vital sign abnormalities. Signs such as fever and tachypnea have been previously correlated to outpatient treatment failure and necessity for hospitalization.^10-12 This study instead focused on patients without concerning vital signs to reduce confounding by such factors in more severe presentations that heighten suspicion for infection and increase likelihood of additional treatment measures. For such patients, suggestive historical factors, such as those discovered in this study, should be considered instead. Interestingly, increased age did not emerge as a significant predictor in this population in contrast to other predictive models that included patients with vital sign abnormalities. Notably, older patients tend to have more variable vital signs, especially in response to physiologic stressors such as infection.¹³ As such, age may serve as a proxy for vital sign abnormalities to some degree in such predictive models, leading to heightened suspicion for infection in older patients. This study demonstrated that in the absence of concerning vital signs, historical rather than demographic factors are more predictive of cellulitis.

Conclusion

Unilateral presentation and leukocytosis emerged as strong independent predictors of lower extremity cellulitis in patients with uncomplicated presentations. Having either of these factors had a sensitivity of 93.7% and a negative predictive value of 76.5%. Other factors such as history of cellulitis, onychomycosis, and recent trauma to the affected site emerged as additional predictors. These historical, examination, and laboratory characteristics may be especially useful for successful diagnosis of cellulitis in varied practice settings, including outpatient clinics and EDs.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease that involves the skin. Cutaneous lupus erythematosus can be classified into various subtypes.¹ These include, but are not limited to, acute CLE, subacute CLE, chronic CLE, intermittent CLE, lupus tumidus, and lupus profundus.^1,2 The CLE subtypes have variable associations with systemic lupus erythematosus. For instance, some subtypes, such as acute CLE, are more strongly associated with systemic lupus erythematosus.

Treatment of CLE is similar to other autoimmune disorders. Although the US Food and Drug Administration (FDA) has not approved any treatments for CLE,^3,4 the most common therapeutic options are disease-modifying antirheumatic drugs. Unfortunately, many of these treatments carry teratogenic effects. Because CLE predominantly affects women, particularly those of childbearing age, it is imperative to understand the available treatment options for those who are pregnant or considering pregnancy for an informed discussion with patients.⁵

For years, the gold standard when considering a medication during pregnancy was the FDA’s classification system. According to this system, medications were classified into 5 letter categories based on their potential teratogenicity, including A (no fetal risk), B (potential animal risk but inconclusive human studies), C (risk cannot be ruled out), D (evidence of fetal risk), and X (contraindicated in pregnancy). In 2014, the FDA decided to no longer use this classification system for medications approved after 2000.⁶ However, because many proposed treatment options for CLE were approved prior to 2001, we have summarized the commonly prescribed medications for CLE according to their prior FDA letter categories.

Treatment Options for CLE During Pregnancy

Prior to initiating systemic medications for the treatment of CLE, topical medications should be considered. Recommended treatment options include corticosteroids and calcineurin inhibitors.⁷ Compared with systemic medications, topical treatments carry minimal side effects, such as skin atrophy, that typically remain localized to areas of application.⁸ Moreover, even with extensive application, no correlation has been found between topical corticosteroid use and fetal growth,⁹ which suggests that topical steroids are safe in pregnancy and should be considered as a first-line treatment option for CLE. Calcineurin inhibitors also are considered safe based on their low level of absorption through the skin and are considered second-line topical treatment options in pregnancy.¹⁰

Kirchner_1.JPG

Although topical medications are effective for the treatment of CLE, many patients require the administration of systemic therapeutics for severe or refractory disease. Based on previously published reports, Figure 1 describes the current recommended systemic treatment options for CLE.¹¹ Unfortunately, many of these medications carry teratogenic risks during pregnancy. The risks and side effects of the medications are described in detail in the following sections and summarized in the eTable.

CT109002090_eTable.JPG

Category B

Systemic Steroids—Systemic steroids are one of the most prescribed medications during pregnancy.¹² Oral steroids have been associated with fast symptom relief, making this class of medications particularly effective during CLE flares; however, long-term management is not recommended because of the side effects, which include osteoporosis and impaired glucose metabolism.¹³

With low transmission across the placenta, there are 3 glucocorticoids that carry the safest profile in pregnancy: prednisone, cortisone, and hydrocortisone.¹⁴ Dexamethasone and betamethasone should be avoided, as both readily cross the placenta and increase fetal exposure.¹⁵ Although teratogenic effects have been associated with steroid use, most studies involving pregnant patients have inconclusive results. For instance, one study described an association between cleft lip/palate with in utero glucocorticoid exposure.¹⁶ However, multiple follow-up studies found no association between the two.^17,18 Studies investigating the relationship between steroids and miscarriages or steroids and low birth weight also are inconclusive. Of note, if used throughout pregnancy, administration of a loading dose of glucocorticoids prior to delivery is recommended because of the increased stress brought on during labor.¹⁹

Sulfasalazine—Sulfasalazine is an immunomodulator commonly used for the treatment of inflammatory bowel disease and rheumatoid arthritis. However, studies also have shown that sulfasalazine is an effective treatment of CLE if standard treatments have failed.^20,21

During pregnancy, patients exposed to sulfasalazine experienced minimal side effects despite transportation across the placenta.²² In comparison with control, pregnant women taking sulfasalazine experienced no increased risk for low fetal weight,²³ congenital abnormalities,²⁴ or spontaneous abortions.²⁵ Of note, sulfasalazine can affect sperm, so male patients also should be counselled.

Category C

Hydroxychloroquine—Hydroxychloroquine is considered a first-line medication for those with CLE based on a symptomatic relief rate of 50% to 70%.²⁶ For those taking hydroxychloroquine during pregnancy, the majority of studies have shown no association between the medication and adverse fetal events, including congenital abnormalities, prematurity, or spontaneous abortions.^27-29 Therefore, hydroxychloroquine is considered safe in pregnancy, and those on the medication should continue standard monitoring, including retinopathy screening.³⁰

Of note, hydroxychloroquine can be stored in tissue for weeks to months after discontinuation.⁵ Therefore, if patients wish to avoid hydroxychloroquine in pregnancy, one should stop taking the medication several months prior to conception.

Dapsone—Dapsone, a medication with both antimicrobial and immunomodulatory properties, is an effective second-line therapy for CLE.³¹ Although large-scale human trials have not been performed, multiple case reports and observational studies have supported the safe use of dapsone in pregnancy.^32-34 However, there are notable side effects, including dose-dependent hemolysis, methemoglobinemia, and hypersensitivity reactions.¹³ Therefore, once treatment is initiated or continued, folic acid supplementation (5 mg daily) and regular serum analysis, including complete blood cell counts, are recommended in pregnant patients.¹⁹

Rituximab—Recent studies have demonstrated that rituximab can be an effective treatment of subacute and chronic CLE.^35,36 Through inhibition of CD20, rituximab causes a decrease in circulating B cells and a reduced immune response. Therefore, experts recommend discontinuation of rituximab for 12 months prior to conception to reduce potential side effects to the fetus, which may include a transient reduction of circulating fetal B cells.³⁷

If continued during pregnancy, most studies suggest discontinuation of rituximab during the third trimester, as it has been associated with neonatal infections and congenital abnormalities.^19,37 However, these results are based on limited case reports, and thus robust research is needed to better understand the effect of rituximab in utero.

Intravenous Immunoglobulin Infusion—Intravenous immunoglobulin (IVIG) infusion is a well-tolerated treatment for many autoimmune disorders.³⁸ Although not first line, limited case studies have demonstrated remission of refractory CLE following IVIG.^39,40 Although no studies have directly investigated the effect of IVIG on fetal development, it has been frequently administered and well tolerated during pregnancy, especially in those with multiple sclerosis or antiphospholipid syndrome.⁴¹ Commonly reported side effects include headache and fatigue, and a rare associated side effect to be aware of is embolic events.^42,43

Cyclosporine—Cyclosporine rarely is used in the treatment of localized CLE due to its extensive side-effect profile, most notably nephrotoxicity.⁴⁴ However, studies have shown that cyclosporine may be efficacious if symptoms extend beyond the skin, involve multiple organs, and/or other treatments have failed.³⁹ For those who are pregnant and wish to continue cyclosporine use, studies have associated low birth weight and premature delivery with its exposure in utero.⁴⁴

Category D

Mycophenolate Mofetil—In conjunction with standard therapy, mycophenolate mofetil (MMF) is an adequate treatment of refractory CLE.⁴⁵ Unfortunately, case reports have demonstrated an increased risk for fetal congenital abnormalities and first-trimester spontaneous abortion with use of MMF during pregnancy.^46,47 Therefore, it is recommended that patients on MMF discontinue the medication at least 6 weeks prior to conception.⁴⁶

Azathioprine—Although azathioprine has been shown to provide relief of discoid lupus erythematosus symptoms,⁴⁸ it currently is only utilized for refractory disease, largely due to notable side effects that particularly affect the gastrointestinal tract and liver.⁴ Moreover, azathioprine use during pregnancy has been associated with prematurity, congenital anomalies, fetal cytopenia, and low birth weight.⁴⁹ With that said, and although not recommended, if patients decide to continue treatment, experts recommend limiting the dose to 2 mg/kg daily to reduce potential adverse events.

Category X

Oral Retinoids—According to the American Academy of Dermatology, retinoids such as isotretinoin and acitretin are considered second-line therapy for CLE.⁵⁰ With that being said, there are well-documented effects on fetal development associated with oral retinoid use, including central nervous system, cardiovascular system, and craniofacial abnormalities.⁵¹ Therefore, its use is contraindicated during pregnancy. To prevent pregnancy while taking isotretinoin, patients must enroll in an online monitoring program called iPLEDGE. This program requires monthly updates by both the physician and the patient, including a negative pregnancy test every month for female patients actively taking the medication.⁵²

The half-lives of the oral retinoids isotretinoin and acitretin are 10 to 20 hours and 50 to 60 hours, respectively.^53,54 However, alcohol consumption converts acitretin into the metabolite etretinate, which can remain in tissue for up to 120 days.^54,55 Therefore, women are advised to avoid alcohol while taking acitretin and avoid conception for 2 to 3 years after cessation of the medication.⁵⁵ For those wishing to restart retinoids after pregnancy, studies show the medication can be safely reinstated 35 days after delivery for those interested in continued treatment.⁵⁶

Thalidomide—Although low-dose thalidomide can treat refractory CLE, its use is restricted because of its known teratogenicity, most notably limb deformities.⁵⁷ If prescribed thalidomide, women will need to enroll in the System for Thalidomide Education and Prescribing Safety program, similar to the iPLEDGE program, and use 2 forms of contraception when sexually active.⁵⁸ Contraception should be continued for 4 weeks following the last dose of thalidomide. After this point, conception is considered safe.⁵⁹

Methotrexate—For nonpregnant patients, low-dose methotrexate (MTX) with folate supplementation is a treatment option for CLE.⁶⁰ However, for those who are pregnant, low-dose MTX is an abortive agent and has been associated with aminopterin syndrome, which includes skull deficits, craniofacial abnormalities, and limb deformities in live births.^19,61 Therefore, MTX is not recommended in pregnancy. Of note, MTX can affect sperm; male patients also should be counselled.

Overall, it is recommended to limit medication use as much as possible in pregnancy. To reduce these exposures, it is imperative to reduce triggers that may lead to symptomatic flares of CLE. Because CLE can be triggered by sun exposure, we advise topical sunscreen to prevent CLE flares that may require additional oral medication.^62,63

Various medications are considered safe for the treatment of CLE in pregnant patients (Figure 2). Based on studies in animal and clinical trials, hydroxychloroquine is considered a safe and effective medication for CLE in pregnancy and is a first-line therapy in nonpregnant patients.^26,27 If flares occur, IVIG or a short course of oral steroids should be considered to manage symptoms.^13,39 For those with severe flares, treatment is difficult, and personalized approaches may be necessary.

Kirchner_2.JPG

Part of the question for the childbearing population is when a patient would like to conceive. For severe cases when hydroxychloroquine is not effective as monotherapy, using a treatment that can encourage remission prior to conception attempts can be a beneficial strategy. Rituximab is an excellent example of such a therapy, as the therapeutic effect outlasts the immunosuppressive effect and therefore is unlikely to affect a future fetus.⁶⁴ Thalidomide also is a potential option prior to conception, based on its short washout period and its ability to achieve notable remission rates in patients with CLE.^57,59 Regardless, patients with CLE should still consult their dermatologist and rheumatologist (if applicable) prior to conception.

Patients of childbearing potential represent a population in which discussion about life goals greatly affects medication options. Having these discussions early and often allows for an open, more successful approach so that treatment regimens are not derailed at the time of conception.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease that involves the skin. Cutaneous lupus erythematosus can be classified into various subtypes.¹ These include, but are not limited to, acute CLE, subacute CLE, chronic CLE, intermittent CLE, lupus tumidus, and lupus profundus.^1,2 The CLE subtypes have variable associations with systemic lupus erythematosus. For instance, some subtypes, such as acute CLE, are more strongly associated with systemic lupus erythematosus.

Treatment of CLE is similar to other autoimmune disorders. Although the US Food and Drug Administration (FDA) has not approved any treatments for CLE,^3,4 the most common therapeutic options are disease-modifying antirheumatic drugs. Unfortunately, many of these treatments carry teratogenic effects. Because CLE predominantly affects women, particularly those of childbearing age, it is imperative to understand the available treatment options for those who are pregnant or considering pregnancy for an informed discussion with patients.⁵

For years, the gold standard when considering a medication during pregnancy was the FDA’s classification system. According to this system, medications were classified into 5 letter categories based on their potential teratogenicity, including A (no fetal risk), B (potential animal risk but inconclusive human studies), C (risk cannot be ruled out), D (evidence of fetal risk), and X (contraindicated in pregnancy). In 2014, the FDA decided to no longer use this classification system for medications approved after 2000.⁶ However, because many proposed treatment options for CLE were approved prior to 2001, we have summarized the commonly prescribed medications for CLE according to their prior FDA letter categories.

Treatment Options for CLE During Pregnancy

Prior to initiating systemic medications for the treatment of CLE, topical medications should be considered. Recommended treatment options include corticosteroids and calcineurin inhibitors.⁷ Compared with systemic medications, topical treatments carry minimal side effects, such as skin atrophy, that typically remain localized to areas of application.⁸ Moreover, even with extensive application, no correlation has been found between topical corticosteroid use and fetal growth,⁹ which suggests that topical steroids are safe in pregnancy and should be considered as a first-line treatment option for CLE. Calcineurin inhibitors also are considered safe based on their low level of absorption through the skin and are considered second-line topical treatment options in pregnancy.¹⁰

Kirchner_1.JPG

Although topical medications are effective for the treatment of CLE, many patients require the administration of systemic therapeutics for severe or refractory disease. Based on previously published reports, Figure 1 describes the current recommended systemic treatment options for CLE.¹¹ Unfortunately, many of these medications carry teratogenic risks during pregnancy. The risks and side effects of the medications are described in detail in the following sections and summarized in the eTable.

CT109002090_eTable.JPG

Category B

Systemic Steroids—Systemic steroids are one of the most prescribed medications during pregnancy.¹² Oral steroids have been associated with fast symptom relief, making this class of medications particularly effective during CLE flares; however, long-term management is not recommended because of the side effects, which include osteoporosis and impaired glucose metabolism.¹³

With low transmission across the placenta, there are 3 glucocorticoids that carry the safest profile in pregnancy: prednisone, cortisone, and hydrocortisone.¹⁴ Dexamethasone and betamethasone should be avoided, as both readily cross the placenta and increase fetal exposure.¹⁵ Although teratogenic effects have been associated with steroid use, most studies involving pregnant patients have inconclusive results. For instance, one study described an association between cleft lip/palate with in utero glucocorticoid exposure.¹⁶ However, multiple follow-up studies found no association between the two.^17,18 Studies investigating the relationship between steroids and miscarriages or steroids and low birth weight also are inconclusive. Of note, if used throughout pregnancy, administration of a loading dose of glucocorticoids prior to delivery is recommended because of the increased stress brought on during labor.¹⁹

Sulfasalazine—Sulfasalazine is an immunomodulator commonly used for the treatment of inflammatory bowel disease and rheumatoid arthritis. However, studies also have shown that sulfasalazine is an effective treatment of CLE if standard treatments have failed.^20,21

During pregnancy, patients exposed to sulfasalazine experienced minimal side effects despite transportation across the placenta.²² In comparison with control, pregnant women taking sulfasalazine experienced no increased risk for low fetal weight,²³ congenital abnormalities,²⁴ or spontaneous abortions.²⁵ Of note, sulfasalazine can affect sperm, so male patients also should be counselled.

Category C

Hydroxychloroquine—Hydroxychloroquine is considered a first-line medication for those with CLE based on a symptomatic relief rate of 50% to 70%.²⁶ For those taking hydroxychloroquine during pregnancy, the majority of studies have shown no association between the medication and adverse fetal events, including congenital abnormalities, prematurity, or spontaneous abortions.^27-29 Therefore, hydroxychloroquine is considered safe in pregnancy, and those on the medication should continue standard monitoring, including retinopathy screening.³⁰

Of note, hydroxychloroquine can be stored in tissue for weeks to months after discontinuation.⁵ Therefore, if patients wish to avoid hydroxychloroquine in pregnancy, one should stop taking the medication several months prior to conception.

Dapsone—Dapsone, a medication with both antimicrobial and immunomodulatory properties, is an effective second-line therapy for CLE.³¹ Although large-scale human trials have not been performed, multiple case reports and observational studies have supported the safe use of dapsone in pregnancy.^32-34 However, there are notable side effects, including dose-dependent hemolysis, methemoglobinemia, and hypersensitivity reactions.¹³ Therefore, once treatment is initiated or continued, folic acid supplementation (5 mg daily) and regular serum analysis, including complete blood cell counts, are recommended in pregnant patients.¹⁹

Rituximab—Recent studies have demonstrated that rituximab can be an effective treatment of subacute and chronic CLE.^35,36 Through inhibition of CD20, rituximab causes a decrease in circulating B cells and a reduced immune response. Therefore, experts recommend discontinuation of rituximab for 12 months prior to conception to reduce potential side effects to the fetus, which may include a transient reduction of circulating fetal B cells.³⁷

If continued during pregnancy, most studies suggest discontinuation of rituximab during the third trimester, as it has been associated with neonatal infections and congenital abnormalities.^19,37 However, these results are based on limited case reports, and thus robust research is needed to better understand the effect of rituximab in utero.

Intravenous Immunoglobulin Infusion—Intravenous immunoglobulin (IVIG) infusion is a well-tolerated treatment for many autoimmune disorders.³⁸ Although not first line, limited case studies have demonstrated remission of refractory CLE following IVIG.^39,40 Although no studies have directly investigated the effect of IVIG on fetal development, it has been frequently administered and well tolerated during pregnancy, especially in those with multiple sclerosis or antiphospholipid syndrome.⁴¹ Commonly reported side effects include headache and fatigue, and a rare associated side effect to be aware of is embolic events.^42,43

Cyclosporine—Cyclosporine rarely is used in the treatment of localized CLE due to its extensive side-effect profile, most notably nephrotoxicity.⁴⁴ However, studies have shown that cyclosporine may be efficacious if symptoms extend beyond the skin, involve multiple organs, and/or other treatments have failed.³⁹ For those who are pregnant and wish to continue cyclosporine use, studies have associated low birth weight and premature delivery with its exposure in utero.⁴⁴

Category D

Mycophenolate Mofetil—In conjunction with standard therapy, mycophenolate mofetil (MMF) is an adequate treatment of refractory CLE.⁴⁵ Unfortunately, case reports have demonstrated an increased risk for fetal congenital abnormalities and first-trimester spontaneous abortion with use of MMF during pregnancy.^46,47 Therefore, it is recommended that patients on MMF discontinue the medication at least 6 weeks prior to conception.⁴⁶

Azathioprine—Although azathioprine has been shown to provide relief of discoid lupus erythematosus symptoms,⁴⁸ it currently is only utilized for refractory disease, largely due to notable side effects that particularly affect the gastrointestinal tract and liver.⁴ Moreover, azathioprine use during pregnancy has been associated with prematurity, congenital anomalies, fetal cytopenia, and low birth weight.⁴⁹ With that said, and although not recommended, if patients decide to continue treatment, experts recommend limiting the dose to 2 mg/kg daily to reduce potential adverse events.

Category X

Oral Retinoids—According to the American Academy of Dermatology, retinoids such as isotretinoin and acitretin are considered second-line therapy for CLE.⁵⁰ With that being said, there are well-documented effects on fetal development associated with oral retinoid use, including central nervous system, cardiovascular system, and craniofacial abnormalities.⁵¹ Therefore, its use is contraindicated during pregnancy. To prevent pregnancy while taking isotretinoin, patients must enroll in an online monitoring program called iPLEDGE. This program requires monthly updates by both the physician and the patient, including a negative pregnancy test every month for female patients actively taking the medication.⁵²

The half-lives of the oral retinoids isotretinoin and acitretin are 10 to 20 hours and 50 to 60 hours, respectively.^53,54 However, alcohol consumption converts acitretin into the metabolite etretinate, which can remain in tissue for up to 120 days.^54,55 Therefore, women are advised to avoid alcohol while taking acitretin and avoid conception for 2 to 3 years after cessation of the medication.⁵⁵ For those wishing to restart retinoids after pregnancy, studies show the medication can be safely reinstated 35 days after delivery for those interested in continued treatment.⁵⁶

Thalidomide—Although low-dose thalidomide can treat refractory CLE, its use is restricted because of its known teratogenicity, most notably limb deformities.⁵⁷ If prescribed thalidomide, women will need to enroll in the System for Thalidomide Education and Prescribing Safety program, similar to the iPLEDGE program, and use 2 forms of contraception when sexually active.⁵⁸ Contraception should be continued for 4 weeks following the last dose of thalidomide. After this point, conception is considered safe.⁵⁹

Methotrexate—For nonpregnant patients, low-dose methotrexate (MTX) with folate supplementation is a treatment option for CLE.⁶⁰ However, for those who are pregnant, low-dose MTX is an abortive agent and has been associated with aminopterin syndrome, which includes skull deficits, craniofacial abnormalities, and limb deformities in live births.^19,61 Therefore, MTX is not recommended in pregnancy. Of note, MTX can affect sperm; male patients also should be counselled.

Overall, it is recommended to limit medication use as much as possible in pregnancy. To reduce these exposures, it is imperative to reduce triggers that may lead to symptomatic flares of CLE. Because CLE can be triggered by sun exposure, we advise topical sunscreen to prevent CLE flares that may require additional oral medication.^62,63

Various medications are considered safe for the treatment of CLE in pregnant patients (Figure 2). Based on studies in animal and clinical trials, hydroxychloroquine is considered a safe and effective medication for CLE in pregnancy and is a first-line therapy in nonpregnant patients.^26,27 If flares occur, IVIG or a short course of oral steroids should be considered to manage symptoms.^13,39 For those with severe flares, treatment is difficult, and personalized approaches may be necessary.

Kirchner_2.JPG

Part of the question for the childbearing population is when a patient would like to conceive. For severe cases when hydroxychloroquine is not effective as monotherapy, using a treatment that can encourage remission prior to conception attempts can be a beneficial strategy. Rituximab is an excellent example of such a therapy, as the therapeutic effect outlasts the immunosuppressive effect and therefore is unlikely to affect a future fetus.⁶⁴ Thalidomide also is a potential option prior to conception, based on its short washout period and its ability to achieve notable remission rates in patients with CLE.^57,59 Regardless, patients with CLE should still consult their dermatologist and rheumatologist (if applicable) prior to conception.

Patients of childbearing potential represent a population in which discussion about life goals greatly affects medication options. Having these discussions early and often allows for an open, more successful approach so that treatment regimens are not derailed at the time of conception.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease that involves the skin. Cutaneous lupus erythematosus can be classified into various subtypes.¹ These include, but are not limited to, acute CLE, subacute CLE, chronic CLE, intermittent CLE, lupus tumidus, and lupus profundus.^1,2 The CLE subtypes have variable associations with systemic lupus erythematosus. For instance, some subtypes, such as acute CLE, are more strongly associated with systemic lupus erythematosus.

Treatment of CLE is similar to other autoimmune disorders. Although the US Food and Drug Administration (FDA) has not approved any treatments for CLE,^3,4 the most common therapeutic options are disease-modifying antirheumatic drugs. Unfortunately, many of these treatments carry teratogenic effects. Because CLE predominantly affects women, particularly those of childbearing age, it is imperative to understand the available treatment options for those who are pregnant or considering pregnancy for an informed discussion with patients.⁵

For years, the gold standard when considering a medication during pregnancy was the FDA’s classification system. According to this system, medications were classified into 5 letter categories based on their potential teratogenicity, including A (no fetal risk), B (potential animal risk but inconclusive human studies), C (risk cannot be ruled out), D (evidence of fetal risk), and X (contraindicated in pregnancy). In 2014, the FDA decided to no longer use this classification system for medications approved after 2000.⁶ However, because many proposed treatment options for CLE were approved prior to 2001, we have summarized the commonly prescribed medications for CLE according to their prior FDA letter categories.

Treatment Options for CLE During Pregnancy

Prior to initiating systemic medications for the treatment of CLE, topical medications should be considered. Recommended treatment options include corticosteroids and calcineurin inhibitors.⁷ Compared with systemic medications, topical treatments carry minimal side effects, such as skin atrophy, that typically remain localized to areas of application.⁸ Moreover, even with extensive application, no correlation has been found between topical corticosteroid use and fetal growth,⁹ which suggests that topical steroids are safe in pregnancy and should be considered as a first-line treatment option for CLE. Calcineurin inhibitors also are considered safe based on their low level of absorption through the skin and are considered second-line topical treatment options in pregnancy.¹⁰

Kirchner_1.JPG

Although topical medications are effective for the treatment of CLE, many patients require the administration of systemic therapeutics for severe or refractory disease. Based on previously published reports, Figure 1 describes the current recommended systemic treatment options for CLE.¹¹ Unfortunately, many of these medications carry teratogenic risks during pregnancy. The risks and side effects of the medications are described in detail in the following sections and summarized in the eTable.

CT109002090_eTable.JPG

Category B

Systemic Steroids—Systemic steroids are one of the most prescribed medications during pregnancy.¹² Oral steroids have been associated with fast symptom relief, making this class of medications particularly effective during CLE flares; however, long-term management is not recommended because of the side effects, which include osteoporosis and impaired glucose metabolism.¹³

With low transmission across the placenta, there are 3 glucocorticoids that carry the safest profile in pregnancy: prednisone, cortisone, and hydrocortisone.¹⁴ Dexamethasone and betamethasone should be avoided, as both readily cross the placenta and increase fetal exposure.¹⁵ Although teratogenic effects have been associated with steroid use, most studies involving pregnant patients have inconclusive results. For instance, one study described an association between cleft lip/palate with in utero glucocorticoid exposure.¹⁶ However, multiple follow-up studies found no association between the two.^17,18 Studies investigating the relationship between steroids and miscarriages or steroids and low birth weight also are inconclusive. Of note, if used throughout pregnancy, administration of a loading dose of glucocorticoids prior to delivery is recommended because of the increased stress brought on during labor.¹⁹

Sulfasalazine—Sulfasalazine is an immunomodulator commonly used for the treatment of inflammatory bowel disease and rheumatoid arthritis. However, studies also have shown that sulfasalazine is an effective treatment of CLE if standard treatments have failed.^20,21

During pregnancy, patients exposed to sulfasalazine experienced minimal side effects despite transportation across the placenta.²² In comparison with control, pregnant women taking sulfasalazine experienced no increased risk for low fetal weight,²³ congenital abnormalities,²⁴ or spontaneous abortions.²⁵ Of note, sulfasalazine can affect sperm, so male patients also should be counselled.

Category C

Hydroxychloroquine—Hydroxychloroquine is considered a first-line medication for those with CLE based on a symptomatic relief rate of 50% to 70%.²⁶ For those taking hydroxychloroquine during pregnancy, the majority of studies have shown no association between the medication and adverse fetal events, including congenital abnormalities, prematurity, or spontaneous abortions.^27-29 Therefore, hydroxychloroquine is considered safe in pregnancy, and those on the medication should continue standard monitoring, including retinopathy screening.³⁰

Of note, hydroxychloroquine can be stored in tissue for weeks to months after discontinuation.⁵ Therefore, if patients wish to avoid hydroxychloroquine in pregnancy, one should stop taking the medication several months prior to conception.

Dapsone—Dapsone, a medication with both antimicrobial and immunomodulatory properties, is an effective second-line therapy for CLE.³¹ Although large-scale human trials have not been performed, multiple case reports and observational studies have supported the safe use of dapsone in pregnancy.^32-34 However, there are notable side effects, including dose-dependent hemolysis, methemoglobinemia, and hypersensitivity reactions.¹³ Therefore, once treatment is initiated or continued, folic acid supplementation (5 mg daily) and regular serum analysis, including complete blood cell counts, are recommended in pregnant patients.¹⁹

Rituximab—Recent studies have demonstrated that rituximab can be an effective treatment of subacute and chronic CLE.^35,36 Through inhibition of CD20, rituximab causes a decrease in circulating B cells and a reduced immune response. Therefore, experts recommend discontinuation of rituximab for 12 months prior to conception to reduce potential side effects to the fetus, which may include a transient reduction of circulating fetal B cells.³⁷

If continued during pregnancy, most studies suggest discontinuation of rituximab during the third trimester, as it has been associated with neonatal infections and congenital abnormalities.^19,37 However, these results are based on limited case reports, and thus robust research is needed to better understand the effect of rituximab in utero.

Intravenous Immunoglobulin Infusion—Intravenous immunoglobulin (IVIG) infusion is a well-tolerated treatment for many autoimmune disorders.³⁸ Although not first line, limited case studies have demonstrated remission of refractory CLE following IVIG.^39,40 Although no studies have directly investigated the effect of IVIG on fetal development, it has been frequently administered and well tolerated during pregnancy, especially in those with multiple sclerosis or antiphospholipid syndrome.⁴¹ Commonly reported side effects include headache and fatigue, and a rare associated side effect to be aware of is embolic events.^42,43

Cyclosporine—Cyclosporine rarely is used in the treatment of localized CLE due to its extensive side-effect profile, most notably nephrotoxicity.⁴⁴ However, studies have shown that cyclosporine may be efficacious if symptoms extend beyond the skin, involve multiple organs, and/or other treatments have failed.³⁹ For those who are pregnant and wish to continue cyclosporine use, studies have associated low birth weight and premature delivery with its exposure in utero.⁴⁴

Category D

Mycophenolate Mofetil—In conjunction with standard therapy, mycophenolate mofetil (MMF) is an adequate treatment of refractory CLE.⁴⁵ Unfortunately, case reports have demonstrated an increased risk for fetal congenital abnormalities and first-trimester spontaneous abortion with use of MMF during pregnancy.^46,47 Therefore, it is recommended that patients on MMF discontinue the medication at least 6 weeks prior to conception.⁴⁶

Azathioprine—Although azathioprine has been shown to provide relief of discoid lupus erythematosus symptoms,⁴⁸ it currently is only utilized for refractory disease, largely due to notable side effects that particularly affect the gastrointestinal tract and liver.⁴ Moreover, azathioprine use during pregnancy has been associated with prematurity, congenital anomalies, fetal cytopenia, and low birth weight.⁴⁹ With that said, and although not recommended, if patients decide to continue treatment, experts recommend limiting the dose to 2 mg/kg daily to reduce potential adverse events.

Category X

Oral Retinoids—According to the American Academy of Dermatology, retinoids such as isotretinoin and acitretin are considered second-line therapy for CLE.⁵⁰ With that being said, there are well-documented effects on fetal development associated with oral retinoid use, including central nervous system, cardiovascular system, and craniofacial abnormalities.⁵¹ Therefore, its use is contraindicated during pregnancy. To prevent pregnancy while taking isotretinoin, patients must enroll in an online monitoring program called iPLEDGE. This program requires monthly updates by both the physician and the patient, including a negative pregnancy test every month for female patients actively taking the medication.⁵²

The half-lives of the oral retinoids isotretinoin and acitretin are 10 to 20 hours and 50 to 60 hours, respectively.^53,54 However, alcohol consumption converts acitretin into the metabolite etretinate, which can remain in tissue for up to 120 days.^54,55 Therefore, women are advised to avoid alcohol while taking acitretin and avoid conception for 2 to 3 years after cessation of the medication.⁵⁵ For those wishing to restart retinoids after pregnancy, studies show the medication can be safely reinstated 35 days after delivery for those interested in continued treatment.⁵⁶

Thalidomide—Although low-dose thalidomide can treat refractory CLE, its use is restricted because of its known teratogenicity, most notably limb deformities.⁵⁷ If prescribed thalidomide, women will need to enroll in the System for Thalidomide Education and Prescribing Safety program, similar to the iPLEDGE program, and use 2 forms of contraception when sexually active.⁵⁸ Contraception should be continued for 4 weeks following the last dose of thalidomide. After this point, conception is considered safe.⁵⁹

Methotrexate—For nonpregnant patients, low-dose methotrexate (MTX) with folate supplementation is a treatment option for CLE.⁶⁰ However, for those who are pregnant, low-dose MTX is an abortive agent and has been associated with aminopterin syndrome, which includes skull deficits, craniofacial abnormalities, and limb deformities in live births.^19,61 Therefore, MTX is not recommended in pregnancy. Of note, MTX can affect sperm; male patients also should be counselled.

Overall, it is recommended to limit medication use as much as possible in pregnancy. To reduce these exposures, it is imperative to reduce triggers that may lead to symptomatic flares of CLE. Because CLE can be triggered by sun exposure, we advise topical sunscreen to prevent CLE flares that may require additional oral medication.^62,63

Various medications are considered safe for the treatment of CLE in pregnant patients (Figure 2). Based on studies in animal and clinical trials, hydroxychloroquine is considered a safe and effective medication for CLE in pregnancy and is a first-line therapy in nonpregnant patients.^26,27 If flares occur, IVIG or a short course of oral steroids should be considered to manage symptoms.^13,39 For those with severe flares, treatment is difficult, and personalized approaches may be necessary.

Kirchner_2.JPG

Part of the question for the childbearing population is when a patient would like to conceive. For severe cases when hydroxychloroquine is not effective as monotherapy, using a treatment that can encourage remission prior to conception attempts can be a beneficial strategy. Rituximab is an excellent example of such a therapy, as the therapeutic effect outlasts the immunosuppressive effect and therefore is unlikely to affect a future fetus.⁶⁴ Thalidomide also is a potential option prior to conception, based on its short washout period and its ability to achieve notable remission rates in patients with CLE.^57,59 Regardless, patients with CLE should still consult their dermatologist and rheumatologist (if applicable) prior to conception.

Patients of childbearing potential represent a population in which discussion about life goals greatly affects medication options. Having these discussions early and often allows for an open, more successful approach so that treatment regimens are not derailed at the time of conception.

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

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

Materials and Methods

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

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

Results

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

CT108004193_Table1.JPG

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

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

CT108004193_Table2.JPG

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

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

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

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

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

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

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

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

Comment

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

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

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

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

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

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

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

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

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

Materials and Methods

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

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

Results

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

CT108004193_Table1.JPG

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

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

CT108004193_Table2.JPG

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

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

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

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

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

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

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

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

Comment

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

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

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

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

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

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

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

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

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

Materials and Methods

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

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

Results

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

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

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

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

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

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

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

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

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

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

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

Comment

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

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

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

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

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

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

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

The virus that causes COVID-19—SARS-CoV-2—has infected more than 128 million individuals, resulting in more than 2.8 million deaths worldwide between December 2019 and April 2021. Disease mortality primarily is driven by hypoxemic respiratory failure and systemic hypercoagulability, resulting in multisystem organ failure.¹ With more than 17 million Americans infected, the virus is estimated to have impacted someone within the social circle of nearly every American.²

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The COVID-19 pandemic has highlighted resource limitations, delayed elective and preventive care, and rapidly increased the adoption of telemedicine, presenting a host of new challenges to providers in every medical specialty, including dermatology. Although COVID-19 primarily is a respiratory disease, clinical manifestations have been observed in nearly every organ, including the skin. The cutaneous manifestations of COVID-19 provide insight into disease diagnosis, prognosis, and pathophysiology. In this article, we review the cutaneous manifestations of COVID-19 and explore the state of knowledge regarding their pathophysiology and clinical significance. Finally, we discuss the role of dermatology consultants in the care of patients with COVID-19, and the impact of the pandemic on the field of dermatology. 

Prevalence of Cutaneous Findings in COVID-19

Early reports characterizing the clinical presentation of patients hospitalized with COVID-19 suggested skin findings associated with the disease were rare. Cohort studies from Europe, China, and New York City in January through March 2020 reported a low prevalence or made no mention of rash.^3-7 However, reports from dermatologists in Italy that emerged in May 2020 indicated a substantially higher proportion of cutaneous disease: 18 of 88 (20.4%) hospitalized patients were found to have cutaneous involvement, primarily consisting of erythematous rash, along with some cases of urticarial and vesicular lesions.⁸ In October 2020, a retrospective cohort study from Spain examining 2761 patients presenting to the emergency department or admitted to the hospital for COVID-19 found that 58 (2.1%) patients had skin lesions attributed to COVID-19.⁹

The wide range in reported prevalence of skin lesions may be due to variable involvement of dermatologic specialists in patient care, particularly in China.¹⁰ Some variation also may be due to variability in the timing of clinical examination, as well as demographic and clinical differences in patient populations. Of note, a multisystem inflammatory disease seen in US children subsequent to infection with COVID-19 has been associated with rash in as many as 74% of cases.¹¹ Although COVID-19 disproportionately impacts people with skin of color, there are few reports of cutaneous manifestations in that population,¹² highlighting the challenges of the dermatologic examination in individuals with darker skin and suggesting the prevalence of dermatologic disease in COVID-19 may be greater than reported. 

Morphologic Patterns of Cutaneous Involvement in COVID-19

Researchers in Europe and the United States have attempted to classify the cutaneous manifestations of COVID-19. A registry established through the American Academy of Dermatology published a compilation of reports from 31 countries, totaling 716 patient profiles.¹³ A prospective Spanish study detailed the cutaneous involvement of 375 patients with suspected or confirmed COVID-19.¹⁴ Together, these efforts have revealed several distinct patterns of cutaneous involvement associated with COVID-19 (Table).^9,15-18 

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Vesicular Rash
Vesicular rash associated with COVID-19 has been described in several studies and case series^8,13,14 and is considered, along with the pseudopernio (or pseudochilblains) morphology, to be one of the more disease-specific patterns in COVID-19.^14,18 Vesicular rash appears to comprise roughly one-tenth of all COVID-19–associated rashes.^13,14 It usually is described as pruritic, with 72% to 83% of patients reporting itch.^13,16 

Small monomorphic or polymorphic vesicles predominantly on the trunk and to a lesser extent the extremities and head have been described by multiple authors.^14,16 Vesicular rash is most common among middle-aged individuals, with studies reporting median and mean ages ranging from 40.5 to 55 years.^9,13,14,16

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Vesicular rash develops concurrent with or after other presenting symptoms of COVID-19; in 2 studies, vesicular rash preceded development of other symptoms in only 15% and 5.6% of cases, respectively.^13,14 Prognostically, vesicular rash is associated with moderate disease severity.^14,16 It may persist for an average of 8 to 10 days.^14,16,18

Histopathologic examination reveals basal layer vacuolar degeneration, hyperchromatic keratinocytes, acantholysis, and dyskeratosis.^9,16,18 

Urticarial Rash
Urticarial lesions represent approximately 7% to 19% of reported COVID-19–associated rashes.^9,13,14 Urticarial rashes in patients testing positive for SARS-CoV-2 primarily occur on the trunk.¹⁴ The urticaria, which typically last about 1 week,¹⁴ are seen most frequently in middle-aged patients (mean/median age, 42–48 years)^13,14 and are associated with pruritus, which has been reported in 74% to 92% of patients.^13,14 Urticarial lesions typically do not precede other symptoms of COVID-19 and are nonspecific, making them less useful diagnostically.¹⁴

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Urticaria appears to be associated with more severe COVID-19 illness in several studies, but this finding may be confounded by several factors, including older age, increased tobacco use, and polypharmacy. Of 104 patients with reported urticarial rash and suspected or confirmed COVID-19 across 3 studies, only 1 death was reported.^9,13,14 

The histopathologic appearance is that of typical hives, demonstrating a perivascular infiltrate of lymphocytes and eosinophils with edema of the upper dermis.^9,19

Morbilliform Eruption
Morbilliform eruption is a commonly reported morphology associated with COVID-19, accounting for 20% to 47% of rashes.^9,13,14 This categorization may have limited utility from a diagnostic and prognostic perspective, given that morbilliform eruptions are common, nonspecific, and heterogenous and can arise from many causes.^9,13,14 Onset of morbilliform eruption appears to coincide with¹⁴ or follow^13,20,21 the development of other COVID-19–related symptoms, with 5% of patients reporting morbilliform rash as the initial manifestation of infection.^13,14 Morbilliform eruptions have been observed to occur in patients with more severe disease.^9,13,14

Certain morphologic subtypes, such as erythema multiforme–like, erythema elevatum diutinum–like, or pseudovesicular, may be more specific to COVID-19 infection.¹⁴ A small case series highlighted 4 patients with erythema multiforme–like eruptions, 3 of whom also were found to have petechial enanthem occurring after COVID-19 diagnosis; however, the investigators were unable to exclude drug reaction as a potential cause of rash in these patients.²² Another case series of 21 patients with COVID-19 and skin rash described a (primarily) petechial enanthem on the palate in 6 (28.5%) patients.²³ It is unclear to what extent oral enanthem may be underrecognized given that some physicians may be disinclined to remove the masks of known COVID-19–positive patients to examine the oral cavity.

The histologic appearance of morbilliform rash seen in association with COVID-19 has been described as spongiotic with interface dermatitis with perivascular lymphocytic inflammation.^9,21

COVID Toes, Pseudochilblains Rash, Perniolike Rash, and Acral Erythema/Edema
Of all the rashes associated with COVID-19, COVID toes, or pseudochilblains rash, has perhaps attracted the most attention. The characteristic violaceous erythema on the fingers and/or toes may be itchy or painful, presenting similar to idiopathic cases of pernio (Figure 1).¹⁴ The entity has been controversial because of an absence of a clear correlation with a positive SARS-CoV-2 polymerase chain reaction test or antibodies to the virus in a subset of reported cases.^24,25 Onset of the rash late in the disease course, generally after symptom resolution in mild or asymptomatic cases, may explain the absence of viral DNA in the nasopharynx by the time of lesion appearance.^14,26 Seronegative patients may have cleared SARS-CoV-2 infection before humoral immunity could occur via a strong type 1 interferon response.²⁵

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Across 3 studies, perniolike skin lesions constituted 18% to 29% of COVID-19–associated skin findings^9,13,14 and persisted for an average of 12 to 14 days.^13,14 Perniolike lesions portend a favorable outcome; patients with COVID toes rarely present with systemic symptoms or laboratory or imaging abnormalities⁹ and less commonly require hospitalization for severe illness. Perniolike lesions have been reported most frequently in younger patients, with a median or mean age of 32 to 35 years.^13,14

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Histology demonstrates lichenoid dermatitis with perivascular and periadnexal lymphocytic infiltrates.⁹ Notably, one study observed interface dermatitis of the intraepidermal portion of the acrosyringium, a rare finding in chilblain lupus, in 83% of patients (N=40).²⁵ Direct immunofluorescence demonstrates a vasculopathic pattern, with some patients showing deposition of IgM or IgG, C3, and fibrinogen in dermal blood vessels. Vascular C9 deposits also have been demonstrated on immunohistochemistry.⁹ Biopsies of perniolike lesions in COVID-19 patients have demonstrated the presence of SARS-CoV-2 RNA,²⁷ have identified SARS-CoV-2 spike protein in endothelial cells on immunohistochemistry, and have visualized intracytoplasmic viral particles in vascular endothelium on electron microscopy.²⁸

Livedoid Rash/Retiform Purpura
Netlike purpuric or violaceous patches signifying vessel damage or occlusion have been seen in association with COVID-19, constituting approximately 6% of COVID-19–associated skin findings in 2 studies.^13,14 Livedoid rash (Figure 2) and retiform purpura (Figure 3) are associated with older age and occur primarily in severely ill patients, including those requiring intensive care. In a registry of 716 patients with COVID-19, 100% of patients with retiform purpura were hospitalized, and 82% had acute respiratory distress syndrome.¹³ In another study, 33% (7/21) of patients with livedoid and necrotic lesions required intensive care, and 10% (2/21) died.¹⁴

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Multisystem Inflammatory Disease in Children

A hyperinflammatory syndrome similar to Kawasaki disease and toxic shock syndrome associated with mucocutaneous, cardiac, and gastrointestinal manifestations has been reported following COVID-19 infection.³¹ This syndrome, known as multisystem inflammatory syndrome in children (MIS-C), predominantly affects adolescents and children older than 5 years,¹¹ typically occurs 2 to 4 weeks after infection, and appears to be at least 100-times less common than COVID-19 infection among the same age group.³¹ Sixty percent³¹ to 74%¹¹ of affected patients have mucocutaneous involvement, with the most common clinical findings being conjunctival injection, palmoplantar erythema, lip hyperemia, periorbital erythema and edema, strawberry tongue, and malar erythema, respectively.³²

Because this condition appears to reflect an immune response to the virus, the majority of cases demonstrate negative SARS-CoV-2 polymerase chain reaction and positive antibody testing.³³ Although cutaneous findings are similar to those seen in Kawasaki disease, certain findings have been noted in MIS-C that are not typical of Kawasaki disease, including heliotrope rash–like periorbital edema and erythema as well as erythema infectiosum–like malar erythema and reticulated erythematous eruptions.³²

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The course of MIS-C can be severe; in one case series of patients presenting with MIS-C, 80% (79/99) required intensive care unit admission, with 10% requiring mechanical ventilation and 2% of patients dying during admission.³¹ Cardiac dysfunction, coagulopathy, and gastrointestinal symptoms are common.^11,31 It has been postulated that a superantigenlike region of the SARS-CoV-2 spike protein, similar to that of staphylococcal enterotoxin B, may underlie MIS-C and account for its similarities to toxic shock syndrome.³⁴ Of note, a similar multisystem inflammatory syndrome associated with COVID-19 also has been described in adults, and it too may present with rash as a cardinal feature.³⁵

Pathophysiology of COVID-19: What the Skin May Reveal About the Disease

The diverse range of cutaneous manifestations in COVID-19 reflects a spectrum of host immunologicresponses to SARS-CoV-2 and may inform the pathophysiology of the disease as well as potential treatment modalities.

Host Response to SARS-CoV-2
The body’s response to viral infection is 2-pronged, involving activation of cellular antiviral defenses mediated by type I and III interferons, as well as recruitment of leukocytes, mobilized by cytokines and chemokines.^36,37 Infection with SARS-CoV-2 results in a unique inflammatory response characterized by suppression of interferons, juxtaposed with a rampant proinflammatory cytokine and chemokine response, reminiscent of a cytokine storm. Reflective of this imbalance, a study of 50 COVID-19 patients and 20 healthy controls found decreased natural killer cells and CD3⁺ T cells in COVID-19 patients, particularly severely or critically ill patients, with an increase in B cells and monocytes.³⁸ This distinctive immune imbalance positions SARS-CoV-2 to thrive in the absence of inhibitory interferon activity while submitting the host to the deleterious effects of a cytokine surge.³⁶

Type I Interferons
The perniolike lesions associated with mild COVID-19 disease¹⁴ may represent a robust immune response via effective stimulation of type I interferons (IFN-1). Similar perniolike lesions are observed in Aicardi-Goutières syndrome³⁷ and familial chilblain lupus, hereditary interferonopathies associated with mutations in the TREX1 (three prime repair exonuclease 1) gene and characterized by inappropriate upregulation of IFN-1,³⁹ resulting in chilblains. It has been suggested that perniolike lesions in COVID-19 result from IFN-1 activation—a robust effective immunologic response to the virus.^14,26,40

On the other end of the spectrum, patients with severe COVID-19 may have a blunted IFN-1 response and reduced IFN-1–stimulated gene expression.^36,38 Notably, low IFN-1 response preceded clinical deterioration and was associated with increased risk for evolution to critical illness.³⁸ Severe disease from COVID-19 also is more commonly observed in older patients and those with comorbidities,¹ both of which are known factors associated with depressed IFN-1 function.^38,41 Reflective of this disparate IFN-1 response, biopsies of COVID-19 perniosis have demonstrated striking expression of myxovirus resistance protein A (MXA), a marker for IFN-1 signaling in tissue, whereas its expression is absent in COVID-19 livedo/retiform purpura.²⁷

Familial chilblain lupus may be effectively treated by the Janus kinase inhibitor baricitinib,³⁹ which inhibits IFN-1 signaling. Baricitinib recently received emergency use authorization by the US Food and Drug Administration for treatment of severe COVID-19 pneumonia,^42,43 hinting to disordered IFN-1 signaling in the COVID-19 pathophysiology.

The impaired IFN-1 response in COVID-19 patients may be due to a unique characteristic of SARS-CoV-2: its ORF3b gene is a potent IFN-1 antagonist. In a series of experiments comparing SARS-CoV-2 to the related virus severe acute respiratory disease coronavirus (which was responsible for an epidemic in 2002), Konno et al⁴⁴ found that SARS-CoV-2 is more effectively able to downregulate host IFN-1, likely due to premature stop codons on ORF3b that produce a truncated version of the gene with amplified anti–IFN-1 activity.

 Cytokine Storm and Coagulation Cascade
This dulled interferon response is juxtaposed with a surge of inflammatory chemokines and cytokines, including IL-6, IL-8, IL-10, and tumor necrosis factor α, impairing innate immunity and leading to end-organ damage. This inflammatory response is associated with the influx of innate immune cells, specifically neutrophils and monocytes, which likely contribute to lung injury in COVID-19 acute respiratory distress syndrome.³⁸ It also is thought to lead to downstream activation of coagulation, with a high incidence of thrombotic events observed in patients with severe COVID-19.¹ In a retrospective study of 184 intensive care patients with COVID-19 receiving at least standard doses of thromboprophylaxis, venous thromboembolism occurred in 27% and arterial thrombotic events occurred in 3.7%.⁴⁵

Livedo racemosa and retiform purpura are cutaneous markers of hypercoagulability, which indicate an increased risk for systemic clotting in COVID-19. A positive feedback loop between the complement and coagulation cascades appears to be important.^{13,14,29,46-48} In addition, a few studies have reported antiphospholipid antibody positivity in hospitalized COVID-19 patients.^49,50

The high incidence of coagulopathy in severe COVID-19 has prompted many institutions to develop aggressive prophylactic anticoagulation protocols. Elevation of proinflammatory cytokines and observation of terminal complement activation in the skin and other organs has led to therapeutic trials of IL-6 inhibitors such as tocilizumab,⁵¹ complement inhibitors such as eculizumab, and Janus kinase inhibitors such as ruxolitinib and baricitinib.^42,48

COVID Long-Haulers
The long-term effects of immune dysregulation in COVID-19 patients remain to be seen. Viral triggering of autoimmune disease is a well-established phenomenon, seen in DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome and other dermatologic diseases, raising the possibility that dermatologists will see a rising incidence of cutaneous autoimmune disease in the aftermath of the pandemic. Disordered interferon stimulation could lead to increased incidence of interferon-mediated disorders, such as sarcoidosis and other granulomatous diseases. Vasculitislike skin lesions could persist beyond the acute infectious period. Recent data from a registry of 990 COVID-19 cases from 39 countries suggest that COVID-19 perniolike lesions may persist as long as 150 days.⁵² In a time of many unknowns, these questions serve as a call to action for rigorous data collection, contribution to existing registries for dermatologic manifestations of COVID-19, and long-term follow-up of COVID-19 patients by the dermatology community. 

Pandemic Dermatology

The pandemic has posed unprecedented challenges for patient care. The use of hydroxychloroquine as a popular but unproven treatment for COVID-19, ⁵³ particularly early in the pandemic, has resulted in drug shortages for patients with lupus and other autoimmune skin diseases. Meanwhile, the need for patients with complex dermatologic conditions to receive systemic immunosuppression has had to be balanced against the associated risks during a global pandemic. To help dermatologists navigate this dilemma, various subspecialty groups have issued guidelines, including the COVID-19 Task Force of the Medical Dermatology Society and Society of Dermatology Hospitalists, which recommends a stepwise approach to shared decision-making with the goal of minimizing both the risk for disease flare and that of infection. The use of systemic steroids and rituximab, as well as the dose of immunosuppression—particularly broad-acting immunosuppression—should be limited where permitted. ⁵⁴

Rapid adoption of telemedicine and remote monitoring strategies has enabled dermatologists to provide safe and timely care when in-person visits have not been possible, including for patients with confirmed or suspected COVID-19, as well as for hospitalized patients. ^55-57 Use of telemedicine has facilitated preservation of personal protective equipment at a time when these important resources have been scarce. For patients with transportation or scheduling barriers, telemedicine has even expanded access to care. 

However, this strategy cannot completely replace comprehensive in-person evaluation. Variability in video and photographic quality limits evaluation, while in-person physical examination can reveal subtle morphologic clues necessary for diagnosis. ^{5 8} Additionally, unequal access to technology may disadvantage some patients. For dermatologists to provide optimal care and continue to contribute accurate and insightful observations into COVID-19, it is essential to be physically present in the clinic and in the hospital when necessary, caring for patients in need of dermatologic expertise. Creative management strategies developed during this time will benefit patients and expand the reach of the specialty . ^{5 8}

Final Thoughts

The COVID-19 pandemic has profoundly challenged the medical community and dermatology is no exception. By documenting and characterizing the diverse cutaneous manifestations of this novel disease, dermatologists have furthered understanding of its pathophysiology and management. By adapting quickly and developing creative ways to deliver care, dermatologists have found ways to contribute, both large and small. As we take stock at this juncture of the pandemic, it is clear there remains much to learn. We hope dermatologists will continue to take an active role in meeting the challenges of this time.

The virus that causes COVID-19—SARS-CoV-2—has infected more than 128 million individuals, resulting in more than 2.8 million deaths worldwide between December 2019 and April 2021. Disease mortality primarily is driven by hypoxemic respiratory failure and systemic hypercoagulability, resulting in multisystem organ failure.¹ With more than 17 million Americans infected, the virus is estimated to have impacted someone within the social circle of nearly every American.²

[embed:render:related:node:237479]

The COVID-19 pandemic has highlighted resource limitations, delayed elective and preventive care, and rapidly increased the adoption of telemedicine, presenting a host of new challenges to providers in every medical specialty, including dermatology. Although COVID-19 primarily is a respiratory disease, clinical manifestations have been observed in nearly every organ, including the skin. The cutaneous manifestations of COVID-19 provide insight into disease diagnosis, prognosis, and pathophysiology. In this article, we review the cutaneous manifestations of COVID-19 and explore the state of knowledge regarding their pathophysiology and clinical significance. Finally, we discuss the role of dermatology consultants in the care of patients with COVID-19, and the impact of the pandemic on the field of dermatology. 

Prevalence of Cutaneous Findings in COVID-19

Early reports characterizing the clinical presentation of patients hospitalized with COVID-19 suggested skin findings associated with the disease were rare. Cohort studies from Europe, China, and New York City in January through March 2020 reported a low prevalence or made no mention of rash.^3-7 However, reports from dermatologists in Italy that emerged in May 2020 indicated a substantially higher proportion of cutaneous disease: 18 of 88 (20.4%) hospitalized patients were found to have cutaneous involvement, primarily consisting of erythematous rash, along with some cases of urticarial and vesicular lesions.⁸ In October 2020, a retrospective cohort study from Spain examining 2761 patients presenting to the emergency department or admitted to the hospital for COVID-19 found that 58 (2.1%) patients had skin lesions attributed to COVID-19.⁹

The wide range in reported prevalence of skin lesions may be due to variable involvement of dermatologic specialists in patient care, particularly in China.¹⁰ Some variation also may be due to variability in the timing of clinical examination, as well as demographic and clinical differences in patient populations. Of note, a multisystem inflammatory disease seen in US children subsequent to infection with COVID-19 has been associated with rash in as many as 74% of cases.¹¹ Although COVID-19 disproportionately impacts people with skin of color, there are few reports of cutaneous manifestations in that population,¹² highlighting the challenges of the dermatologic examination in individuals with darker skin and suggesting the prevalence of dermatologic disease in COVID-19 may be greater than reported. 

Morphologic Patterns of Cutaneous Involvement in COVID-19

Researchers in Europe and the United States have attempted to classify the cutaneous manifestations of COVID-19. A registry established through the American Academy of Dermatology published a compilation of reports from 31 countries, totaling 716 patient profiles.¹³ A prospective Spanish study detailed the cutaneous involvement of 375 patients with suspected or confirmed COVID-19.¹⁴ Together, these efforts have revealed several distinct patterns of cutaneous involvement associated with COVID-19 (Table).^9,15-18 

CT107004209_Table.JPG

Vesicular Rash
Vesicular rash associated with COVID-19 has been described in several studies and case series^8,13,14 and is considered, along with the pseudopernio (or pseudochilblains) morphology, to be one of the more disease-specific patterns in COVID-19.^14,18 Vesicular rash appears to comprise roughly one-tenth of all COVID-19–associated rashes.^13,14 It usually is described as pruritic, with 72% to 83% of patients reporting itch.^13,16 

Small monomorphic or polymorphic vesicles predominantly on the trunk and to a lesser extent the extremities and head have been described by multiple authors.^14,16 Vesicular rash is most common among middle-aged individuals, with studies reporting median and mean ages ranging from 40.5 to 55 years.^9,13,14,16

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Vesicular rash develops concurrent with or after other presenting symptoms of COVID-19; in 2 studies, vesicular rash preceded development of other symptoms in only 15% and 5.6% of cases, respectively.^13,14 Prognostically, vesicular rash is associated with moderate disease severity.^14,16 It may persist for an average of 8 to 10 days.^14,16,18

Histopathologic examination reveals basal layer vacuolar degeneration, hyperchromatic keratinocytes, acantholysis, and dyskeratosis.^9,16,18 

Urticarial Rash
Urticarial lesions represent approximately 7% to 19% of reported COVID-19–associated rashes.^9,13,14 Urticarial rashes in patients testing positive for SARS-CoV-2 primarily occur on the trunk.¹⁴ The urticaria, which typically last about 1 week,¹⁴ are seen most frequently in middle-aged patients (mean/median age, 42–48 years)^13,14 and are associated with pruritus, which has been reported in 74% to 92% of patients.^13,14 Urticarial lesions typically do not precede other symptoms of COVID-19 and are nonspecific, making them less useful diagnostically.¹⁴

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Urticaria appears to be associated with more severe COVID-19 illness in several studies, but this finding may be confounded by several factors, including older age, increased tobacco use, and polypharmacy. Of 104 patients with reported urticarial rash and suspected or confirmed COVID-19 across 3 studies, only 1 death was reported.^9,13,14 

The histopathologic appearance is that of typical hives, demonstrating a perivascular infiltrate of lymphocytes and eosinophils with edema of the upper dermis.^9,19

Morbilliform Eruption
Morbilliform eruption is a commonly reported morphology associated with COVID-19, accounting for 20% to 47% of rashes.^9,13,14 This categorization may have limited utility from a diagnostic and prognostic perspective, given that morbilliform eruptions are common, nonspecific, and heterogenous and can arise from many causes.^9,13,14 Onset of morbilliform eruption appears to coincide with¹⁴ or follow^13,20,21 the development of other COVID-19–related symptoms, with 5% of patients reporting morbilliform rash as the initial manifestation of infection.^13,14 Morbilliform eruptions have been observed to occur in patients with more severe disease.^9,13,14

Certain morphologic subtypes, such as erythema multiforme–like, erythema elevatum diutinum–like, or pseudovesicular, may be more specific to COVID-19 infection.¹⁴ A small case series highlighted 4 patients with erythema multiforme–like eruptions, 3 of whom also were found to have petechial enanthem occurring after COVID-19 diagnosis; however, the investigators were unable to exclude drug reaction as a potential cause of rash in these patients.²² Another case series of 21 patients with COVID-19 and skin rash described a (primarily) petechial enanthem on the palate in 6 (28.5%) patients.²³ It is unclear to what extent oral enanthem may be underrecognized given that some physicians may be disinclined to remove the masks of known COVID-19–positive patients to examine the oral cavity.

The histologic appearance of morbilliform rash seen in association with COVID-19 has been described as spongiotic with interface dermatitis with perivascular lymphocytic inflammation.^9,21

COVID Toes, Pseudochilblains Rash, Perniolike Rash, and Acral Erythema/Edema
Of all the rashes associated with COVID-19, COVID toes, or pseudochilblains rash, has perhaps attracted the most attention. The characteristic violaceous erythema on the fingers and/or toes may be itchy or painful, presenting similar to idiopathic cases of pernio (Figure 1).¹⁴ The entity has been controversial because of an absence of a clear correlation with a positive SARS-CoV-2 polymerase chain reaction test or antibodies to the virus in a subset of reported cases.^24,25 Onset of the rash late in the disease course, generally after symptom resolution in mild or asymptomatic cases, may explain the absence of viral DNA in the nasopharynx by the time of lesion appearance.^14,26 Seronegative patients may have cleared SARS-CoV-2 infection before humoral immunity could occur via a strong type 1 interferon response.²⁵

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Across 3 studies, perniolike skin lesions constituted 18% to 29% of COVID-19–associated skin findings^9,13,14 and persisted for an average of 12 to 14 days.^13,14 Perniolike lesions portend a favorable outcome; patients with COVID toes rarely present with systemic symptoms or laboratory or imaging abnormalities⁹ and less commonly require hospitalization for severe illness. Perniolike lesions have been reported most frequently in younger patients, with a median or mean age of 32 to 35 years.^13,14

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Histology demonstrates lichenoid dermatitis with perivascular and periadnexal lymphocytic infiltrates.⁹ Notably, one study observed interface dermatitis of the intraepidermal portion of the acrosyringium, a rare finding in chilblain lupus, in 83% of patients (N=40).²⁵ Direct immunofluorescence demonstrates a vasculopathic pattern, with some patients showing deposition of IgM or IgG, C3, and fibrinogen in dermal blood vessels. Vascular C9 deposits also have been demonstrated on immunohistochemistry.⁹ Biopsies of perniolike lesions in COVID-19 patients have demonstrated the presence of SARS-CoV-2 RNA,²⁷ have identified SARS-CoV-2 spike protein in endothelial cells on immunohistochemistry, and have visualized intracytoplasmic viral particles in vascular endothelium on electron microscopy.²⁸

Livedoid Rash/Retiform Purpura
Netlike purpuric or violaceous patches signifying vessel damage or occlusion have been seen in association with COVID-19, constituting approximately 6% of COVID-19–associated skin findings in 2 studies.^13,14 Livedoid rash (Figure 2) and retiform purpura (Figure 3) are associated with older age and occur primarily in severely ill patients, including those requiring intensive care. In a registry of 716 patients with COVID-19, 100% of patients with retiform purpura were hospitalized, and 82% had acute respiratory distress syndrome.¹³ In another study, 33% (7/21) of patients with livedoid and necrotic lesions required intensive care, and 10% (2/21) died.¹⁴

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Multisystem Inflammatory Disease in Children

A hyperinflammatory syndrome similar to Kawasaki disease and toxic shock syndrome associated with mucocutaneous, cardiac, and gastrointestinal manifestations has been reported following COVID-19 infection.³¹ This syndrome, known as multisystem inflammatory syndrome in children (MIS-C), predominantly affects adolescents and children older than 5 years,¹¹ typically occurs 2 to 4 weeks after infection, and appears to be at least 100-times less common than COVID-19 infection among the same age group.³¹ Sixty percent³¹ to 74%¹¹ of affected patients have mucocutaneous involvement, with the most common clinical findings being conjunctival injection, palmoplantar erythema, lip hyperemia, periorbital erythema and edema, strawberry tongue, and malar erythema, respectively.³²

Because this condition appears to reflect an immune response to the virus, the majority of cases demonstrate negative SARS-CoV-2 polymerase chain reaction and positive antibody testing.³³ Although cutaneous findings are similar to those seen in Kawasaki disease, certain findings have been noted in MIS-C that are not typical of Kawasaki disease, including heliotrope rash–like periorbital edema and erythema as well as erythema infectiosum–like malar erythema and reticulated erythematous eruptions.³²

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The course of MIS-C can be severe; in one case series of patients presenting with MIS-C, 80% (79/99) required intensive care unit admission, with 10% requiring mechanical ventilation and 2% of patients dying during admission.³¹ Cardiac dysfunction, coagulopathy, and gastrointestinal symptoms are common.^11,31 It has been postulated that a superantigenlike region of the SARS-CoV-2 spike protein, similar to that of staphylococcal enterotoxin B, may underlie MIS-C and account for its similarities to toxic shock syndrome.³⁴ Of note, a similar multisystem inflammatory syndrome associated with COVID-19 also has been described in adults, and it too may present with rash as a cardinal feature.³⁵

Pathophysiology of COVID-19: What the Skin May Reveal About the Disease

The diverse range of cutaneous manifestations in COVID-19 reflects a spectrum of host immunologicresponses to SARS-CoV-2 and may inform the pathophysiology of the disease as well as potential treatment modalities.

Host Response to SARS-CoV-2
The body’s response to viral infection is 2-pronged, involving activation of cellular antiviral defenses mediated by type I and III interferons, as well as recruitment of leukocytes, mobilized by cytokines and chemokines.^36,37 Infection with SARS-CoV-2 results in a unique inflammatory response characterized by suppression of interferons, juxtaposed with a rampant proinflammatory cytokine and chemokine response, reminiscent of a cytokine storm. Reflective of this imbalance, a study of 50 COVID-19 patients and 20 healthy controls found decreased natural killer cells and CD3⁺ T cells in COVID-19 patients, particularly severely or critically ill patients, with an increase in B cells and monocytes.³⁸ This distinctive immune imbalance positions SARS-CoV-2 to thrive in the absence of inhibitory interferon activity while submitting the host to the deleterious effects of a cytokine surge.³⁶

Type I Interferons
The perniolike lesions associated with mild COVID-19 disease¹⁴ may represent a robust immune response via effective stimulation of type I interferons (IFN-1). Similar perniolike lesions are observed in Aicardi-Goutières syndrome³⁷ and familial chilblain lupus, hereditary interferonopathies associated with mutations in the TREX1 (three prime repair exonuclease 1) gene and characterized by inappropriate upregulation of IFN-1,³⁹ resulting in chilblains. It has been suggested that perniolike lesions in COVID-19 result from IFN-1 activation—a robust effective immunologic response to the virus.^14,26,40

On the other end of the spectrum, patients with severe COVID-19 may have a blunted IFN-1 response and reduced IFN-1–stimulated gene expression.^36,38 Notably, low IFN-1 response preceded clinical deterioration and was associated with increased risk for evolution to critical illness.³⁸ Severe disease from COVID-19 also is more commonly observed in older patients and those with comorbidities,¹ both of which are known factors associated with depressed IFN-1 function.^38,41 Reflective of this disparate IFN-1 response, biopsies of COVID-19 perniosis have demonstrated striking expression of myxovirus resistance protein A (MXA), a marker for IFN-1 signaling in tissue, whereas its expression is absent in COVID-19 livedo/retiform purpura.²⁷

Familial chilblain lupus may be effectively treated by the Janus kinase inhibitor baricitinib,³⁹ which inhibits IFN-1 signaling. Baricitinib recently received emergency use authorization by the US Food and Drug Administration for treatment of severe COVID-19 pneumonia,^42,43 hinting to disordered IFN-1 signaling in the COVID-19 pathophysiology.

The impaired IFN-1 response in COVID-19 patients may be due to a unique characteristic of SARS-CoV-2: its ORF3b gene is a potent IFN-1 antagonist. In a series of experiments comparing SARS-CoV-2 to the related virus severe acute respiratory disease coronavirus (which was responsible for an epidemic in 2002), Konno et al⁴⁴ found that SARS-CoV-2 is more effectively able to downregulate host IFN-1, likely due to premature stop codons on ORF3b that produce a truncated version of the gene with amplified anti–IFN-1 activity.

 Cytokine Storm and Coagulation Cascade
This dulled interferon response is juxtaposed with a surge of inflammatory chemokines and cytokines, including IL-6, IL-8, IL-10, and tumor necrosis factor α, impairing innate immunity and leading to end-organ damage. This inflammatory response is associated with the influx of innate immune cells, specifically neutrophils and monocytes, which likely contribute to lung injury in COVID-19 acute respiratory distress syndrome.³⁸ It also is thought to lead to downstream activation of coagulation, with a high incidence of thrombotic events observed in patients with severe COVID-19.¹ In a retrospective study of 184 intensive care patients with COVID-19 receiving at least standard doses of thromboprophylaxis, venous thromboembolism occurred in 27% and arterial thrombotic events occurred in 3.7%.⁴⁵

Livedo racemosa and retiform purpura are cutaneous markers of hypercoagulability, which indicate an increased risk for systemic clotting in COVID-19. A positive feedback loop between the complement and coagulation cascades appears to be important.^{13,14,29,46-48} In addition, a few studies have reported antiphospholipid antibody positivity in hospitalized COVID-19 patients.^49,50

The high incidence of coagulopathy in severe COVID-19 has prompted many institutions to develop aggressive prophylactic anticoagulation protocols. Elevation of proinflammatory cytokines and observation of terminal complement activation in the skin and other organs has led to therapeutic trials of IL-6 inhibitors such as tocilizumab,⁵¹ complement inhibitors such as eculizumab, and Janus kinase inhibitors such as ruxolitinib and baricitinib.^42,48

COVID Long-Haulers
The long-term effects of immune dysregulation in COVID-19 patients remain to be seen. Viral triggering of autoimmune disease is a well-established phenomenon, seen in DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome and other dermatologic diseases, raising the possibility that dermatologists will see a rising incidence of cutaneous autoimmune disease in the aftermath of the pandemic. Disordered interferon stimulation could lead to increased incidence of interferon-mediated disorders, such as sarcoidosis and other granulomatous diseases. Vasculitislike skin lesions could persist beyond the acute infectious period. Recent data from a registry of 990 COVID-19 cases from 39 countries suggest that COVID-19 perniolike lesions may persist as long as 150 days.⁵² In a time of many unknowns, these questions serve as a call to action for rigorous data collection, contribution to existing registries for dermatologic manifestations of COVID-19, and long-term follow-up of COVID-19 patients by the dermatology community. 

Pandemic Dermatology

The pandemic has posed unprecedented challenges for patient care. The use of hydroxychloroquine as a popular but unproven treatment for COVID-19, ⁵³ particularly early in the pandemic, has resulted in drug shortages for patients with lupus and other autoimmune skin diseases. Meanwhile, the need for patients with complex dermatologic conditions to receive systemic immunosuppression has had to be balanced against the associated risks during a global pandemic. To help dermatologists navigate this dilemma, various subspecialty groups have issued guidelines, including the COVID-19 Task Force of the Medical Dermatology Society and Society of Dermatology Hospitalists, which recommends a stepwise approach to shared decision-making with the goal of minimizing both the risk for disease flare and that of infection. The use of systemic steroids and rituximab, as well as the dose of immunosuppression—particularly broad-acting immunosuppression—should be limited where permitted. ⁵⁴

Rapid adoption of telemedicine and remote monitoring strategies has enabled dermatologists to provide safe and timely care when in-person visits have not been possible, including for patients with confirmed or suspected COVID-19, as well as for hospitalized patients. ^55-57 Use of telemedicine has facilitated preservation of personal protective equipment at a time when these important resources have been scarce. For patients with transportation or scheduling barriers, telemedicine has even expanded access to care. 

However, this strategy cannot completely replace comprehensive in-person evaluation. Variability in video and photographic quality limits evaluation, while in-person physical examination can reveal subtle morphologic clues necessary for diagnosis. ^{5 8} Additionally, unequal access to technology may disadvantage some patients. For dermatologists to provide optimal care and continue to contribute accurate and insightful observations into COVID-19, it is essential to be physically present in the clinic and in the hospital when necessary, caring for patients in need of dermatologic expertise. Creative management strategies developed during this time will benefit patients and expand the reach of the specialty . ^{5 8}

Final Thoughts

The COVID-19 pandemic has profoundly challenged the medical community and dermatology is no exception. By documenting and characterizing the diverse cutaneous manifestations of this novel disease, dermatologists have furthered understanding of its pathophysiology and management. By adapting quickly and developing creative ways to deliver care, dermatologists have found ways to contribute, both large and small. As we take stock at this juncture of the pandemic, it is clear there remains much to learn. We hope dermatologists will continue to take an active role in meeting the challenges of this time.

The virus that causes COVID-19—SARS-CoV-2—has infected more than 128 million individuals, resulting in more than 2.8 million deaths worldwide between December 2019 and April 2021. Disease mortality primarily is driven by hypoxemic respiratory failure and systemic hypercoagulability, resulting in multisystem organ failure.¹ With more than 17 million Americans infected, the virus is estimated to have impacted someone within the social circle of nearly every American.²

[embed:render:related:node:237479]

The COVID-19 pandemic has highlighted resource limitations, delayed elective and preventive care, and rapidly increased the adoption of telemedicine, presenting a host of new challenges to providers in every medical specialty, including dermatology. Although COVID-19 primarily is a respiratory disease, clinical manifestations have been observed in nearly every organ, including the skin. The cutaneous manifestations of COVID-19 provide insight into disease diagnosis, prognosis, and pathophysiology. In this article, we review the cutaneous manifestations of COVID-19 and explore the state of knowledge regarding their pathophysiology and clinical significance. Finally, we discuss the role of dermatology consultants in the care of patients with COVID-19, and the impact of the pandemic on the field of dermatology. 

Prevalence of Cutaneous Findings in COVID-19

Early reports characterizing the clinical presentation of patients hospitalized with COVID-19 suggested skin findings associated with the disease were rare. Cohort studies from Europe, China, and New York City in January through March 2020 reported a low prevalence or made no mention of rash.^3-7 However, reports from dermatologists in Italy that emerged in May 2020 indicated a substantially higher proportion of cutaneous disease: 18 of 88 (20.4%) hospitalized patients were found to have cutaneous involvement, primarily consisting of erythematous rash, along with some cases of urticarial and vesicular lesions.⁸ In October 2020, a retrospective cohort study from Spain examining 2761 patients presenting to the emergency department or admitted to the hospital for COVID-19 found that 58 (2.1%) patients had skin lesions attributed to COVID-19.⁹

The wide range in reported prevalence of skin lesions may be due to variable involvement of dermatologic specialists in patient care, particularly in China.¹⁰ Some variation also may be due to variability in the timing of clinical examination, as well as demographic and clinical differences in patient populations. Of note, a multisystem inflammatory disease seen in US children subsequent to infection with COVID-19 has been associated with rash in as many as 74% of cases.¹¹ Although COVID-19 disproportionately impacts people with skin of color, there are few reports of cutaneous manifestations in that population,¹² highlighting the challenges of the dermatologic examination in individuals with darker skin and suggesting the prevalence of dermatologic disease in COVID-19 may be greater than reported. 

Morphologic Patterns of Cutaneous Involvement in COVID-19

Researchers in Europe and the United States have attempted to classify the cutaneous manifestations of COVID-19. A registry established through the American Academy of Dermatology published a compilation of reports from 31 countries, totaling 716 patient profiles.¹³ A prospective Spanish study detailed the cutaneous involvement of 375 patients with suspected or confirmed COVID-19.¹⁴ Together, these efforts have revealed several distinct patterns of cutaneous involvement associated with COVID-19 (Table).^9,15-18 

CT107004209_Table.JPG

Vesicular Rash
Vesicular rash associated with COVID-19 has been described in several studies and case series^8,13,14 and is considered, along with the pseudopernio (or pseudochilblains) morphology, to be one of the more disease-specific patterns in COVID-19.^14,18 Vesicular rash appears to comprise roughly one-tenth of all COVID-19–associated rashes.^13,14 It usually is described as pruritic, with 72% to 83% of patients reporting itch.^13,16 

Small monomorphic or polymorphic vesicles predominantly on the trunk and to a lesser extent the extremities and head have been described by multiple authors.^14,16 Vesicular rash is most common among middle-aged individuals, with studies reporting median and mean ages ranging from 40.5 to 55 years.^9,13,14,16

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Vesicular rash develops concurrent with or after other presenting symptoms of COVID-19; in 2 studies, vesicular rash preceded development of other symptoms in only 15% and 5.6% of cases, respectively.^13,14 Prognostically, vesicular rash is associated with moderate disease severity.^14,16 It may persist for an average of 8 to 10 days.^14,16,18

Histopathologic examination reveals basal layer vacuolar degeneration, hyperchromatic keratinocytes, acantholysis, and dyskeratosis.^9,16,18 

Urticarial Rash
Urticarial lesions represent approximately 7% to 19% of reported COVID-19–associated rashes.^9,13,14 Urticarial rashes in patients testing positive for SARS-CoV-2 primarily occur on the trunk.¹⁴ The urticaria, which typically last about 1 week,¹⁴ are seen most frequently in middle-aged patients (mean/median age, 42–48 years)^13,14 and are associated with pruritus, which has been reported in 74% to 92% of patients.^13,14 Urticarial lesions typically do not precede other symptoms of COVID-19 and are nonspecific, making them less useful diagnostically.¹⁴

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Urticaria appears to be associated with more severe COVID-19 illness in several studies, but this finding may be confounded by several factors, including older age, increased tobacco use, and polypharmacy. Of 104 patients with reported urticarial rash and suspected or confirmed COVID-19 across 3 studies, only 1 death was reported.^9,13,14 

The histopathologic appearance is that of typical hives, demonstrating a perivascular infiltrate of lymphocytes and eosinophils with edema of the upper dermis.^9,19

Morbilliform Eruption
Morbilliform eruption is a commonly reported morphology associated with COVID-19, accounting for 20% to 47% of rashes.^9,13,14 This categorization may have limited utility from a diagnostic and prognostic perspective, given that morbilliform eruptions are common, nonspecific, and heterogenous and can arise from many causes.^9,13,14 Onset of morbilliform eruption appears to coincide with¹⁴ or follow^13,20,21 the development of other COVID-19–related symptoms, with 5% of patients reporting morbilliform rash as the initial manifestation of infection.^13,14 Morbilliform eruptions have been observed to occur in patients with more severe disease.^9,13,14

Certain morphologic subtypes, such as erythema multiforme–like, erythema elevatum diutinum–like, or pseudovesicular, may be more specific to COVID-19 infection.¹⁴ A small case series highlighted 4 patients with erythema multiforme–like eruptions, 3 of whom also were found to have petechial enanthem occurring after COVID-19 diagnosis; however, the investigators were unable to exclude drug reaction as a potential cause of rash in these patients.²² Another case series of 21 patients with COVID-19 and skin rash described a (primarily) petechial enanthem on the palate in 6 (28.5%) patients.²³ It is unclear to what extent oral enanthem may be underrecognized given that some physicians may be disinclined to remove the masks of known COVID-19–positive patients to examine the oral cavity.

The histologic appearance of morbilliform rash seen in association with COVID-19 has been described as spongiotic with interface dermatitis with perivascular lymphocytic inflammation.^9,21

COVID Toes, Pseudochilblains Rash, Perniolike Rash, and Acral Erythema/Edema
Of all the rashes associated with COVID-19, COVID toes, or pseudochilblains rash, has perhaps attracted the most attention. The characteristic violaceous erythema on the fingers and/or toes may be itchy or painful, presenting similar to idiopathic cases of pernio (Figure 1).¹⁴ The entity has been controversial because of an absence of a clear correlation with a positive SARS-CoV-2 polymerase chain reaction test or antibodies to the virus in a subset of reported cases.^24,25 Onset of the rash late in the disease course, generally after symptom resolution in mild or asymptomatic cases, may explain the absence of viral DNA in the nasopharynx by the time of lesion appearance.^14,26 Seronegative patients may have cleared SARS-CoV-2 infection before humoral immunity could occur via a strong type 1 interferon response.²⁵

Alum_1.JPG

Across 3 studies, perniolike skin lesions constituted 18% to 29% of COVID-19–associated skin findings^9,13,14 and persisted for an average of 12 to 14 days.^13,14 Perniolike lesions portend a favorable outcome; patients with COVID toes rarely present with systemic symptoms or laboratory or imaging abnormalities⁹ and less commonly require hospitalization for severe illness. Perniolike lesions have been reported most frequently in younger patients, with a median or mean age of 32 to 35 years.^13,14

[embed:render:related:node:231153]

Histology demonstrates lichenoid dermatitis with perivascular and periadnexal lymphocytic infiltrates.⁹ Notably, one study observed interface dermatitis of the intraepidermal portion of the acrosyringium, a rare finding in chilblain lupus, in 83% of patients (N=40).²⁵ Direct immunofluorescence demonstrates a vasculopathic pattern, with some patients showing deposition of IgM or IgG, C3, and fibrinogen in dermal blood vessels. Vascular C9 deposits also have been demonstrated on immunohistochemistry.⁹ Biopsies of perniolike lesions in COVID-19 patients have demonstrated the presence of SARS-CoV-2 RNA,²⁷ have identified SARS-CoV-2 spike protein in endothelial cells on immunohistochemistry, and have visualized intracytoplasmic viral particles in vascular endothelium on electron microscopy.²⁸

Livedoid Rash/Retiform Purpura
Netlike purpuric or violaceous patches signifying vessel damage or occlusion have been seen in association with COVID-19, constituting approximately 6% of COVID-19–associated skin findings in 2 studies.^13,14 Livedoid rash (Figure 2) and retiform purpura (Figure 3) are associated with older age and occur primarily in severely ill patients, including those requiring intensive care. In a registry of 716 patients with COVID-19, 100% of patients with retiform purpura were hospitalized, and 82% had acute respiratory distress syndrome.¹³ In another study, 33% (7/21) of patients with livedoid and necrotic lesions required intensive care, and 10% (2/21) died.¹⁴

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Multisystem Inflammatory Disease in Children

A hyperinflammatory syndrome similar to Kawasaki disease and toxic shock syndrome associated with mucocutaneous, cardiac, and gastrointestinal manifestations has been reported following COVID-19 infection.³¹ This syndrome, known as multisystem inflammatory syndrome in children (MIS-C), predominantly affects adolescents and children older than 5 years,¹¹ typically occurs 2 to 4 weeks after infection, and appears to be at least 100-times less common than COVID-19 infection among the same age group.³¹ Sixty percent³¹ to 74%¹¹ of affected patients have mucocutaneous involvement, with the most common clinical findings being conjunctival injection, palmoplantar erythema, lip hyperemia, periorbital erythema and edema, strawberry tongue, and malar erythema, respectively.³²

Because this condition appears to reflect an immune response to the virus, the majority of cases demonstrate negative SARS-CoV-2 polymerase chain reaction and positive antibody testing.³³ Although cutaneous findings are similar to those seen in Kawasaki disease, certain findings have been noted in MIS-C that are not typical of Kawasaki disease, including heliotrope rash–like periorbital edema and erythema as well as erythema infectiosum–like malar erythema and reticulated erythematous eruptions.³²

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The course of MIS-C can be severe; in one case series of patients presenting with MIS-C, 80% (79/99) required intensive care unit admission, with 10% requiring mechanical ventilation and 2% of patients dying during admission.³¹ Cardiac dysfunction, coagulopathy, and gastrointestinal symptoms are common.^11,31 It has been postulated that a superantigenlike region of the SARS-CoV-2 spike protein, similar to that of staphylococcal enterotoxin B, may underlie MIS-C and account for its similarities to toxic shock syndrome.³⁴ Of note, a similar multisystem inflammatory syndrome associated with COVID-19 also has been described in adults, and it too may present with rash as a cardinal feature.³⁵

Pathophysiology of COVID-19: What the Skin May Reveal About the Disease

The diverse range of cutaneous manifestations in COVID-19 reflects a spectrum of host immunologicresponses to SARS-CoV-2 and may inform the pathophysiology of the disease as well as potential treatment modalities.

Host Response to SARS-CoV-2
The body’s response to viral infection is 2-pronged, involving activation of cellular antiviral defenses mediated by type I and III interferons, as well as recruitment of leukocytes, mobilized by cytokines and chemokines.^36,37 Infection with SARS-CoV-2 results in a unique inflammatory response characterized by suppression of interferons, juxtaposed with a rampant proinflammatory cytokine and chemokine response, reminiscent of a cytokine storm. Reflective of this imbalance, a study of 50 COVID-19 patients and 20 healthy controls found decreased natural killer cells and CD3⁺ T cells in COVID-19 patients, particularly severely or critically ill patients, with an increase in B cells and monocytes.³⁸ This distinctive immune imbalance positions SARS-CoV-2 to thrive in the absence of inhibitory interferon activity while submitting the host to the deleterious effects of a cytokine surge.³⁶

Type I Interferons
The perniolike lesions associated with mild COVID-19 disease¹⁴ may represent a robust immune response via effective stimulation of type I interferons (IFN-1). Similar perniolike lesions are observed in Aicardi-Goutières syndrome³⁷ and familial chilblain lupus, hereditary interferonopathies associated with mutations in the TREX1 (three prime repair exonuclease 1) gene and characterized by inappropriate upregulation of IFN-1,³⁹ resulting in chilblains. It has been suggested that perniolike lesions in COVID-19 result from IFN-1 activation—a robust effective immunologic response to the virus.^14,26,40

On the other end of the spectrum, patients with severe COVID-19 may have a blunted IFN-1 response and reduced IFN-1–stimulated gene expression.^36,38 Notably, low IFN-1 response preceded clinical deterioration and was associated with increased risk for evolution to critical illness.³⁸ Severe disease from COVID-19 also is more commonly observed in older patients and those with comorbidities,¹ both of which are known factors associated with depressed IFN-1 function.^38,41 Reflective of this disparate IFN-1 response, biopsies of COVID-19 perniosis have demonstrated striking expression of myxovirus resistance protein A (MXA), a marker for IFN-1 signaling in tissue, whereas its expression is absent in COVID-19 livedo/retiform purpura.²⁷

Familial chilblain lupus may be effectively treated by the Janus kinase inhibitor baricitinib,³⁹ which inhibits IFN-1 signaling. Baricitinib recently received emergency use authorization by the US Food and Drug Administration for treatment of severe COVID-19 pneumonia,^42,43 hinting to disordered IFN-1 signaling in the COVID-19 pathophysiology.

The impaired IFN-1 response in COVID-19 patients may be due to a unique characteristic of SARS-CoV-2: its ORF3b gene is a potent IFN-1 antagonist. In a series of experiments comparing SARS-CoV-2 to the related virus severe acute respiratory disease coronavirus (which was responsible for an epidemic in 2002), Konno et al⁴⁴ found that SARS-CoV-2 is more effectively able to downregulate host IFN-1, likely due to premature stop codons on ORF3b that produce a truncated version of the gene with amplified anti–IFN-1 activity.

 Cytokine Storm and Coagulation Cascade
This dulled interferon response is juxtaposed with a surge of inflammatory chemokines and cytokines, including IL-6, IL-8, IL-10, and tumor necrosis factor α, impairing innate immunity and leading to end-organ damage. This inflammatory response is associated with the influx of innate immune cells, specifically neutrophils and monocytes, which likely contribute to lung injury in COVID-19 acute respiratory distress syndrome.³⁸ It also is thought to lead to downstream activation of coagulation, with a high incidence of thrombotic events observed in patients with severe COVID-19.¹ In a retrospective study of 184 intensive care patients with COVID-19 receiving at least standard doses of thromboprophylaxis, venous thromboembolism occurred in 27% and arterial thrombotic events occurred in 3.7%.⁴⁵

Livedo racemosa and retiform purpura are cutaneous markers of hypercoagulability, which indicate an increased risk for systemic clotting in COVID-19. A positive feedback loop between the complement and coagulation cascades appears to be important.^{13,14,29,46-48} In addition, a few studies have reported antiphospholipid antibody positivity in hospitalized COVID-19 patients.^49,50

The high incidence of coagulopathy in severe COVID-19 has prompted many institutions to develop aggressive prophylactic anticoagulation protocols. Elevation of proinflammatory cytokines and observation of terminal complement activation in the skin and other organs has led to therapeutic trials of IL-6 inhibitors such as tocilizumab,⁵¹ complement inhibitors such as eculizumab, and Janus kinase inhibitors such as ruxolitinib and baricitinib.^42,48

COVID Long-Haulers
The long-term effects of immune dysregulation in COVID-19 patients remain to be seen. Viral triggering of autoimmune disease is a well-established phenomenon, seen in DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome and other dermatologic diseases, raising the possibility that dermatologists will see a rising incidence of cutaneous autoimmune disease in the aftermath of the pandemic. Disordered interferon stimulation could lead to increased incidence of interferon-mediated disorders, such as sarcoidosis and other granulomatous diseases. Vasculitislike skin lesions could persist beyond the acute infectious period. Recent data from a registry of 990 COVID-19 cases from 39 countries suggest that COVID-19 perniolike lesions may persist as long as 150 days.⁵² In a time of many unknowns, these questions serve as a call to action for rigorous data collection, contribution to existing registries for dermatologic manifestations of COVID-19, and long-term follow-up of COVID-19 patients by the dermatology community. 

Pandemic Dermatology

The pandemic has posed unprecedented challenges for patient care. The use of hydroxychloroquine as a popular but unproven treatment for COVID-19, ⁵³ particularly early in the pandemic, has resulted in drug shortages for patients with lupus and other autoimmune skin diseases. Meanwhile, the need for patients with complex dermatologic conditions to receive systemic immunosuppression has had to be balanced against the associated risks during a global pandemic. To help dermatologists navigate this dilemma, various subspecialty groups have issued guidelines, including the COVID-19 Task Force of the Medical Dermatology Society and Society of Dermatology Hospitalists, which recommends a stepwise approach to shared decision-making with the goal of minimizing both the risk for disease flare and that of infection. The use of systemic steroids and rituximab, as well as the dose of immunosuppression—particularly broad-acting immunosuppression—should be limited where permitted. ⁵⁴

Rapid adoption of telemedicine and remote monitoring strategies has enabled dermatologists to provide safe and timely care when in-person visits have not been possible, including for patients with confirmed or suspected COVID-19, as well as for hospitalized patients. ^55-57 Use of telemedicine has facilitated preservation of personal protective equipment at a time when these important resources have been scarce. For patients with transportation or scheduling barriers, telemedicine has even expanded access to care. 

However, this strategy cannot completely replace comprehensive in-person evaluation. Variability in video and photographic quality limits evaluation, while in-person physical examination can reveal subtle morphologic clues necessary for diagnosis. ^{5 8} Additionally, unequal access to technology may disadvantage some patients. For dermatologists to provide optimal care and continue to contribute accurate and insightful observations into COVID-19, it is essential to be physically present in the clinic and in the hospital when necessary, caring for patients in need of dermatologic expertise. Creative management strategies developed during this time will benefit patients and expand the reach of the specialty . ^{5 8}

Final Thoughts

The COVID-19 pandemic has profoundly challenged the medical community and dermatology is no exception. By documenting and characterizing the diverse cutaneous manifestations of this novel disease, dermatologists have furthered understanding of its pathophysiology and management. By adapting quickly and developing creative ways to deliver care, dermatologists have found ways to contribute, both large and small. As we take stock at this juncture of the pandemic, it is clear there remains much to learn. We hope dermatologists will continue to take an active role in meeting the challenges of this time.

Pyoderma gangrenosum (PG) is a rare, chronic, ulcerative, neutrophilic dermatosis of unclear etiology. Large, multicentered, randomized controlled trials (RCTs) are challenging due to the rarity of PG and the lack of a diagnostic confirmatory test; therefore, evidence-based guidelines for diagnosis and treatment are not well established. Current management of PG primarily is guided by case series, small clinical trials, and expert opinion.^1-4 We conducted a survey of expert medical dermatologists to highlight best practices in diagnostic and therapeutic approaches to PG.

[embed:render:related:node:213731]

Methods

The Society of Dermatology Hospitalists (SDH) Scientific Task Force gathered expert opinions from members of the SDH and Rheumatologic Dermatology Society (RDS) regarding PG workup and treatment through an online survey of 15 items (eTable 1). Subscribers of the SDH and RDS LISTSERVs were invited via email to participate in the survey from January 2016 to February 2016. Anonymous survey responses were collected and collated using SurveyMonkey. The survey results identified expert recommendations for evaluation, diagnosis, and treatment of PG and are reported as the sum of the percentage of respondents who answered always (almost 100% of the time) or often (more than half the time) following a particular course of action. A subanalysis was performed defining 2 groups of respondents based on the number of cases of PG treated per year (≥10 vs <10). Survey responses between each group were compared using χ² analysis with statistical significance set at P=.05.

CT106003119_eTable1.jpg

Results

Fifty-one respondents completed the survey out of 140 surveyed (36% response rate). All respondents were dermatologists, and 96% (49/51) were affiliated with an academic institution. Among the respondents, the number of PG cases managed per year ranged from 2 to 35.

[embed:render:related:node:156205]

Respondents consistently ordered skin biopsies (92% [47/51]) and tissue cultures (90% [46/51]), as well as certain ancillary tests, including complete blood cell count (96% [49/51]), complete metabolic panel (86% [44/51]), serum protein electrophoresis (76% [39/51]), and hepatitis panel (71% [36/51]). Other frequently ordered studies were rheumatoid factor (69% [35/51]), antinuclear antibodies (67% [34/51]), and antineutrophilic antibodies (65% [33/51]). Respondents frequently ordered erythrocyte sedimentation rate (59% [30/51]), C-reactive protein (55% [28/51]), cryoglobulins (53% [27/51]), urine protein electrophoresis (53% [27/51]), hypercoagulability workup (49% [25/51]), and serum immunofixation test (49% [25/51]). Human immunodeficiency virus testing (43% [22/51]), chest radiograph (41% [21/51]), colonoscopy (41% [21/51]) and referral to other specialties for workup—gastroenterology (38% [19/51]), hematology/oncology (14% [7/51]), and rheumatology (10% [5/51])—were less frequently ordered (eTable 2).

CT106003119_eTable2.jpg

CT106003119_Table.jpg

CT106003119_eTable3.jpg

Comment

Skin biopsies and tissue cultures were strongly recommended (>90% survey respondents) for the initial evaluation of lesions suspected to be PG to evaluate for typical histopathologic changes that appear early in the disease, to rule out PG mimickers such as infectious or vascular causes, and to prevent the detrimental effects of inappropriate treatment and delayed diagnosis.⁵

[embed:render:related:node:81592]

Suspected PG warrants a reasonable search for related conditions because more than 50% of PG cases are associated with comorbidities such as rheumatoid arthritis, inflammatory bowel disease, and hematologic disease/malignancy.^6,7 A complete blood cell count and comprehensive metabolic panel were recommended by most respondents, aiding in the preliminary screening for hematologic and infectious causes as well as detecting liver and kidney dysfunction associated with systemic conditions. Additionally, exclusion of infection or malignancy may be particularly important if the patient will undergo systemic immunosuppression. In challenging PG cases when initial findings are inconclusive and the clinical presentation does not direct workup (eg, colonoscopy to evaluate gastrointestinal tract symptoms), serum protein electrophoresis, hepatitis panel, rheumatoid factor, antinuclear antibodies, and antineutrophilic antibody tests also were frequently ordered by respondents to further evaluate for underlying or associated conditions.

This consensus regarding skin biopsies and certain ancillary tests is consistent with the proposed diagnostic criteria for classic ulcerative PG in which the absence or exclusion of other relevant causes of cutaneous ulcers is required based on the criteria.⁸ The importance of ensuring an accurate diagnosis is paramount, as a 10% misdiagnosis rate has been documented in the literature.⁵

Importantly, a stepwise diagnostic workup for PG is proposed based on survey results, which may limit unnecessary testing and the associated costs to the health care system (Figure 1). Selection of additional testing is guided by initial test results and features of the patient’s clinical presentation, including age, review of systems, and associated comorbidities. Available data suggest that underlying inflammatory bowel disease is more frequent in PG patients who are younger than 65 years, whereas those who are 65 years and older are more likely to have inflammatory arthritis, cancer, or an underlying hematologic disorder.⁹

Afifi_new_Fig1.jpg

Afifi_new_Fig2.jpg

[embed:render:related:node:111408]

Respondents strongly recommended petrolatum-impregnated gauze and other nonadhesive dressings, including alginate and hydrocolloid dressings, as part of PG wound care. Topical antimicrobials and compression stockings also were recommended by respondents. These practices aim to promote moist environments for healing, avoid maceration, prevent superinfection, optimize wound healing, and minimize damage from adhesive injury.¹² Wound debridement and grafting generally were not recommended. However, pathergy is not a universal phenomenon in PG, and wounds that are no longer in the inflammatory phase may benefit from gentle debridement of necrotic tissue and/or grafting in select cases.¹⁰

Conclusion

An approach to modifying PG management based on clinical presentation and the practice of combination therapy with multiple systemic agents in refractory PG cases was not addressed in our survey. The low response rate is a limitation; however, the opinions of 51 medical dermatologist experts who regularly manage PG (in contrast to papers based on individualized clinical experience) can provide important clinical guidance until more scientific evidence is established.
 

Acknowledgments
We would like to thank the SDH and RDS membership for their participation in this survey. We especially acknowledge the other members of the SDH Scientific Task Force for their feedback: Misha Rosenbach, MD (Philadelphia, Pennsylvania); Robert G. Micheletti, MD (Philadelphia, Pennsylvania); Karolyn Wanat, MD (Milwaukee, Wisconsin); Amy Chen, MD (Cromwell, Connecticut); and A. Rambi Cardones, MD (Durham, North Carolina).

Pyoderma gangrenosum (PG) is a rare, chronic, ulcerative, neutrophilic dermatosis of unclear etiology. Large, multicentered, randomized controlled trials (RCTs) are challenging due to the rarity of PG and the lack of a diagnostic confirmatory test; therefore, evidence-based guidelines for diagnosis and treatment are not well established. Current management of PG primarily is guided by case series, small clinical trials, and expert opinion.^1-4 We conducted a survey of expert medical dermatologists to highlight best practices in diagnostic and therapeutic approaches to PG.

[embed:render:related:node:213731]

Methods

The Society of Dermatology Hospitalists (SDH) Scientific Task Force gathered expert opinions from members of the SDH and Rheumatologic Dermatology Society (RDS) regarding PG workup and treatment through an online survey of 15 items (eTable 1). Subscribers of the SDH and RDS LISTSERVs were invited via email to participate in the survey from January 2016 to February 2016. Anonymous survey responses were collected and collated using SurveyMonkey. The survey results identified expert recommendations for evaluation, diagnosis, and treatment of PG and are reported as the sum of the percentage of respondents who answered always (almost 100% of the time) or often (more than half the time) following a particular course of action. A subanalysis was performed defining 2 groups of respondents based on the number of cases of PG treated per year (≥10 vs <10). Survey responses between each group were compared using χ² analysis with statistical significance set at P=.05.

CT106003119_eTable1.jpg

Results

Fifty-one respondents completed the survey out of 140 surveyed (36% response rate). All respondents were dermatologists, and 96% (49/51) were affiliated with an academic institution. Among the respondents, the number of PG cases managed per year ranged from 2 to 35.

[embed:render:related:node:156205]

Respondents consistently ordered skin biopsies (92% [47/51]) and tissue cultures (90% [46/51]), as well as certain ancillary tests, including complete blood cell count (96% [49/51]), complete metabolic panel (86% [44/51]), serum protein electrophoresis (76% [39/51]), and hepatitis panel (71% [36/51]). Other frequently ordered studies were rheumatoid factor (69% [35/51]), antinuclear antibodies (67% [34/51]), and antineutrophilic antibodies (65% [33/51]). Respondents frequently ordered erythrocyte sedimentation rate (59% [30/51]), C-reactive protein (55% [28/51]), cryoglobulins (53% [27/51]), urine protein electrophoresis (53% [27/51]), hypercoagulability workup (49% [25/51]), and serum immunofixation test (49% [25/51]). Human immunodeficiency virus testing (43% [22/51]), chest radiograph (41% [21/51]), colonoscopy (41% [21/51]) and referral to other specialties for workup—gastroenterology (38% [19/51]), hematology/oncology (14% [7/51]), and rheumatology (10% [5/51])—were less frequently ordered (eTable 2).

CT106003119_eTable2.jpg

CT106003119_Table.jpg

CT106003119_eTable3.jpg

Comment

Skin biopsies and tissue cultures were strongly recommended (>90% survey respondents) for the initial evaluation of lesions suspected to be PG to evaluate for typical histopathologic changes that appear early in the disease, to rule out PG mimickers such as infectious or vascular causes, and to prevent the detrimental effects of inappropriate treatment and delayed diagnosis.⁵

[embed:render:related:node:81592]

Suspected PG warrants a reasonable search for related conditions because more than 50% of PG cases are associated with comorbidities such as rheumatoid arthritis, inflammatory bowel disease, and hematologic disease/malignancy.^6,7 A complete blood cell count and comprehensive metabolic panel were recommended by most respondents, aiding in the preliminary screening for hematologic and infectious causes as well as detecting liver and kidney dysfunction associated with systemic conditions. Additionally, exclusion of infection or malignancy may be particularly important if the patient will undergo systemic immunosuppression. In challenging PG cases when initial findings are inconclusive and the clinical presentation does not direct workup (eg, colonoscopy to evaluate gastrointestinal tract symptoms), serum protein electrophoresis, hepatitis panel, rheumatoid factor, antinuclear antibodies, and antineutrophilic antibody tests also were frequently ordered by respondents to further evaluate for underlying or associated conditions.

This consensus regarding skin biopsies and certain ancillary tests is consistent with the proposed diagnostic criteria for classic ulcerative PG in which the absence or exclusion of other relevant causes of cutaneous ulcers is required based on the criteria.⁸ The importance of ensuring an accurate diagnosis is paramount, as a 10% misdiagnosis rate has been documented in the literature.⁵

Importantly, a stepwise diagnostic workup for PG is proposed based on survey results, which may limit unnecessary testing and the associated costs to the health care system (Figure 1). Selection of additional testing is guided by initial test results and features of the patient’s clinical presentation, including age, review of systems, and associated comorbidities. Available data suggest that underlying inflammatory bowel disease is more frequent in PG patients who are younger than 65 years, whereas those who are 65 years and older are more likely to have inflammatory arthritis, cancer, or an underlying hematologic disorder.⁹

Afifi_new_Fig1.jpg

Afifi_new_Fig2.jpg

[embed:render:related:node:111408]

Respondents strongly recommended petrolatum-impregnated gauze and other nonadhesive dressings, including alginate and hydrocolloid dressings, as part of PG wound care. Topical antimicrobials and compression stockings also were recommended by respondents. These practices aim to promote moist environments for healing, avoid maceration, prevent superinfection, optimize wound healing, and minimize damage from adhesive injury.¹² Wound debridement and grafting generally were not recommended. However, pathergy is not a universal phenomenon in PG, and wounds that are no longer in the inflammatory phase may benefit from gentle debridement of necrotic tissue and/or grafting in select cases.¹⁰

Conclusion

An approach to modifying PG management based on clinical presentation and the practice of combination therapy with multiple systemic agents in refractory PG cases was not addressed in our survey. The low response rate is a limitation; however, the opinions of 51 medical dermatologist experts who regularly manage PG (in contrast to papers based on individualized clinical experience) can provide important clinical guidance until more scientific evidence is established.
 

Acknowledgments
We would like to thank the SDH and RDS membership for their participation in this survey. We especially acknowledge the other members of the SDH Scientific Task Force for their feedback: Misha Rosenbach, MD (Philadelphia, Pennsylvania); Robert G. Micheletti, MD (Philadelphia, Pennsylvania); Karolyn Wanat, MD (Milwaukee, Wisconsin); Amy Chen, MD (Cromwell, Connecticut); and A. Rambi Cardones, MD (Durham, North Carolina).

Pyoderma gangrenosum (PG) is a rare, chronic, ulcerative, neutrophilic dermatosis of unclear etiology. Large, multicentered, randomized controlled trials (RCTs) are challenging due to the rarity of PG and the lack of a diagnostic confirmatory test; therefore, evidence-based guidelines for diagnosis and treatment are not well established. Current management of PG primarily is guided by case series, small clinical trials, and expert opinion.^1-4 We conducted a survey of expert medical dermatologists to highlight best practices in diagnostic and therapeutic approaches to PG.

[embed:render:related:node:213731]

Methods

The Society of Dermatology Hospitalists (SDH) Scientific Task Force gathered expert opinions from members of the SDH and Rheumatologic Dermatology Society (RDS) regarding PG workup and treatment through an online survey of 15 items (eTable 1). Subscribers of the SDH and RDS LISTSERVs were invited via email to participate in the survey from January 2016 to February 2016. Anonymous survey responses were collected and collated using SurveyMonkey. The survey results identified expert recommendations for evaluation, diagnosis, and treatment of PG and are reported as the sum of the percentage of respondents who answered always (almost 100% of the time) or often (more than half the time) following a particular course of action. A subanalysis was performed defining 2 groups of respondents based on the number of cases of PG treated per year (≥10 vs <10). Survey responses between each group were compared using χ² analysis with statistical significance set at P=.05.

CT106003119_eTable1.jpg

Results

Fifty-one respondents completed the survey out of 140 surveyed (36% response rate). All respondents were dermatologists, and 96% (49/51) were affiliated with an academic institution. Among the respondents, the number of PG cases managed per year ranged from 2 to 35.

[embed:render:related:node:156205]

Respondents consistently ordered skin biopsies (92% [47/51]) and tissue cultures (90% [46/51]), as well as certain ancillary tests, including complete blood cell count (96% [49/51]), complete metabolic panel (86% [44/51]), serum protein electrophoresis (76% [39/51]), and hepatitis panel (71% [36/51]). Other frequently ordered studies were rheumatoid factor (69% [35/51]), antinuclear antibodies (67% [34/51]), and antineutrophilic antibodies (65% [33/51]). Respondents frequently ordered erythrocyte sedimentation rate (59% [30/51]), C-reactive protein (55% [28/51]), cryoglobulins (53% [27/51]), urine protein electrophoresis (53% [27/51]), hypercoagulability workup (49% [25/51]), and serum immunofixation test (49% [25/51]). Human immunodeficiency virus testing (43% [22/51]), chest radiograph (41% [21/51]), colonoscopy (41% [21/51]) and referral to other specialties for workup—gastroenterology (38% [19/51]), hematology/oncology (14% [7/51]), and rheumatology (10% [5/51])—were less frequently ordered (eTable 2).

CT106003119_eTable2.jpg

CT106003119_Table.jpg

CT106003119_eTable3.jpg

Comment

Skin biopsies and tissue cultures were strongly recommended (>90% survey respondents) for the initial evaluation of lesions suspected to be PG to evaluate for typical histopathologic changes that appear early in the disease, to rule out PG mimickers such as infectious or vascular causes, and to prevent the detrimental effects of inappropriate treatment and delayed diagnosis.⁵

[embed:render:related:node:81592]

Suspected PG warrants a reasonable search for related conditions because more than 50% of PG cases are associated with comorbidities such as rheumatoid arthritis, inflammatory bowel disease, and hematologic disease/malignancy.^6,7 A complete blood cell count and comprehensive metabolic panel were recommended by most respondents, aiding in the preliminary screening for hematologic and infectious causes as well as detecting liver and kidney dysfunction associated with systemic conditions. Additionally, exclusion of infection or malignancy may be particularly important if the patient will undergo systemic immunosuppression. In challenging PG cases when initial findings are inconclusive and the clinical presentation does not direct workup (eg, colonoscopy to evaluate gastrointestinal tract symptoms), serum protein electrophoresis, hepatitis panel, rheumatoid factor, antinuclear antibodies, and antineutrophilic antibody tests also were frequently ordered by respondents to further evaluate for underlying or associated conditions.

This consensus regarding skin biopsies and certain ancillary tests is consistent with the proposed diagnostic criteria for classic ulcerative PG in which the absence or exclusion of other relevant causes of cutaneous ulcers is required based on the criteria.⁸ The importance of ensuring an accurate diagnosis is paramount, as a 10% misdiagnosis rate has been documented in the literature.⁵

Importantly, a stepwise diagnostic workup for PG is proposed based on survey results, which may limit unnecessary testing and the associated costs to the health care system (Figure 1). Selection of additional testing is guided by initial test results and features of the patient’s clinical presentation, including age, review of systems, and associated comorbidities. Available data suggest that underlying inflammatory bowel disease is more frequent in PG patients who are younger than 65 years, whereas those who are 65 years and older are more likely to have inflammatory arthritis, cancer, or an underlying hematologic disorder.⁹

Afifi_new_Fig1.jpg

Afifi_new_Fig2.jpg

[embed:render:related:node:111408]

Respondents strongly recommended petrolatum-impregnated gauze and other nonadhesive dressings, including alginate and hydrocolloid dressings, as part of PG wound care. Topical antimicrobials and compression stockings also were recommended by respondents. These practices aim to promote moist environments for healing, avoid maceration, prevent superinfection, optimize wound healing, and minimize damage from adhesive injury.¹² Wound debridement and grafting generally were not recommended. However, pathergy is not a universal phenomenon in PG, and wounds that are no longer in the inflammatory phase may benefit from gentle debridement of necrotic tissue and/or grafting in select cases.¹⁰

Conclusion

An approach to modifying PG management based on clinical presentation and the practice of combination therapy with multiple systemic agents in refractory PG cases was not addressed in our survey. The low response rate is a limitation; however, the opinions of 51 medical dermatologist experts who regularly manage PG (in contrast to papers based on individualized clinical experience) can provide important clinical guidance until more scientific evidence is established.
 

Acknowledgments
We would like to thank the SDH and RDS membership for their participation in this survey. We especially acknowledge the other members of the SDH Scientific Task Force for their feedback: Misha Rosenbach, MD (Philadelphia, Pennsylvania); Robert G. Micheletti, MD (Philadelphia, Pennsylvania); Karolyn Wanat, MD (Milwaukee, Wisconsin); Amy Chen, MD (Cromwell, Connecticut); and A. Rambi Cardones, MD (Durham, North Carolina).