Infection with Mycobacterium haemophilum, a rare, slow-growing organism, most commonly presents as ulcerating cutaneous lesions and subcutaneous nodules in immunocompromised adults.¹ The most common clinical presentation in adults includes cutaneous lesions, nodules, cysts, and papules, with signs and symptoms of erythema, pain, pruritus, and drainage.² Disseminated disease states of septic arthritis, pulmonary infiltration, and osteomyelitis, though life-threatening, are less common manifestations reported in highly immunocompromised persons.³

Infection with M haemophilum presents a challenge to the dermatology community because it is infrequently suspected and misidentified, resulting in delayed diagnosis. Additionally, M haemophilum is an extremely fastidious organism that requires heme-supplemented culture media and a carefully regulated low temperature for many consecutive weeks to yield valid culture results.¹ These features contribute to complications and delays in diagnosis of an already overlooked source of infection.

We discuss the clinical presentation, diagnosis, and treatment of 3 unusual cases of cutaneous M haemophilum infection involving the upper arms. The findings in these cases highlight the challenges inherent in diagnosis as well as the obstacles that arise in providing effective, long-term treatment of this infection.

Case Reports

Patient 1
A 69-year-old woman with a medical history of a single functioning kidney and moderate psoriasis managed with low-dosage methotrexate presented with an erythematous nonhealing wound on the left forearm that developed after she was scratched by a dog. The pustules, appearing as bright red, tender, warm abscesses, had been present for 3 months and were distributed on the left proximal and distal dorsal forearm (Figure 1A). The patient reported no recent travel, sick contacts, allergies, or new medications.

A shave biopsy was initially obtained. Swab specimens were sent for bacterial, fungal, and mycobacterial culture following discontinuation of methotrexate. Initial histopathologic analysis revealed aggregates of histiocytes and multinucleated giant cells within the dermis, surrounded by infiltrates of lymphocytes and neutrophils (Figure 2), consistent with a dermal noncaseating granulomatosis. Acid-fast bacilli (AFB), periodic acid–Schiff, Gram, and Grocott-Gomori methenamine-silver stains were negative for pathogenic microorganisms. There was no evidence of vasculitis.

Despite negative special stains, an infectious cause was still suspected. Oral doxycycline monohydrate 100 mg twice daily, oral fluconazole 200 mg daily, and econazole cream 1% were prescribed because of concern for mycobacterial infection and initial growth of Candida parapsilosis in the swab culture.

A punch biopsy also was performed at this time for both repeat histopathologic analysis and tissue culture. Follow-up appointments were scheduled every 2 weeks. Staining by AFB of the repeat histopathologic specimen was negative.

The patient demonstrated symptomatic and aesthetic improvement (Figure 1B) during consecutive regular follow-up appointments while culture results were pending. No lesions appeared above the left elbow and she had no lymphadenopathy. Results of blood chemistry analyses and complete blood cell count throughout follow-up were normal.

The final tissue culture report obtained 7 weeks after initial presentation showed growth of M haemophilum despite a negative smear. The swab culture that initially was taken did not grow pathogenic organisms.

The patient was referred to an infectious disease specialist who confirmed that the atypical mycobacterial infection likely was the main source of the cutaneous lesions. She was instructed to continue econazole cream 1% and was given prescriptions for clarithromycin 500 mg twice daily, ciprofloxacin 500 mg twice daily, and rifampin 300 mg twice daily for a total duration of 12 to 18 months. The patient has remained on this triple-drug regimen and demonstrated improvement in the lesions. She has been off methotrexate while on antibiotic therapy.

Patient 2
A 79-year-old man with a medical history of chronic lymphocytic leukemia, basal cell carcinoma, and squamous cell carcinoma presented with a nonhealing, painful, red lesion on the left forearm of 1 week’s duration. Physical examination revealed a violaceous nontender plaque with erosions and desquamation that was initially diagnosed as a carbuncle. The patient reported a similar eruption on the right foot that was successfully treated with silver sulfadiazine by another physician.

Biopsy was performed by the shave method for histologic analysis and tissue culture. Doxycycline 100 mg twice daily was prescribed because of high suspicion of infection. Histologic findings revealed granulomatous inflammation with pseudoepitheliomatous hyperplasia, reported as squamous cell carcinoma. A second opinion confirmed suspicion of an infectious process; the patient remained on doxycycline. During follow-up, the lesion progressed to a 5-cm plaque studded with pustules and satellite papules. Multiple additional tissue cultures were performed over 2 months until “light growth” of M haemophilum was reported.

The patient showed minimal improvement on tetracycline antibiotics. His condition was complicated by a photosensitivity reaction to doxycycline on the left and right forearms, hands, and nose. Consequently, triamcinolone was prescribed, doxycycline was discontinued, and minocycline 100 mg twice daily and ciprofloxacin 500 mg twice daily were prescribed.

Nine months after initial presentation, the lesions were still present but remarkably improved. The antibiotic regimen was discontinued after 11 months.

Patient 3
A 77-year-old woman with a history of rheumatoid arthritis treated with methotrexate and abatacept as well as cutaneous T-cell lymphoma treated with narrowband UVB radiation presented to the emergency department with fever and an inflamed right forearm (Figure 3A). Initial bacterial cultures of the wound and blood were negative.

Arm edema and pustules slowly resolved, but the eschar and verrucous plaques continued to slowly progress while the patient was off immunosuppression. She was kept off antibiotics until mycobacterial culture was positive at 4 weeks, at which time she was placed on doxycycline and clarithromycin. Final identification of M haemophilum was made at 6 weeks; consequently, doxycycline was discontinued and she was referred to infectious disease for multidrug therapy. She remained afebrile during the entire 6 weeks until cultures were final.

While immunosuppressants were discontinued and clarithromycin was administered, the plaque changed from an edematous pustular dermatitis to a verrucous crusted plaque. Neither epitrochlear nor axillary lymphadenopathy was noted during the treatment period. The infectious disease specialist prescribed azithromycin, ethambutol, and rifampin, which produced marked improvement (Figure 3B). The patient has remained off immunosuppressive therapy while on antibiotics.

Comment

Clinical Presentation and Diagnosis
Mycobacterium haemophilum is a rare infectious organism that affects primarily immunocompromised adults but also has been identified in immunocompetent adults and pediatric patients.² Commonly affected immunosuppressed groups include solid organ transplant recipients, bone marrow transplant recipients, human immunodeficiency virus–positive patients, and patients with rheumatoid arthritis.

The infection typically presents as small violaceous papules and pustules that become painful and erythematous, with progression and draining ulceration in later stages.² In our cases, all lesions tended to evolve into a verrucous plaque that slowly resolved with antibiotic therapy.

Due to the rarity of this infection, the initial differential diagnosis can include infection with other mycobacteria, Sporothrix, Staphylococcus aureus, and other fungal pathogens. Misdiagnosis is a common obstacle in the treatment of M haemophilum due to its rarity, often negative AFB stains, and slow growth on culture media; therefore, tissue culture is essential to successful diagnosis and management. The natural reservoir of M haemophilum is unknown, but infection has been associated with contaminated water sources.¹ In one case (patient 1), symptoms developed after a dog scratch; the other 2 patients were unaware of injury to the skin.Laboratory diagnosis of M haemophilum is inherently difficult and protracted. The species is a highly fastidious and slow-growing Mycobacterium that requires cooler (30°C) incubation for many weeks on agar medium enriched with hemin or ferric ammonium citrate to obtain valid growth.¹ To secure timely diagnosis, the organism’s slow agar growth warrants immediate tissue culture and biopsy when an immunocompromised patient presents with clinical features of atypical infection of an extremity. Mycobacterium haemophilum infection likely is underreported because of these difficulties in diagnosis.

Management
Although there are no standard guidelines for antibiotic treatment of M haemophilum, the current literature recommends triple-drug therapy with clarithromycin, ciprofloxacin, and rifamycin for at least 12 to 24 months.²

Upon clinical suspicion of an atypical Mycobacterium, we recommend a macrolide antibiotic over doxycycline, however, because this class of agents maintains broad coverage while being more specific for atypical mycobacteria. Although an atypical Mycobacterium was suspected early in the presentation in our cases, we discourage immediate use of triple-agent antibiotic therapy until laboratory evidence is procured to minimize antibiotic overuse in patients who do not have a final diagnosis. Single-agent therapy for prolonged treatment is discouraged for atypical mycobacterial infections because of the high risk of antibiotic resistance. Therapy should be tailored to the needs of the individual based on the extent of dissemination of disease and the severity of immunosuppression.^1,2

Additionally, underlying disease that results in immunosuppression might necessitate treatment reevaluation (as occurred in our cases) requiring cessation of immunosuppressive drugs, extended careful monitoring, and pharmacotherapeutic readjustment through the course of treatment. The degree to which antibiotics contribute to eradication of M haemophilum is unknown; therefore, it is recommended that long-term antibiotic use and treatment aimed at recovering the immunocompromised state (eg, highly active antiretroviral therapy in a patient with AIDS) be implemented.²

Conclusion

Our 3 cases of M haemophilum infection involved the upper extremities of immunosuppressed patients older than 65 years. This propensity to affect the upper extremities could possibly be due to the lower temperature required for growth of M haemophilum. Initial histopathologic study showed granulomatous and neutrophilic infiltrates, yet histopathologic specimens from all 3 patients failed to display positive AFB staining, which delayed the initial antibiotic choice. In all cases, diagnosis was made by tissue culture after swab culture failed to grow the pathogen. Furthermore, the 3 cases took approximately 6 weeks to achieve final identification of the organism. Neither clinical lymphadenopathy nor systemic spread was noted in our patients; immunosuppression was discontinued when possible.

Mycobacterium haemophilum is an uncommon but potentially life-threatening infection that should be suspected in immunocompromised adults who present with atypical cellulitis of the extremities. The ultimate diagnosis often is delayed because the organism grows slowly (as long as 8 weeks) in tissue culture. For that reason, empiric antibiotic treatment, including a macrolide, should be considered in patients with disseminated or severe infection or critical immunosuppression and in those who do not demonstrate improvement in symptoms once immunosuppressants are withheld. A prolonged course of multiple-drug antibiotic therapy has proved to be effective for treating cutaneous infection with M haemophilum.

Infection with Mycobacterium haemophilum, a rare, slow-growing organism, most commonly presents as ulcerating cutaneous lesions and subcutaneous nodules in immunocompromised adults.¹ The most common clinical presentation in adults includes cutaneous lesions, nodules, cysts, and papules, with signs and symptoms of erythema, pain, pruritus, and drainage.² Disseminated disease states of septic arthritis, pulmonary infiltration, and osteomyelitis, though life-threatening, are less common manifestations reported in highly immunocompromised persons.³

Infection with M haemophilum presents a challenge to the dermatology community because it is infrequently suspected and misidentified, resulting in delayed diagnosis. Additionally, M haemophilum is an extremely fastidious organism that requires heme-supplemented culture media and a carefully regulated low temperature for many consecutive weeks to yield valid culture results.¹ These features contribute to complications and delays in diagnosis of an already overlooked source of infection.

We discuss the clinical presentation, diagnosis, and treatment of 3 unusual cases of cutaneous M haemophilum infection involving the upper arms. The findings in these cases highlight the challenges inherent in diagnosis as well as the obstacles that arise in providing effective, long-term treatment of this infection.

Case Reports

Patient 1
A 69-year-old woman with a medical history of a single functioning kidney and moderate psoriasis managed with low-dosage methotrexate presented with an erythematous nonhealing wound on the left forearm that developed after she was scratched by a dog. The pustules, appearing as bright red, tender, warm abscesses, had been present for 3 months and were distributed on the left proximal and distal dorsal forearm (Figure 1A). The patient reported no recent travel, sick contacts, allergies, or new medications.

A shave biopsy was initially obtained. Swab specimens were sent for bacterial, fungal, and mycobacterial culture following discontinuation of methotrexate. Initial histopathologic analysis revealed aggregates of histiocytes and multinucleated giant cells within the dermis, surrounded by infiltrates of lymphocytes and neutrophils (Figure 2), consistent with a dermal noncaseating granulomatosis. Acid-fast bacilli (AFB), periodic acid–Schiff, Gram, and Grocott-Gomori methenamine-silver stains were negative for pathogenic microorganisms. There was no evidence of vasculitis.

Despite negative special stains, an infectious cause was still suspected. Oral doxycycline monohydrate 100 mg twice daily, oral fluconazole 200 mg daily, and econazole cream 1% were prescribed because of concern for mycobacterial infection and initial growth of Candida parapsilosis in the swab culture.

A punch biopsy also was performed at this time for both repeat histopathologic analysis and tissue culture. Follow-up appointments were scheduled every 2 weeks. Staining by AFB of the repeat histopathologic specimen was negative.

The patient demonstrated symptomatic and aesthetic improvement (Figure 1B) during consecutive regular follow-up appointments while culture results were pending. No lesions appeared above the left elbow and she had no lymphadenopathy. Results of blood chemistry analyses and complete blood cell count throughout follow-up were normal.

The final tissue culture report obtained 7 weeks after initial presentation showed growth of M haemophilum despite a negative smear. The swab culture that initially was taken did not grow pathogenic organisms.

The patient was referred to an infectious disease specialist who confirmed that the atypical mycobacterial infection likely was the main source of the cutaneous lesions. She was instructed to continue econazole cream 1% and was given prescriptions for clarithromycin 500 mg twice daily, ciprofloxacin 500 mg twice daily, and rifampin 300 mg twice daily for a total duration of 12 to 18 months. The patient has remained on this triple-drug regimen and demonstrated improvement in the lesions. She has been off methotrexate while on antibiotic therapy.

Patient 2
A 79-year-old man with a medical history of chronic lymphocytic leukemia, basal cell carcinoma, and squamous cell carcinoma presented with a nonhealing, painful, red lesion on the left forearm of 1 week’s duration. Physical examination revealed a violaceous nontender plaque with erosions and desquamation that was initially diagnosed as a carbuncle. The patient reported a similar eruption on the right foot that was successfully treated with silver sulfadiazine by another physician.

Biopsy was performed by the shave method for histologic analysis and tissue culture. Doxycycline 100 mg twice daily was prescribed because of high suspicion of infection. Histologic findings revealed granulomatous inflammation with pseudoepitheliomatous hyperplasia, reported as squamous cell carcinoma. A second opinion confirmed suspicion of an infectious process; the patient remained on doxycycline. During follow-up, the lesion progressed to a 5-cm plaque studded with pustules and satellite papules. Multiple additional tissue cultures were performed over 2 months until “light growth” of M haemophilum was reported.

The patient showed minimal improvement on tetracycline antibiotics. His condition was complicated by a photosensitivity reaction to doxycycline on the left and right forearms, hands, and nose. Consequently, triamcinolone was prescribed, doxycycline was discontinued, and minocycline 100 mg twice daily and ciprofloxacin 500 mg twice daily were prescribed.

Nine months after initial presentation, the lesions were still present but remarkably improved. The antibiotic regimen was discontinued after 11 months.

Patient 3
A 77-year-old woman with a history of rheumatoid arthritis treated with methotrexate and abatacept as well as cutaneous T-cell lymphoma treated with narrowband UVB radiation presented to the emergency department with fever and an inflamed right forearm (Figure 3A). Initial bacterial cultures of the wound and blood were negative.

Arm edema and pustules slowly resolved, but the eschar and verrucous plaques continued to slowly progress while the patient was off immunosuppression. She was kept off antibiotics until mycobacterial culture was positive at 4 weeks, at which time she was placed on doxycycline and clarithromycin. Final identification of M haemophilum was made at 6 weeks; consequently, doxycycline was discontinued and she was referred to infectious disease for multidrug therapy. She remained afebrile during the entire 6 weeks until cultures were final.

While immunosuppressants were discontinued and clarithromycin was administered, the plaque changed from an edematous pustular dermatitis to a verrucous crusted plaque. Neither epitrochlear nor axillary lymphadenopathy was noted during the treatment period. The infectious disease specialist prescribed azithromycin, ethambutol, and rifampin, which produced marked improvement (Figure 3B). The patient has remained off immunosuppressive therapy while on antibiotics.

Comment

Clinical Presentation and Diagnosis
Mycobacterium haemophilum is a rare infectious organism that affects primarily immunocompromised adults but also has been identified in immunocompetent adults and pediatric patients.² Commonly affected immunosuppressed groups include solid organ transplant recipients, bone marrow transplant recipients, human immunodeficiency virus–positive patients, and patients with rheumatoid arthritis.

The infection typically presents as small violaceous papules and pustules that become painful and erythematous, with progression and draining ulceration in later stages.² In our cases, all lesions tended to evolve into a verrucous plaque that slowly resolved with antibiotic therapy.

Due to the rarity of this infection, the initial differential diagnosis can include infection with other mycobacteria, Sporothrix, Staphylococcus aureus, and other fungal pathogens. Misdiagnosis is a common obstacle in the treatment of M haemophilum due to its rarity, often negative AFB stains, and slow growth on culture media; therefore, tissue culture is essential to successful diagnosis and management. The natural reservoir of M haemophilum is unknown, but infection has been associated with contaminated water sources.¹ In one case (patient 1), symptoms developed after a dog scratch; the other 2 patients were unaware of injury to the skin.Laboratory diagnosis of M haemophilum is inherently difficult and protracted. The species is a highly fastidious and slow-growing Mycobacterium that requires cooler (30°C) incubation for many weeks on agar medium enriched with hemin or ferric ammonium citrate to obtain valid growth.¹ To secure timely diagnosis, the organism’s slow agar growth warrants immediate tissue culture and biopsy when an immunocompromised patient presents with clinical features of atypical infection of an extremity. Mycobacterium haemophilum infection likely is underreported because of these difficulties in diagnosis.

Management
Although there are no standard guidelines for antibiotic treatment of M haemophilum, the current literature recommends triple-drug therapy with clarithromycin, ciprofloxacin, and rifamycin for at least 12 to 24 months.²

Upon clinical suspicion of an atypical Mycobacterium, we recommend a macrolide antibiotic over doxycycline, however, because this class of agents maintains broad coverage while being more specific for atypical mycobacteria. Although an atypical Mycobacterium was suspected early in the presentation in our cases, we discourage immediate use of triple-agent antibiotic therapy until laboratory evidence is procured to minimize antibiotic overuse in patients who do not have a final diagnosis. Single-agent therapy for prolonged treatment is discouraged for atypical mycobacterial infections because of the high risk of antibiotic resistance. Therapy should be tailored to the needs of the individual based on the extent of dissemination of disease and the severity of immunosuppression.^1,2

Additionally, underlying disease that results in immunosuppression might necessitate treatment reevaluation (as occurred in our cases) requiring cessation of immunosuppressive drugs, extended careful monitoring, and pharmacotherapeutic readjustment through the course of treatment. The degree to which antibiotics contribute to eradication of M haemophilum is unknown; therefore, it is recommended that long-term antibiotic use and treatment aimed at recovering the immunocompromised state (eg, highly active antiretroviral therapy in a patient with AIDS) be implemented.²

Conclusion

Our 3 cases of M haemophilum infection involved the upper extremities of immunosuppressed patients older than 65 years. This propensity to affect the upper extremities could possibly be due to the lower temperature required for growth of M haemophilum. Initial histopathologic study showed granulomatous and neutrophilic infiltrates, yet histopathologic specimens from all 3 patients failed to display positive AFB staining, which delayed the initial antibiotic choice. In all cases, diagnosis was made by tissue culture after swab culture failed to grow the pathogen. Furthermore, the 3 cases took approximately 6 weeks to achieve final identification of the organism. Neither clinical lymphadenopathy nor systemic spread was noted in our patients; immunosuppression was discontinued when possible.

Mycobacterium haemophilum is an uncommon but potentially life-threatening infection that should be suspected in immunocompromised adults who present with atypical cellulitis of the extremities. The ultimate diagnosis often is delayed because the organism grows slowly (as long as 8 weeks) in tissue culture. For that reason, empiric antibiotic treatment, including a macrolide, should be considered in patients with disseminated or severe infection or critical immunosuppression and in those who do not demonstrate improvement in symptoms once immunosuppressants are withheld. A prolonged course of multiple-drug antibiotic therapy has proved to be effective for treating cutaneous infection with M haemophilum.

Infection with Mycobacterium haemophilum, a rare, slow-growing organism, most commonly presents as ulcerating cutaneous lesions and subcutaneous nodules in immunocompromised adults.¹ The most common clinical presentation in adults includes cutaneous lesions, nodules, cysts, and papules, with signs and symptoms of erythema, pain, pruritus, and drainage.² Disseminated disease states of septic arthritis, pulmonary infiltration, and osteomyelitis, though life-threatening, are less common manifestations reported in highly immunocompromised persons.³

Infection with M haemophilum presents a challenge to the dermatology community because it is infrequently suspected and misidentified, resulting in delayed diagnosis. Additionally, M haemophilum is an extremely fastidious organism that requires heme-supplemented culture media and a carefully regulated low temperature for many consecutive weeks to yield valid culture results.¹ These features contribute to complications and delays in diagnosis of an already overlooked source of infection.

We discuss the clinical presentation, diagnosis, and treatment of 3 unusual cases of cutaneous M haemophilum infection involving the upper arms. The findings in these cases highlight the challenges inherent in diagnosis as well as the obstacles that arise in providing effective, long-term treatment of this infection.

Case Reports

Patient 1
A 69-year-old woman with a medical history of a single functioning kidney and moderate psoriasis managed with low-dosage methotrexate presented with an erythematous nonhealing wound on the left forearm that developed after she was scratched by a dog. The pustules, appearing as bright red, tender, warm abscesses, had been present for 3 months and were distributed on the left proximal and distal dorsal forearm (Figure 1A). The patient reported no recent travel, sick contacts, allergies, or new medications.

A shave biopsy was initially obtained. Swab specimens were sent for bacterial, fungal, and mycobacterial culture following discontinuation of methotrexate. Initial histopathologic analysis revealed aggregates of histiocytes and multinucleated giant cells within the dermis, surrounded by infiltrates of lymphocytes and neutrophils (Figure 2), consistent with a dermal noncaseating granulomatosis. Acid-fast bacilli (AFB), periodic acid–Schiff, Gram, and Grocott-Gomori methenamine-silver stains were negative for pathogenic microorganisms. There was no evidence of vasculitis.

Despite negative special stains, an infectious cause was still suspected. Oral doxycycline monohydrate 100 mg twice daily, oral fluconazole 200 mg daily, and econazole cream 1% were prescribed because of concern for mycobacterial infection and initial growth of Candida parapsilosis in the swab culture.

A punch biopsy also was performed at this time for both repeat histopathologic analysis and tissue culture. Follow-up appointments were scheduled every 2 weeks. Staining by AFB of the repeat histopathologic specimen was negative.

The patient demonstrated symptomatic and aesthetic improvement (Figure 1B) during consecutive regular follow-up appointments while culture results were pending. No lesions appeared above the left elbow and she had no lymphadenopathy. Results of blood chemistry analyses and complete blood cell count throughout follow-up were normal.

The final tissue culture report obtained 7 weeks after initial presentation showed growth of M haemophilum despite a negative smear. The swab culture that initially was taken did not grow pathogenic organisms.

The patient was referred to an infectious disease specialist who confirmed that the atypical mycobacterial infection likely was the main source of the cutaneous lesions. She was instructed to continue econazole cream 1% and was given prescriptions for clarithromycin 500 mg twice daily, ciprofloxacin 500 mg twice daily, and rifampin 300 mg twice daily for a total duration of 12 to 18 months. The patient has remained on this triple-drug regimen and demonstrated improvement in the lesions. She has been off methotrexate while on antibiotic therapy.

Patient 2
A 79-year-old man with a medical history of chronic lymphocytic leukemia, basal cell carcinoma, and squamous cell carcinoma presented with a nonhealing, painful, red lesion on the left forearm of 1 week’s duration. Physical examination revealed a violaceous nontender plaque with erosions and desquamation that was initially diagnosed as a carbuncle. The patient reported a similar eruption on the right foot that was successfully treated with silver sulfadiazine by another physician.

Biopsy was performed by the shave method for histologic analysis and tissue culture. Doxycycline 100 mg twice daily was prescribed because of high suspicion of infection. Histologic findings revealed granulomatous inflammation with pseudoepitheliomatous hyperplasia, reported as squamous cell carcinoma. A second opinion confirmed suspicion of an infectious process; the patient remained on doxycycline. During follow-up, the lesion progressed to a 5-cm plaque studded with pustules and satellite papules. Multiple additional tissue cultures were performed over 2 months until “light growth” of M haemophilum was reported.

The patient showed minimal improvement on tetracycline antibiotics. His condition was complicated by a photosensitivity reaction to doxycycline on the left and right forearms, hands, and nose. Consequently, triamcinolone was prescribed, doxycycline was discontinued, and minocycline 100 mg twice daily and ciprofloxacin 500 mg twice daily were prescribed.

Nine months after initial presentation, the lesions were still present but remarkably improved. The antibiotic regimen was discontinued after 11 months.

Patient 3
A 77-year-old woman with a history of rheumatoid arthritis treated with methotrexate and abatacept as well as cutaneous T-cell lymphoma treated with narrowband UVB radiation presented to the emergency department with fever and an inflamed right forearm (Figure 3A). Initial bacterial cultures of the wound and blood were negative.

Arm edema and pustules slowly resolved, but the eschar and verrucous plaques continued to slowly progress while the patient was off immunosuppression. She was kept off antibiotics until mycobacterial culture was positive at 4 weeks, at which time she was placed on doxycycline and clarithromycin. Final identification of M haemophilum was made at 6 weeks; consequently, doxycycline was discontinued and she was referred to infectious disease for multidrug therapy. She remained afebrile during the entire 6 weeks until cultures were final.

While immunosuppressants were discontinued and clarithromycin was administered, the plaque changed from an edematous pustular dermatitis to a verrucous crusted plaque. Neither epitrochlear nor axillary lymphadenopathy was noted during the treatment period. The infectious disease specialist prescribed azithromycin, ethambutol, and rifampin, which produced marked improvement (Figure 3B). The patient has remained off immunosuppressive therapy while on antibiotics.

Comment

Clinical Presentation and Diagnosis
Mycobacterium haemophilum is a rare infectious organism that affects primarily immunocompromised adults but also has been identified in immunocompetent adults and pediatric patients.² Commonly affected immunosuppressed groups include solid organ transplant recipients, bone marrow transplant recipients, human immunodeficiency virus–positive patients, and patients with rheumatoid arthritis.

The infection typically presents as small violaceous papules and pustules that become painful and erythematous, with progression and draining ulceration in later stages.² In our cases, all lesions tended to evolve into a verrucous plaque that slowly resolved with antibiotic therapy.

Due to the rarity of this infection, the initial differential diagnosis can include infection with other mycobacteria, Sporothrix, Staphylococcus aureus, and other fungal pathogens. Misdiagnosis is a common obstacle in the treatment of M haemophilum due to its rarity, often negative AFB stains, and slow growth on culture media; therefore, tissue culture is essential to successful diagnosis and management. The natural reservoir of M haemophilum is unknown, but infection has been associated with contaminated water sources.¹ In one case (patient 1), symptoms developed after a dog scratch; the other 2 patients were unaware of injury to the skin.Laboratory diagnosis of M haemophilum is inherently difficult and protracted. The species is a highly fastidious and slow-growing Mycobacterium that requires cooler (30°C) incubation for many weeks on agar medium enriched with hemin or ferric ammonium citrate to obtain valid growth.¹ To secure timely diagnosis, the organism’s slow agar growth warrants immediate tissue culture and biopsy when an immunocompromised patient presents with clinical features of atypical infection of an extremity. Mycobacterium haemophilum infection likely is underreported because of these difficulties in diagnosis.

Management
Although there are no standard guidelines for antibiotic treatment of M haemophilum, the current literature recommends triple-drug therapy with clarithromycin, ciprofloxacin, and rifamycin for at least 12 to 24 months.²

Upon clinical suspicion of an atypical Mycobacterium, we recommend a macrolide antibiotic over doxycycline, however, because this class of agents maintains broad coverage while being more specific for atypical mycobacteria. Although an atypical Mycobacterium was suspected early in the presentation in our cases, we discourage immediate use of triple-agent antibiotic therapy until laboratory evidence is procured to minimize antibiotic overuse in patients who do not have a final diagnosis. Single-agent therapy for prolonged treatment is discouraged for atypical mycobacterial infections because of the high risk of antibiotic resistance. Therapy should be tailored to the needs of the individual based on the extent of dissemination of disease and the severity of immunosuppression.^1,2

Additionally, underlying disease that results in immunosuppression might necessitate treatment reevaluation (as occurred in our cases) requiring cessation of immunosuppressive drugs, extended careful monitoring, and pharmacotherapeutic readjustment through the course of treatment. The degree to which antibiotics contribute to eradication of M haemophilum is unknown; therefore, it is recommended that long-term antibiotic use and treatment aimed at recovering the immunocompromised state (eg, highly active antiretroviral therapy in a patient with AIDS) be implemented.²

Conclusion

Our 3 cases of M haemophilum infection involved the upper extremities of immunosuppressed patients older than 65 years. This propensity to affect the upper extremities could possibly be due to the lower temperature required for growth of M haemophilum. Initial histopathologic study showed granulomatous and neutrophilic infiltrates, yet histopathologic specimens from all 3 patients failed to display positive AFB staining, which delayed the initial antibiotic choice. In all cases, diagnosis was made by tissue culture after swab culture failed to grow the pathogen. Furthermore, the 3 cases took approximately 6 weeks to achieve final identification of the organism. Neither clinical lymphadenopathy nor systemic spread was noted in our patients; immunosuppression was discontinued when possible.

Mycobacterium haemophilum is an uncommon but potentially life-threatening infection that should be suspected in immunocompromised adults who present with atypical cellulitis of the extremities. The ultimate diagnosis often is delayed because the organism grows slowly (as long as 8 weeks) in tissue culture. For that reason, empiric antibiotic treatment, including a macrolide, should be considered in patients with disseminated or severe infection or critical immunosuppression and in those who do not demonstrate improvement in symptoms once immunosuppressants are withheld. A prolonged course of multiple-drug antibiotic therapy has proved to be effective for treating cutaneous infection with M haemophilum.

Case Report

A 79-year-old man with chronic lymphocytic leukemia (CLL) who was being treated with ibrutinib presented to the emergency department with a dry cough, ataxia and falls, and vision loss. Physical examination was remarkable for diffuse crackles heard throughout the right lung and bilateral lower extremity weakness. Additionally, he had 4 pink mobile nodules on the left side of the forehead, right side of the chin, left submental area, and left postauricular scalp, which arose approximately 2 weeks prior to presentation. The left postauricular lesion had been tender at times and had developed a crust. The cutaneous lesions were all smaller than 2 cm.

The patient had a history of squamous cell carcinoma of the skin and was under the care of a dermatologist as an outpatient. His dermatologist had described him as an active gardener; he was noted to have healing abrasions on the forearms due to gardening raspberry bushes.

Computed tomography of the head revealed a 14-mm, ring-enhancing lesion in the left paramedian posterior frontal lobe with surrounding white matter vasogenic edema (Figure 1). Computed tomography of the chest revealed a peripheral mass on the right upper lobe measuring 6.3 cm at its greatest dimension (Figure 2).

Clinically, the constellation of symptoms was thought to represent an infectious process or less likely metastatic malignancy. Biopsies of the nodule on the right side of the chin were performed and sent for culture and histologic examination. Sections from the anterior right chin showed compact orthokeratosis overlying a slightly spongiotic epidermis (Figure 3). Within the deep dermis, there was a dense mixed inflammatory infiltrate comprising predominantly neutrophils, with occasional eosinophils, lymphocytes, and histiocytes (Figure 4).

Gram stain revealed gram-variable, branching, bacterial organisms morphologically consistent with Nocardia. Grocott-Gomori methenamine-silver and periodic acid–Schiff stains also highlighted the bacterial organisms (Figure 5). An auramine-O stain was negative for acid-fast microorganisms. After 3 days on a blood agar plate, cultures of a specimen of the chin nodule grew branching filamentous bacterial organisms consistent with Nocardia.

Comment

Presentation and Diagnosis
Nocardiosis is an infrequently encountered opportunistic infection that typically targets skin, lungs, and the central nervous system (CNS). Nocardia species characteristically are gram-positive, thin rods that form beaded, right-angle, branching filaments.¹ More than 50 Nocardia species have been clinically isolated.²

Definitive diagnosis requires culture. Nocardia grows well on nonselective media, such as blood or Löwenstein-Jensen agar; growth can be enhanced with 10% CO₂. Growth can be slow, however, and takes from 48 hours to several weeks. Nocardia typically grows as buff or pigmented, waxy, cerebriform colonies at 3 to 5 days’ incubation.¹

Cause of Infection
Nocardia species are commonly found in the environment—soil, plant matter, water, and decomposing organic material—as well as in the gastrointestinal tract and skin of animals. Infection has been reported in cattle, dogs, horses, swine, birds, cats, foxes, and a few other animals.² A history of exposure, such as gardening or handling animals, should increase suspicion of Nocardia.³ Although infection is classically thought to affect immunocompromised patients, there are case reports of immunocompetent individuals developing disseminated infection.^4-7 However, infected immunocompetent individuals typically have localized cutaneous infection, which often includes cellulitis, abscesses, or sporotrichoid patterns.² Cutaneous infections typically are the result of direct inoculation of the skin through a penetrating injury.⁸

Disseminated nocardiosis can be caused by numerous species and generally is the result of primary pulmonary infection.⁹ In these cases, skin disease is present in approximately 10% of patients. Disseminated infection from cutaneous nocardiosis is uncommon; when it does occur, the most common site of dissemination is the CNS, resulting in abscess or cerebritis.¹⁰ Therefore, CNS involvement should always be ruled out on diagnosis in immunocompromised patients, even if neurologic symptoms are absent.⁹ Nearly 80% of patients with disseminated disease are, in fact, immunocompromised.⁸

Association With CLL
Chronic lymphocytic leukemia is associated with profound immunodeficiency caused by quantitative and qualitative aberrations in both innate and adaptive immunity. This perturbation of the immune system predisposes the patient to infection.^11,12 Early in the course of CLL, a patient develops neutropenia, which predisposes to bacterial infection; later, the patient develops a sustained B- and T-cell immunodeficiency that predisposes to opportunistic infection.¹³ Treatment-naïve patients with CLL are commonly diagnosed with respiratory and urinary tract infections.¹² Chronic lymphocytic leukemia patients treated with alemtuzumab or purine analogs have been reported to have the highest risk for major infection.¹⁴

Ibrutinib is a commonly used treatment of CLL because it induces apoptosis in B cells, which are abnormal in CLL. Ibrutinib functions by inhibiting the Bruton tyrosine kinase pathway, which is essential in B-cell production and maintenance.¹⁵ Studies have reported a high rate of infection in ibrutinib-treated CLL patients^14,16; salvage ibrutinib therapy has been associated with higher infection risk than primary ibrutinib therapy.^16,17 Long-term follow-up studies have shown a decreased rate of infection in ibrutinib-treated CLL after 2 years or longer of treatment, suggesting a reconstitution of normal B cells and humoral immunity with longer ibrutinib therapy.^16,17

Many infections have been identified in association with ibrutinib therapy, including invasive aspergillosis, disseminated fusariosis, cerebral mucormycosis, disseminated cryptococcosis, and Pneumocystis jirovecii pneumonia.^18-22 Disseminated nocardiosis has been reported in a few patients with CLL, though the treatment they received for CLL varied from case to case.^23-25

Identification and Treatment
Clinical and microscopic identification of Nocardia organisms can be exceedingly difficult. Primary cutaneous nocardiosis clinically presents as tumors or nodules that often have a sporotrichoid pattern along the lymphatics. In disease that disseminates to skin, nocardiosis presents as vesiculopustules or abscesses. The biopsy specimen most often shows a dense dermal and subcutaneous infiltrate of neutrophils with abscess formation. Long-standing lesions might show chronic inflammation and nonspecific granulomas.

The appearance of Nocardia organisms is quite subtle on hematoxylin and eosin staining and can be easily missed. Special stains, such as Gram and Grocott-Gomori methenamine-silver stains as well as stains for acid-fast organisms, can be invaluable in diagnosing this disease. Biopsy in immunocompromised patients when nocardiosis is part of the differential diagnosis requires extra attention because the organisms can be gram variable and only partially acid fast, as was the case in our patient. Organisms typically will be positive with silver stains.

Trimethoprim-sulfamethoxazole typically is the first-line treatment of nocardiosis. Although prognosis is excellent when disease is confined to skin, disseminated infection has 25% mortality.⁸ Diagnosticians should maintain a high index of suspicion for the disease, especially in immunocompromised patients, because clinical and imaging findings can be nonspecific.

Conclusion

Our patient’s primary risk factor for nocardiosis was his immunocompromised state. In addition, he was an avid gardener, which increased his risk for exposure to the microorganism. Given the timing of disease progression, our case most likely represents primary cutaneous nocardiosis with dissemination to brain, lungs, and other organs, leading to death, and serves as a reminder to dermatologists and pathologists to establish a broad differential diagnosis when dealing with an infectious process in immunocompromised patients.

Case Report

A 79-year-old man with chronic lymphocytic leukemia (CLL) who was being treated with ibrutinib presented to the emergency department with a dry cough, ataxia and falls, and vision loss. Physical examination was remarkable for diffuse crackles heard throughout the right lung and bilateral lower extremity weakness. Additionally, he had 4 pink mobile nodules on the left side of the forehead, right side of the chin, left submental area, and left postauricular scalp, which arose approximately 2 weeks prior to presentation. The left postauricular lesion had been tender at times and had developed a crust. The cutaneous lesions were all smaller than 2 cm.

The patient had a history of squamous cell carcinoma of the skin and was under the care of a dermatologist as an outpatient. His dermatologist had described him as an active gardener; he was noted to have healing abrasions on the forearms due to gardening raspberry bushes.

Computed tomography of the head revealed a 14-mm, ring-enhancing lesion in the left paramedian posterior frontal lobe with surrounding white matter vasogenic edema (Figure 1). Computed tomography of the chest revealed a peripheral mass on the right upper lobe measuring 6.3 cm at its greatest dimension (Figure 2).

Clinically, the constellation of symptoms was thought to represent an infectious process or less likely metastatic malignancy. Biopsies of the nodule on the right side of the chin were performed and sent for culture and histologic examination. Sections from the anterior right chin showed compact orthokeratosis overlying a slightly spongiotic epidermis (Figure 3). Within the deep dermis, there was a dense mixed inflammatory infiltrate comprising predominantly neutrophils, with occasional eosinophils, lymphocytes, and histiocytes (Figure 4).

Gram stain revealed gram-variable, branching, bacterial organisms morphologically consistent with Nocardia. Grocott-Gomori methenamine-silver and periodic acid–Schiff stains also highlighted the bacterial organisms (Figure 5). An auramine-O stain was negative for acid-fast microorganisms. After 3 days on a blood agar plate, cultures of a specimen of the chin nodule grew branching filamentous bacterial organisms consistent with Nocardia.

Comment

Presentation and Diagnosis
Nocardiosis is an infrequently encountered opportunistic infection that typically targets skin, lungs, and the central nervous system (CNS). Nocardia species characteristically are gram-positive, thin rods that form beaded, right-angle, branching filaments.¹ More than 50 Nocardia species have been clinically isolated.²

Definitive diagnosis requires culture. Nocardia grows well on nonselective media, such as blood or Löwenstein-Jensen agar; growth can be enhanced with 10% CO₂. Growth can be slow, however, and takes from 48 hours to several weeks. Nocardia typically grows as buff or pigmented, waxy, cerebriform colonies at 3 to 5 days’ incubation.¹

Cause of Infection
Nocardia species are commonly found in the environment—soil, plant matter, water, and decomposing organic material—as well as in the gastrointestinal tract and skin of animals. Infection has been reported in cattle, dogs, horses, swine, birds, cats, foxes, and a few other animals.² A history of exposure, such as gardening or handling animals, should increase suspicion of Nocardia.³ Although infection is classically thought to affect immunocompromised patients, there are case reports of immunocompetent individuals developing disseminated infection.^4-7 However, infected immunocompetent individuals typically have localized cutaneous infection, which often includes cellulitis, abscesses, or sporotrichoid patterns.² Cutaneous infections typically are the result of direct inoculation of the skin through a penetrating injury.⁸

Disseminated nocardiosis can be caused by numerous species and generally is the result of primary pulmonary infection.⁹ In these cases, skin disease is present in approximately 10% of patients. Disseminated infection from cutaneous nocardiosis is uncommon; when it does occur, the most common site of dissemination is the CNS, resulting in abscess or cerebritis.¹⁰ Therefore, CNS involvement should always be ruled out on diagnosis in immunocompromised patients, even if neurologic symptoms are absent.⁹ Nearly 80% of patients with disseminated disease are, in fact, immunocompromised.⁸

Association With CLL
Chronic lymphocytic leukemia is associated with profound immunodeficiency caused by quantitative and qualitative aberrations in both innate and adaptive immunity. This perturbation of the immune system predisposes the patient to infection.^11,12 Early in the course of CLL, a patient develops neutropenia, which predisposes to bacterial infection; later, the patient develops a sustained B- and T-cell immunodeficiency that predisposes to opportunistic infection.¹³ Treatment-naïve patients with CLL are commonly diagnosed with respiratory and urinary tract infections.¹² Chronic lymphocytic leukemia patients treated with alemtuzumab or purine analogs have been reported to have the highest risk for major infection.¹⁴

Ibrutinib is a commonly used treatment of CLL because it induces apoptosis in B cells, which are abnormal in CLL. Ibrutinib functions by inhibiting the Bruton tyrosine kinase pathway, which is essential in B-cell production and maintenance.¹⁵ Studies have reported a high rate of infection in ibrutinib-treated CLL patients^14,16; salvage ibrutinib therapy has been associated with higher infection risk than primary ibrutinib therapy.^16,17 Long-term follow-up studies have shown a decreased rate of infection in ibrutinib-treated CLL after 2 years or longer of treatment, suggesting a reconstitution of normal B cells and humoral immunity with longer ibrutinib therapy.^16,17

Many infections have been identified in association with ibrutinib therapy, including invasive aspergillosis, disseminated fusariosis, cerebral mucormycosis, disseminated cryptococcosis, and Pneumocystis jirovecii pneumonia.^18-22 Disseminated nocardiosis has been reported in a few patients with CLL, though the treatment they received for CLL varied from case to case.^23-25

Identification and Treatment
Clinical and microscopic identification of Nocardia organisms can be exceedingly difficult. Primary cutaneous nocardiosis clinically presents as tumors or nodules that often have a sporotrichoid pattern along the lymphatics. In disease that disseminates to skin, nocardiosis presents as vesiculopustules or abscesses. The biopsy specimen most often shows a dense dermal and subcutaneous infiltrate of neutrophils with abscess formation. Long-standing lesions might show chronic inflammation and nonspecific granulomas.

The appearance of Nocardia organisms is quite subtle on hematoxylin and eosin staining and can be easily missed. Special stains, such as Gram and Grocott-Gomori methenamine-silver stains as well as stains for acid-fast organisms, can be invaluable in diagnosing this disease. Biopsy in immunocompromised patients when nocardiosis is part of the differential diagnosis requires extra attention because the organisms can be gram variable and only partially acid fast, as was the case in our patient. Organisms typically will be positive with silver stains.

Trimethoprim-sulfamethoxazole typically is the first-line treatment of nocardiosis. Although prognosis is excellent when disease is confined to skin, disseminated infection has 25% mortality.⁸ Diagnosticians should maintain a high index of suspicion for the disease, especially in immunocompromised patients, because clinical and imaging findings can be nonspecific.

Conclusion

Our patient’s primary risk factor for nocardiosis was his immunocompromised state. In addition, he was an avid gardener, which increased his risk for exposure to the microorganism. Given the timing of disease progression, our case most likely represents primary cutaneous nocardiosis with dissemination to brain, lungs, and other organs, leading to death, and serves as a reminder to dermatologists and pathologists to establish a broad differential diagnosis when dealing with an infectious process in immunocompromised patients.

Case Report

A 79-year-old man with chronic lymphocytic leukemia (CLL) who was being treated with ibrutinib presented to the emergency department with a dry cough, ataxia and falls, and vision loss. Physical examination was remarkable for diffuse crackles heard throughout the right lung and bilateral lower extremity weakness. Additionally, he had 4 pink mobile nodules on the left side of the forehead, right side of the chin, left submental area, and left postauricular scalp, which arose approximately 2 weeks prior to presentation. The left postauricular lesion had been tender at times and had developed a crust. The cutaneous lesions were all smaller than 2 cm.

The patient had a history of squamous cell carcinoma of the skin and was under the care of a dermatologist as an outpatient. His dermatologist had described him as an active gardener; he was noted to have healing abrasions on the forearms due to gardening raspberry bushes.

Computed tomography of the head revealed a 14-mm, ring-enhancing lesion in the left paramedian posterior frontal lobe with surrounding white matter vasogenic edema (Figure 1). Computed tomography of the chest revealed a peripheral mass on the right upper lobe measuring 6.3 cm at its greatest dimension (Figure 2).

Clinically, the constellation of symptoms was thought to represent an infectious process or less likely metastatic malignancy. Biopsies of the nodule on the right side of the chin were performed and sent for culture and histologic examination. Sections from the anterior right chin showed compact orthokeratosis overlying a slightly spongiotic epidermis (Figure 3). Within the deep dermis, there was a dense mixed inflammatory infiltrate comprising predominantly neutrophils, with occasional eosinophils, lymphocytes, and histiocytes (Figure 4).

Gram stain revealed gram-variable, branching, bacterial organisms morphologically consistent with Nocardia. Grocott-Gomori methenamine-silver and periodic acid–Schiff stains also highlighted the bacterial organisms (Figure 5). An auramine-O stain was negative for acid-fast microorganisms. After 3 days on a blood agar plate, cultures of a specimen of the chin nodule grew branching filamentous bacterial organisms consistent with Nocardia.

Comment

Presentation and Diagnosis
Nocardiosis is an infrequently encountered opportunistic infection that typically targets skin, lungs, and the central nervous system (CNS). Nocardia species characteristically are gram-positive, thin rods that form beaded, right-angle, branching filaments.¹ More than 50 Nocardia species have been clinically isolated.²

Definitive diagnosis requires culture. Nocardia grows well on nonselective media, such as blood or Löwenstein-Jensen agar; growth can be enhanced with 10% CO₂. Growth can be slow, however, and takes from 48 hours to several weeks. Nocardia typically grows as buff or pigmented, waxy, cerebriform colonies at 3 to 5 days’ incubation.¹

Cause of Infection
Nocardia species are commonly found in the environment—soil, plant matter, water, and decomposing organic material—as well as in the gastrointestinal tract and skin of animals. Infection has been reported in cattle, dogs, horses, swine, birds, cats, foxes, and a few other animals.² A history of exposure, such as gardening or handling animals, should increase suspicion of Nocardia.³ Although infection is classically thought to affect immunocompromised patients, there are case reports of immunocompetent individuals developing disseminated infection.^4-7 However, infected immunocompetent individuals typically have localized cutaneous infection, which often includes cellulitis, abscesses, or sporotrichoid patterns.² Cutaneous infections typically are the result of direct inoculation of the skin through a penetrating injury.⁸

Disseminated nocardiosis can be caused by numerous species and generally is the result of primary pulmonary infection.⁹ In these cases, skin disease is present in approximately 10% of patients. Disseminated infection from cutaneous nocardiosis is uncommon; when it does occur, the most common site of dissemination is the CNS, resulting in abscess or cerebritis.¹⁰ Therefore, CNS involvement should always be ruled out on diagnosis in immunocompromised patients, even if neurologic symptoms are absent.⁹ Nearly 80% of patients with disseminated disease are, in fact, immunocompromised.⁸

Association With CLL
Chronic lymphocytic leukemia is associated with profound immunodeficiency caused by quantitative and qualitative aberrations in both innate and adaptive immunity. This perturbation of the immune system predisposes the patient to infection.^11,12 Early in the course of CLL, a patient develops neutropenia, which predisposes to bacterial infection; later, the patient develops a sustained B- and T-cell immunodeficiency that predisposes to opportunistic infection.¹³ Treatment-naïve patients with CLL are commonly diagnosed with respiratory and urinary tract infections.¹² Chronic lymphocytic leukemia patients treated with alemtuzumab or purine analogs have been reported to have the highest risk for major infection.¹⁴

Ibrutinib is a commonly used treatment of CLL because it induces apoptosis in B cells, which are abnormal in CLL. Ibrutinib functions by inhibiting the Bruton tyrosine kinase pathway, which is essential in B-cell production and maintenance.¹⁵ Studies have reported a high rate of infection in ibrutinib-treated CLL patients^14,16; salvage ibrutinib therapy has been associated with higher infection risk than primary ibrutinib therapy.^16,17 Long-term follow-up studies have shown a decreased rate of infection in ibrutinib-treated CLL after 2 years or longer of treatment, suggesting a reconstitution of normal B cells and humoral immunity with longer ibrutinib therapy.^16,17

Many infections have been identified in association with ibrutinib therapy, including invasive aspergillosis, disseminated fusariosis, cerebral mucormycosis, disseminated cryptococcosis, and Pneumocystis jirovecii pneumonia.^18-22 Disseminated nocardiosis has been reported in a few patients with CLL, though the treatment they received for CLL varied from case to case.^23-25

Identification and Treatment
Clinical and microscopic identification of Nocardia organisms can be exceedingly difficult. Primary cutaneous nocardiosis clinically presents as tumors or nodules that often have a sporotrichoid pattern along the lymphatics. In disease that disseminates to skin, nocardiosis presents as vesiculopustules or abscesses. The biopsy specimen most often shows a dense dermal and subcutaneous infiltrate of neutrophils with abscess formation. Long-standing lesions might show chronic inflammation and nonspecific granulomas.

The appearance of Nocardia organisms is quite subtle on hematoxylin and eosin staining and can be easily missed. Special stains, such as Gram and Grocott-Gomori methenamine-silver stains as well as stains for acid-fast organisms, can be invaluable in diagnosing this disease. Biopsy in immunocompromised patients when nocardiosis is part of the differential diagnosis requires extra attention because the organisms can be gram variable and only partially acid fast, as was the case in our patient. Organisms typically will be positive with silver stains.

Trimethoprim-sulfamethoxazole typically is the first-line treatment of nocardiosis. Although prognosis is excellent when disease is confined to skin, disseminated infection has 25% mortality.⁸ Diagnosticians should maintain a high index of suspicion for the disease, especially in immunocompromised patients, because clinical and imaging findings can be nonspecific.

Conclusion

Our patient’s primary risk factor for nocardiosis was his immunocompromised state. In addition, he was an avid gardener, which increased his risk for exposure to the microorganism. Given the timing of disease progression, our case most likely represents primary cutaneous nocardiosis with dissemination to brain, lungs, and other organs, leading to death, and serves as a reminder to dermatologists and pathologists to establish a broad differential diagnosis when dealing with an infectious process in immunocompromised patients.

As the largest and most exposed organ in the body, the skin experiences trauma from both extrinsic and intrinsic aging factors, resulting in loss of elasticity, increased laxity, wrinkling, and rough-textured appearance.¹ Chronologically aged skin appears dry, thin, and finely wrinkled; photoaged skin appears leathery with coarse wrinkles and uneven pigmentation.² In recent years, numerous systemic nutrients have been proposed to improve skin appearance. This article reviews the efficacy of these vitamins and supplements.

Carotenoids

Carotenoids are a group of lipophilic molecules derived from vitamin A.^3,4 Ingestion of carotenoids may play a role in photoprotection against UV radiation (UVR) by acting as acceptors of reactive oxygen species.^4-6 Stahl et al⁷ investigated lycopene’s usefulness in protection against UVR-induced erythema. Over 10 weeks, 9 volunteers received 40 g of tomato paste containing 16 mg daily of lycopene while 10 controls received placebo. A solar simulator was used to induce erythema of the skin at weeks 0, 4, and 10. At week 10, erythema formation was 40% lower in the lycopene group compared to controls (P=.02).⁷

In another study assessing the photoprotective effects of a novel nutritional and phytonutrient blend of carotenoids, 36 women with Fitzpatrick skin types I and II were treated for 8 weeks.⁸ Presupplementation, UVR-induced erythema, and skin carotenoid concentrations were determined along with facial skin attributes and characteristics. Results showed protection against UVR-induced skin damage, with reductions in erythema at 3 minimal erythema doses (MEDs)(P=.01). Additionally, significant improvements were noted in facial skin elasticity, radiance, and overall appearance (all P<.05).⁸

In 2013, Meinke et al⁹ conducted an 8-week, double-blind, placebo-controlled study on 24 volunteers whose diets were supplemented with moderate amounts of carotenoids, including lutein, beta-carotene, and lycopene. Utilizing novel techniques to measure the skin’s ability to scavenge free radicals, they discovered that dietary carotenoids provided notable protection against stress-induced radical formation and increased baseline radical scavenging activity of the skin by 34%. The authors concluded that dietary supplementation could avoid premature skin aging.⁹

Vitamins C and E

Vitamin C is an essential vitamin that must be obtained through dietary sources.¹⁰ It functions as a free radical scavenger and is a necessary cofactor for the synthesis and stabilization of collagen.

A study evaluated the effect of UVR-induced oxidative stress and the association with vitamin C supplementation among 20 white patients with Fitzpatrick skin types II or III.¹¹ The volunteers were treated with UVR on two 1-cm sites on the buttock. Six punch biopsies of these sites and 2 control biopsies from nonexposed skin were taken. Volunteers took vitamin C supplements (500 mg) for 8 weeks, and the exposure and biopsy were repeated. Researchers concluded that supplementation with vitamin C had no effect on the MED, with identical concentrations at baseline and after 8 weeks of supplementation. Additionally, there was no evidence that vitamin C affects UVR-induced oxidative stress.¹¹

In 2007, Cosgrove et al¹² conducted a study to assess the associations between nutrient intake and skin aging in more than 4000 women aged 40 to 74 years. Higher dietary vitamin C intakes were associated with a significantly lower likelihood of senile xerosis and wrinkled appearance (P<.009).¹²

Vitamin E is a lipid-soluble, membrane-bound vitamin, and its most active form is α-tocopherol.^11,13 Vitamin E functions as an antioxidant and protects cellular membranes from lipid peroxidation by free radicals.^13-15 Once oxidized, vitamin E can be regenerated to its reduced form by vitamin C.¹¹ Their synergistic effects on skin protection have been studied extensively. A double-blind, placebo-controlled study of 10 patients compared 2 g of vitamin C combined with 1000 IU of vitamin E vs placebo.¹⁶ The patients’ skin reaction before and after 8 days of treatment were assessed by determination of MED and the cutaneous blood flow of skin irradiated with UV light. Results showed that the median MED of those taking vitamins increased from 80 to 96.5 mJ/cm² (P<.01) and decreased for the placebo group. Investigators concluded that the combination of vitamins C and E reduces the sunburn reaction and leads to a reduction in the sequelae of UV-induced skin damage.¹⁶ A prospective, randomized, placebo-controlled study by Fuchs and Kern¹⁷ replicated these findings, also concluding that combinations of vitamins C and E provide improved photoprotective effects than either vitamin alone.

Vitamin D

Vitamin D is a fat-soluble vitamin obtained through dietary intake and exposure to UV light.^3,18,19 Precursors of vitamin D require interaction with UV light for conversion into active forms. The highest concentrations of 7-dehydrocholesterol are found in keratinocytes in the basal cell and spinous cell layers of the skin where they are protected from UV light by melanin. As such, individuals with higher melanin content in their skin require more exposure to UV light to produce the same levels of vitamin D as those with less melanin,²⁰ leading to a high rate of vitamin D deficiency in dark-skinned individuals. Because of their prodifferentiating and antiproliferative effects, vitamin D analogs have been very effective in the treatment of psoriasis.^20,21 Vitamin D deficiency also has been implicated in the pathogenesis of vitiligo. A systematic review and meta-analysis conducted in 2016 found that a significant relationship existed between low 25-hydroxyvitamin D levels and vitiligo (P<.01), but no causal relationship could be established.²²

A 2017 double-blind, placebo-controlled study performed by Scott et al²³ aimed to elucidate the relationship between vitamin D concentrations and sunburn. Twenty adults received either placebo or high-dose vitamin D₃ (200,000 IU) 1 hour after experimental sunburn induced by an erythemogenic dose of UVR. Investigators measured participants’ concentrations of the proinflammatory mediators tumor necrosis factor α and nitric oxide synthase via skin biopsy 48 hours later. Patients in the experimental group were found to have significantly reduced expression of both tumor necrosis factor α (P=.04) and nitric oxide synthase (P=.02). Additionally, participants with significantly higher vitamin D₃ levels following supplementation (P=.007) demonstrated increased skin expression of the anti-inflammatory marker arginase-1 (P=.005) as well as a persistent reduction in skin redness (P=.02). Investigators concluded that vitamin D plays a large role in skin homeostasis and implicated vitamin D’s upregulation of arginase-1 as a potent mechanism of its anti-inflammatory effects.²³

Collagen

As humans age, the density of collagen in the dermis decreases, leading to sagging and wrinkling of skin.²⁴ Oral supplementation of collagen has been examined for its dermatologic benefits, primarily increasing the thickness and density of collagen in the dermal layer. In 2014, Proksch et al²⁵ performed a double-blind, placebo-controlled trial in which 69 women were randomized to receive 2.5 or 5 g of collagen peptides or placebo for 8 weeks. Both treatment groups demonstrated improvements in skin elasticity as well as improved skin moisture and decreased skin evaporation; however, changes in the latter 2 qualities failed to reach statistical significance.²⁵

The results of this study were replicated by Asserin et al.²⁶ One hundred six female patients were randomly assigned to receive 10 g of collagen peptides or placebo daily for 8 weeks. The collagen group demonstrated significantly improved skin hydration (P=.003) and increased density of collagen in the dermis (P=.007) relative to placebo.²⁶

In another randomized, double-blind, placebo-controlled study, 71 women consumed a 20-mL beverage containing either 3000 mg of collagen peptides or placebo for 12 weeks.²⁷ Participants in the treatment group demonstrated significant decreases in periorbital wrinkles (P<.05) and enhanced facial skin moisture (P<.001) and elasticity (P<.001) after 12 weeks. Researchers concluded that oral supplementation with collagen peptides holds promise as a natural supplement to provide cutaneous antiaging properties.²⁷

Ceramides

Ceramides are lipids composed of a sphingoid base conjugated to a fatty acid and serve as the main component of the stratum corneum of the skin. Ceramides are crucial for the maintenance of skin barrier integrity and for preventing transepidermal water loss.²⁸ In a 3-month study of 51 women with dry skin, Guillou et al²⁹ showed that a ceramide wheat extract capsule significantly increased corneometry measurements of skin hydration on the arms (P<.001) and the legs (P=.012) compared to placebo.

Mixed Supplements

The discovery that nutritional contents can affect skin appearance has energized the development of combination supplements containing multiple vitamins and micronutrients. Imedeen is a biomarine complex and antioxidant supplement with several different formulations, including Prime Renewal, Time Perfection, and Derma One (Pfizer Inc). The ingredients include a combination of a biomarine complex (blend of fish proteins and polysaccharides), lycopene, grape seed extract, vitamin C, vitamin E, and zinc. Several trials have been conducted to assess the efficacy of the supplements on improving the appearance of photodamaged and aged skin (Table).

A placebo-controlled, randomized study of 144 participants conducted by Kieffer and Efsen³⁰ assessed the efficacy of Imedeen supplements over 12 months. The trial included a 3-month placebo-controlled study and 9-month uncontrolled continuation. Imedeen’s efficacy was measured using clinical evaluation, transepidermal water loss, self-evaluation, and photograph evaluation. After 1 year of treatment, improvement occurred in photograph evaluation of fine lines, overall photoaging, telangiectasia and hyperpigmentation, and self-evaluation of skin condition.³⁰ Additional double-blind, placebo-controlled, randomized studies assessing the efficacy of Imedeen have shown increased dermal and epidermal thickness, improvement of stratum corneum moisturization, and improved overall facial complexion.^31-33

Several combined supplements containing collagen peptide as the main ingredient have been created for use in skin care. Collagen is found in the extracellular matrix of the dermis and is responsible for the resiliency and strength of skin.^34,35 Damage to the dermis can occur with prolonged UV light exposure and is seen histologically as disorganized collagen fibrils and grossly as wrinkles and photoaged skin.^35,36

A study assessed the effect of BioCell Collagen (BioCell Technology, LLC), a supplement containing type II collagen, on skin aging.³⁷ Twenty-six women underwent baseline visual assessments of their skin before taking 2 tablets of the supplement daily. Twelve weeks of supplementation led to significant reduction in global lines and wrinkles (13.2%; P=.028) as well as skin dryness and scaling (76%; P=.002). Assessment of collagen content at 6 weeks revealed a significant increase from baseline (6.3%; P=.002), though the difference after 12 weeks was not significant (3.5%; P=.134). The authors concluded that although preliminary data suggested that BioCell Collagen may reduce visible signs of aging, a controlled study was necessary to verify this finding.³⁷

A single-blind, case-controlled study assessed a similar supplement, Celergen, that contained marine collagen peptides.³⁸ Forty-one adults took 2 capsules each day for 60 days. Assessment of their skin physiology was conducted at the enrollment visit, 2 months later, and after the treatment period ended. Skin elasticity, transepidermal water loss, epidermal and dermal thickness, and density were measured. Investigators found that Celergen administration significantly enhanced skin elasticity and sebum production (P<.0001) but did not influence cutaneous moisture. The dermal thickness and homogenous distribution of collagen fibers were enhanced in 11 patients while properties of the epidermis remained unchanged. The study determined that supplementation remarkably improved skin elasticity, sebum production, and dermal ultrasonic markers.³⁸

A double-blind, randomized, placebo-controlled study assessed a collagen- and antioxidant-containing supplement, Gold Collagen Forte, on skin properties.³⁹ The treatment and placebo groups each consisted of 60 patients who consumed 1 bottle (50 mL) of the product each day for 90 days. Patients completed a self-assessment of their skin regarding photoaging, focusing on the crow’s-feet area and nasolabial folds, while skin elasticity was assessed with the SkinLab USB elasticity module. Results showed a significant increase in skin elasticity (+7.5%; P≤.001). Self-assessment results showed improvements in both the treatment and placebo groups, and investigators concluded that Gold Collagen Forte may have photoprotective effects and help improve skin health.³⁹

Safety

Although trials have demonstrated vitamin supplementation to be safe and effective for skin enhancement, it is important to consider potential vitamin toxicities. High doses of vitamin C supplementation have been shown to cause damage via lipid peroxidation.⁴⁰ In a study assessing if high levels of beta-carotene and vitamin E were associated with a lower risk for lung cancer, data showed that these supplements may actually have harmful effects.^40,41 Additionally, consumption of high-dose dietary supplements has been associated with an increased risk for severe medical events, including disability and death among adolescents and young adults.⁴²

Conclusion

Numerous trials have indicated that the use of systemic vitamins can have beneficial effects on the protection and appearance of skin. Photodamage from UV light–induced erythema can be decreased by carotenoids and vitamins C and E. Similarly, supplements that combine multiple nutrients with collagen have been shown to improve the appearance of aging skin by decreasing the prominence of wrinkles. Given the growing number of products and advertisements that exist in the supplement marketplace, it is crucial for clinicians to ground their recommendations to patients in the scientific data of robust studies.

As the largest and most exposed organ in the body, the skin experiences trauma from both extrinsic and intrinsic aging factors, resulting in loss of elasticity, increased laxity, wrinkling, and rough-textured appearance.¹ Chronologically aged skin appears dry, thin, and finely wrinkled; photoaged skin appears leathery with coarse wrinkles and uneven pigmentation.² In recent years, numerous systemic nutrients have been proposed to improve skin appearance. This article reviews the efficacy of these vitamins and supplements.

Carotenoids

Carotenoids are a group of lipophilic molecules derived from vitamin A.^3,4 Ingestion of carotenoids may play a role in photoprotection against UV radiation (UVR) by acting as acceptors of reactive oxygen species.^4-6 Stahl et al⁷ investigated lycopene’s usefulness in protection against UVR-induced erythema. Over 10 weeks, 9 volunteers received 40 g of tomato paste containing 16 mg daily of lycopene while 10 controls received placebo. A solar simulator was used to induce erythema of the skin at weeks 0, 4, and 10. At week 10, erythema formation was 40% lower in the lycopene group compared to controls (P=.02).⁷

In another study assessing the photoprotective effects of a novel nutritional and phytonutrient blend of carotenoids, 36 women with Fitzpatrick skin types I and II were treated for 8 weeks.⁸ Presupplementation, UVR-induced erythema, and skin carotenoid concentrations were determined along with facial skin attributes and characteristics. Results showed protection against UVR-induced skin damage, with reductions in erythema at 3 minimal erythema doses (MEDs)(P=.01). Additionally, significant improvements were noted in facial skin elasticity, radiance, and overall appearance (all P<.05).⁸

In 2013, Meinke et al⁹ conducted an 8-week, double-blind, placebo-controlled study on 24 volunteers whose diets were supplemented with moderate amounts of carotenoids, including lutein, beta-carotene, and lycopene. Utilizing novel techniques to measure the skin’s ability to scavenge free radicals, they discovered that dietary carotenoids provided notable protection against stress-induced radical formation and increased baseline radical scavenging activity of the skin by 34%. The authors concluded that dietary supplementation could avoid premature skin aging.⁹

Vitamins C and E

Vitamin C is an essential vitamin that must be obtained through dietary sources.¹⁰ It functions as a free radical scavenger and is a necessary cofactor for the synthesis and stabilization of collagen.

A study evaluated the effect of UVR-induced oxidative stress and the association with vitamin C supplementation among 20 white patients with Fitzpatrick skin types II or III.¹¹ The volunteers were treated with UVR on two 1-cm sites on the buttock. Six punch biopsies of these sites and 2 control biopsies from nonexposed skin were taken. Volunteers took vitamin C supplements (500 mg) for 8 weeks, and the exposure and biopsy were repeated. Researchers concluded that supplementation with vitamin C had no effect on the MED, with identical concentrations at baseline and after 8 weeks of supplementation. Additionally, there was no evidence that vitamin C affects UVR-induced oxidative stress.¹¹

In 2007, Cosgrove et al¹² conducted a study to assess the associations between nutrient intake and skin aging in more than 4000 women aged 40 to 74 years. Higher dietary vitamin C intakes were associated with a significantly lower likelihood of senile xerosis and wrinkled appearance (P<.009).¹²

Vitamin E is a lipid-soluble, membrane-bound vitamin, and its most active form is α-tocopherol.^11,13 Vitamin E functions as an antioxidant and protects cellular membranes from lipid peroxidation by free radicals.^13-15 Once oxidized, vitamin E can be regenerated to its reduced form by vitamin C.¹¹ Their synergistic effects on skin protection have been studied extensively. A double-blind, placebo-controlled study of 10 patients compared 2 g of vitamin C combined with 1000 IU of vitamin E vs placebo.¹⁶ The patients’ skin reaction before and after 8 days of treatment were assessed by determination of MED and the cutaneous blood flow of skin irradiated with UV light. Results showed that the median MED of those taking vitamins increased from 80 to 96.5 mJ/cm² (P<.01) and decreased for the placebo group. Investigators concluded that the combination of vitamins C and E reduces the sunburn reaction and leads to a reduction in the sequelae of UV-induced skin damage.¹⁶ A prospective, randomized, placebo-controlled study by Fuchs and Kern¹⁷ replicated these findings, also concluding that combinations of vitamins C and E provide improved photoprotective effects than either vitamin alone.

Vitamin D

Vitamin D is a fat-soluble vitamin obtained through dietary intake and exposure to UV light.^3,18,19 Precursors of vitamin D require interaction with UV light for conversion into active forms. The highest concentrations of 7-dehydrocholesterol are found in keratinocytes in the basal cell and spinous cell layers of the skin where they are protected from UV light by melanin. As such, individuals with higher melanin content in their skin require more exposure to UV light to produce the same levels of vitamin D as those with less melanin,²⁰ leading to a high rate of vitamin D deficiency in dark-skinned individuals. Because of their prodifferentiating and antiproliferative effects, vitamin D analogs have been very effective in the treatment of psoriasis.^20,21 Vitamin D deficiency also has been implicated in the pathogenesis of vitiligo. A systematic review and meta-analysis conducted in 2016 found that a significant relationship existed between low 25-hydroxyvitamin D levels and vitiligo (P<.01), but no causal relationship could be established.²²

A 2017 double-blind, placebo-controlled study performed by Scott et al²³ aimed to elucidate the relationship between vitamin D concentrations and sunburn. Twenty adults received either placebo or high-dose vitamin D₃ (200,000 IU) 1 hour after experimental sunburn induced by an erythemogenic dose of UVR. Investigators measured participants’ concentrations of the proinflammatory mediators tumor necrosis factor α and nitric oxide synthase via skin biopsy 48 hours later. Patients in the experimental group were found to have significantly reduced expression of both tumor necrosis factor α (P=.04) and nitric oxide synthase (P=.02). Additionally, participants with significantly higher vitamin D₃ levels following supplementation (P=.007) demonstrated increased skin expression of the anti-inflammatory marker arginase-1 (P=.005) as well as a persistent reduction in skin redness (P=.02). Investigators concluded that vitamin D plays a large role in skin homeostasis and implicated vitamin D’s upregulation of arginase-1 as a potent mechanism of its anti-inflammatory effects.²³

Collagen

As humans age, the density of collagen in the dermis decreases, leading to sagging and wrinkling of skin.²⁴ Oral supplementation of collagen has been examined for its dermatologic benefits, primarily increasing the thickness and density of collagen in the dermal layer. In 2014, Proksch et al²⁵ performed a double-blind, placebo-controlled trial in which 69 women were randomized to receive 2.5 or 5 g of collagen peptides or placebo for 8 weeks. Both treatment groups demonstrated improvements in skin elasticity as well as improved skin moisture and decreased skin evaporation; however, changes in the latter 2 qualities failed to reach statistical significance.²⁵

The results of this study were replicated by Asserin et al.²⁶ One hundred six female patients were randomly assigned to receive 10 g of collagen peptides or placebo daily for 8 weeks. The collagen group demonstrated significantly improved skin hydration (P=.003) and increased density of collagen in the dermis (P=.007) relative to placebo.²⁶

In another randomized, double-blind, placebo-controlled study, 71 women consumed a 20-mL beverage containing either 3000 mg of collagen peptides or placebo for 12 weeks.²⁷ Participants in the treatment group demonstrated significant decreases in periorbital wrinkles (P<.05) and enhanced facial skin moisture (P<.001) and elasticity (P<.001) after 12 weeks. Researchers concluded that oral supplementation with collagen peptides holds promise as a natural supplement to provide cutaneous antiaging properties.²⁷

Ceramides

Ceramides are lipids composed of a sphingoid base conjugated to a fatty acid and serve as the main component of the stratum corneum of the skin. Ceramides are crucial for the maintenance of skin barrier integrity and for preventing transepidermal water loss.²⁸ In a 3-month study of 51 women with dry skin, Guillou et al²⁹ showed that a ceramide wheat extract capsule significantly increased corneometry measurements of skin hydration on the arms (P<.001) and the legs (P=.012) compared to placebo.

Mixed Supplements

The discovery that nutritional contents can affect skin appearance has energized the development of combination supplements containing multiple vitamins and micronutrients. Imedeen is a biomarine complex and antioxidant supplement with several different formulations, including Prime Renewal, Time Perfection, and Derma One (Pfizer Inc). The ingredients include a combination of a biomarine complex (blend of fish proteins and polysaccharides), lycopene, grape seed extract, vitamin C, vitamin E, and zinc. Several trials have been conducted to assess the efficacy of the supplements on improving the appearance of photodamaged and aged skin (Table).

A placebo-controlled, randomized study of 144 participants conducted by Kieffer and Efsen³⁰ assessed the efficacy of Imedeen supplements over 12 months. The trial included a 3-month placebo-controlled study and 9-month uncontrolled continuation. Imedeen’s efficacy was measured using clinical evaluation, transepidermal water loss, self-evaluation, and photograph evaluation. After 1 year of treatment, improvement occurred in photograph evaluation of fine lines, overall photoaging, telangiectasia and hyperpigmentation, and self-evaluation of skin condition.³⁰ Additional double-blind, placebo-controlled, randomized studies assessing the efficacy of Imedeen have shown increased dermal and epidermal thickness, improvement of stratum corneum moisturization, and improved overall facial complexion.^31-33

Several combined supplements containing collagen peptide as the main ingredient have been created for use in skin care. Collagen is found in the extracellular matrix of the dermis and is responsible for the resiliency and strength of skin.^34,35 Damage to the dermis can occur with prolonged UV light exposure and is seen histologically as disorganized collagen fibrils and grossly as wrinkles and photoaged skin.^35,36

A study assessed the effect of BioCell Collagen (BioCell Technology, LLC), a supplement containing type II collagen, on skin aging.³⁷ Twenty-six women underwent baseline visual assessments of their skin before taking 2 tablets of the supplement daily. Twelve weeks of supplementation led to significant reduction in global lines and wrinkles (13.2%; P=.028) as well as skin dryness and scaling (76%; P=.002). Assessment of collagen content at 6 weeks revealed a significant increase from baseline (6.3%; P=.002), though the difference after 12 weeks was not significant (3.5%; P=.134). The authors concluded that although preliminary data suggested that BioCell Collagen may reduce visible signs of aging, a controlled study was necessary to verify this finding.³⁷

A single-blind, case-controlled study assessed a similar supplement, Celergen, that contained marine collagen peptides.³⁸ Forty-one adults took 2 capsules each day for 60 days. Assessment of their skin physiology was conducted at the enrollment visit, 2 months later, and after the treatment period ended. Skin elasticity, transepidermal water loss, epidermal and dermal thickness, and density were measured. Investigators found that Celergen administration significantly enhanced skin elasticity and sebum production (P<.0001) but did not influence cutaneous moisture. The dermal thickness and homogenous distribution of collagen fibers were enhanced in 11 patients while properties of the epidermis remained unchanged. The study determined that supplementation remarkably improved skin elasticity, sebum production, and dermal ultrasonic markers.³⁸

A double-blind, randomized, placebo-controlled study assessed a collagen- and antioxidant-containing supplement, Gold Collagen Forte, on skin properties.³⁹ The treatment and placebo groups each consisted of 60 patients who consumed 1 bottle (50 mL) of the product each day for 90 days. Patients completed a self-assessment of their skin regarding photoaging, focusing on the crow’s-feet area and nasolabial folds, while skin elasticity was assessed with the SkinLab USB elasticity module. Results showed a significant increase in skin elasticity (+7.5%; P≤.001). Self-assessment results showed improvements in both the treatment and placebo groups, and investigators concluded that Gold Collagen Forte may have photoprotective effects and help improve skin health.³⁹

Safety

Although trials have demonstrated vitamin supplementation to be safe and effective for skin enhancement, it is important to consider potential vitamin toxicities. High doses of vitamin C supplementation have been shown to cause damage via lipid peroxidation.⁴⁰ In a study assessing if high levels of beta-carotene and vitamin E were associated with a lower risk for lung cancer, data showed that these supplements may actually have harmful effects.^40,41 Additionally, consumption of high-dose dietary supplements has been associated with an increased risk for severe medical events, including disability and death among adolescents and young adults.⁴²

Conclusion

Numerous trials have indicated that the use of systemic vitamins can have beneficial effects on the protection and appearance of skin. Photodamage from UV light–induced erythema can be decreased by carotenoids and vitamins C and E. Similarly, supplements that combine multiple nutrients with collagen have been shown to improve the appearance of aging skin by decreasing the prominence of wrinkles. Given the growing number of products and advertisements that exist in the supplement marketplace, it is crucial for clinicians to ground their recommendations to patients in the scientific data of robust studies.

As the largest and most exposed organ in the body, the skin experiences trauma from both extrinsic and intrinsic aging factors, resulting in loss of elasticity, increased laxity, wrinkling, and rough-textured appearance.¹ Chronologically aged skin appears dry, thin, and finely wrinkled; photoaged skin appears leathery with coarse wrinkles and uneven pigmentation.² In recent years, numerous systemic nutrients have been proposed to improve skin appearance. This article reviews the efficacy of these vitamins and supplements.

Carotenoids

Carotenoids are a group of lipophilic molecules derived from vitamin A.^3,4 Ingestion of carotenoids may play a role in photoprotection against UV radiation (UVR) by acting as acceptors of reactive oxygen species.^4-6 Stahl et al⁷ investigated lycopene’s usefulness in protection against UVR-induced erythema. Over 10 weeks, 9 volunteers received 40 g of tomato paste containing 16 mg daily of lycopene while 10 controls received placebo. A solar simulator was used to induce erythema of the skin at weeks 0, 4, and 10. At week 10, erythema formation was 40% lower in the lycopene group compared to controls (P=.02).⁷

In another study assessing the photoprotective effects of a novel nutritional and phytonutrient blend of carotenoids, 36 women with Fitzpatrick skin types I and II were treated for 8 weeks.⁸ Presupplementation, UVR-induced erythema, and skin carotenoid concentrations were determined along with facial skin attributes and characteristics. Results showed protection against UVR-induced skin damage, with reductions in erythema at 3 minimal erythema doses (MEDs)(P=.01). Additionally, significant improvements were noted in facial skin elasticity, radiance, and overall appearance (all P<.05).⁸

In 2013, Meinke et al⁹ conducted an 8-week, double-blind, placebo-controlled study on 24 volunteers whose diets were supplemented with moderate amounts of carotenoids, including lutein, beta-carotene, and lycopene. Utilizing novel techniques to measure the skin’s ability to scavenge free radicals, they discovered that dietary carotenoids provided notable protection against stress-induced radical formation and increased baseline radical scavenging activity of the skin by 34%. The authors concluded that dietary supplementation could avoid premature skin aging.⁹

Vitamins C and E

Vitamin C is an essential vitamin that must be obtained through dietary sources.¹⁰ It functions as a free radical scavenger and is a necessary cofactor for the synthesis and stabilization of collagen.

A study evaluated the effect of UVR-induced oxidative stress and the association with vitamin C supplementation among 20 white patients with Fitzpatrick skin types II or III.¹¹ The volunteers were treated with UVR on two 1-cm sites on the buttock. Six punch biopsies of these sites and 2 control biopsies from nonexposed skin were taken. Volunteers took vitamin C supplements (500 mg) for 8 weeks, and the exposure and biopsy were repeated. Researchers concluded that supplementation with vitamin C had no effect on the MED, with identical concentrations at baseline and after 8 weeks of supplementation. Additionally, there was no evidence that vitamin C affects UVR-induced oxidative stress.¹¹

In 2007, Cosgrove et al¹² conducted a study to assess the associations between nutrient intake and skin aging in more than 4000 women aged 40 to 74 years. Higher dietary vitamin C intakes were associated with a significantly lower likelihood of senile xerosis and wrinkled appearance (P<.009).¹²

Vitamin E is a lipid-soluble, membrane-bound vitamin, and its most active form is α-tocopherol.^11,13 Vitamin E functions as an antioxidant and protects cellular membranes from lipid peroxidation by free radicals.^13-15 Once oxidized, vitamin E can be regenerated to its reduced form by vitamin C.¹¹ Their synergistic effects on skin protection have been studied extensively. A double-blind, placebo-controlled study of 10 patients compared 2 g of vitamin C combined with 1000 IU of vitamin E vs placebo.¹⁶ The patients’ skin reaction before and after 8 days of treatment were assessed by determination of MED and the cutaneous blood flow of skin irradiated with UV light. Results showed that the median MED of those taking vitamins increased from 80 to 96.5 mJ/cm² (P<.01) and decreased for the placebo group. Investigators concluded that the combination of vitamins C and E reduces the sunburn reaction and leads to a reduction in the sequelae of UV-induced skin damage.¹⁶ A prospective, randomized, placebo-controlled study by Fuchs and Kern¹⁷ replicated these findings, also concluding that combinations of vitamins C and E provide improved photoprotective effects than either vitamin alone.

Vitamin D

Vitamin D is a fat-soluble vitamin obtained through dietary intake and exposure to UV light.^3,18,19 Precursors of vitamin D require interaction with UV light for conversion into active forms. The highest concentrations of 7-dehydrocholesterol are found in keratinocytes in the basal cell and spinous cell layers of the skin where they are protected from UV light by melanin. As such, individuals with higher melanin content in their skin require more exposure to UV light to produce the same levels of vitamin D as those with less melanin,²⁰ leading to a high rate of vitamin D deficiency in dark-skinned individuals. Because of their prodifferentiating and antiproliferative effects, vitamin D analogs have been very effective in the treatment of psoriasis.^20,21 Vitamin D deficiency also has been implicated in the pathogenesis of vitiligo. A systematic review and meta-analysis conducted in 2016 found that a significant relationship existed between low 25-hydroxyvitamin D levels and vitiligo (P<.01), but no causal relationship could be established.²²

A 2017 double-blind, placebo-controlled study performed by Scott et al²³ aimed to elucidate the relationship between vitamin D concentrations and sunburn. Twenty adults received either placebo or high-dose vitamin D₃ (200,000 IU) 1 hour after experimental sunburn induced by an erythemogenic dose of UVR. Investigators measured participants’ concentrations of the proinflammatory mediators tumor necrosis factor α and nitric oxide synthase via skin biopsy 48 hours later. Patients in the experimental group were found to have significantly reduced expression of both tumor necrosis factor α (P=.04) and nitric oxide synthase (P=.02). Additionally, participants with significantly higher vitamin D₃ levels following supplementation (P=.007) demonstrated increased skin expression of the anti-inflammatory marker arginase-1 (P=.005) as well as a persistent reduction in skin redness (P=.02). Investigators concluded that vitamin D plays a large role in skin homeostasis and implicated vitamin D’s upregulation of arginase-1 as a potent mechanism of its anti-inflammatory effects.²³

Collagen

As humans age, the density of collagen in the dermis decreases, leading to sagging and wrinkling of skin.²⁴ Oral supplementation of collagen has been examined for its dermatologic benefits, primarily increasing the thickness and density of collagen in the dermal layer. In 2014, Proksch et al²⁵ performed a double-blind, placebo-controlled trial in which 69 women were randomized to receive 2.5 or 5 g of collagen peptides or placebo for 8 weeks. Both treatment groups demonstrated improvements in skin elasticity as well as improved skin moisture and decreased skin evaporation; however, changes in the latter 2 qualities failed to reach statistical significance.²⁵

The results of this study were replicated by Asserin et al.²⁶ One hundred six female patients were randomly assigned to receive 10 g of collagen peptides or placebo daily for 8 weeks. The collagen group demonstrated significantly improved skin hydration (P=.003) and increased density of collagen in the dermis (P=.007) relative to placebo.²⁶

In another randomized, double-blind, placebo-controlled study, 71 women consumed a 20-mL beverage containing either 3000 mg of collagen peptides or placebo for 12 weeks.²⁷ Participants in the treatment group demonstrated significant decreases in periorbital wrinkles (P<.05) and enhanced facial skin moisture (P<.001) and elasticity (P<.001) after 12 weeks. Researchers concluded that oral supplementation with collagen peptides holds promise as a natural supplement to provide cutaneous antiaging properties.²⁷

Ceramides

Ceramides are lipids composed of a sphingoid base conjugated to a fatty acid and serve as the main component of the stratum corneum of the skin. Ceramides are crucial for the maintenance of skin barrier integrity and for preventing transepidermal water loss.²⁸ In a 3-month study of 51 women with dry skin, Guillou et al²⁹ showed that a ceramide wheat extract capsule significantly increased corneometry measurements of skin hydration on the arms (P<.001) and the legs (P=.012) compared to placebo.

Mixed Supplements

The discovery that nutritional contents can affect skin appearance has energized the development of combination supplements containing multiple vitamins and micronutrients. Imedeen is a biomarine complex and antioxidant supplement with several different formulations, including Prime Renewal, Time Perfection, and Derma One (Pfizer Inc). The ingredients include a combination of a biomarine complex (blend of fish proteins and polysaccharides), lycopene, grape seed extract, vitamin C, vitamin E, and zinc. Several trials have been conducted to assess the efficacy of the supplements on improving the appearance of photodamaged and aged skin (Table).

A placebo-controlled, randomized study of 144 participants conducted by Kieffer and Efsen³⁰ assessed the efficacy of Imedeen supplements over 12 months. The trial included a 3-month placebo-controlled study and 9-month uncontrolled continuation. Imedeen’s efficacy was measured using clinical evaluation, transepidermal water loss, self-evaluation, and photograph evaluation. After 1 year of treatment, improvement occurred in photograph evaluation of fine lines, overall photoaging, telangiectasia and hyperpigmentation, and self-evaluation of skin condition.³⁰ Additional double-blind, placebo-controlled, randomized studies assessing the efficacy of Imedeen have shown increased dermal and epidermal thickness, improvement of stratum corneum moisturization, and improved overall facial complexion.^31-33

Several combined supplements containing collagen peptide as the main ingredient have been created for use in skin care. Collagen is found in the extracellular matrix of the dermis and is responsible for the resiliency and strength of skin.^34,35 Damage to the dermis can occur with prolonged UV light exposure and is seen histologically as disorganized collagen fibrils and grossly as wrinkles and photoaged skin.^35,36

A study assessed the effect of BioCell Collagen (BioCell Technology, LLC), a supplement containing type II collagen, on skin aging.³⁷ Twenty-six women underwent baseline visual assessments of their skin before taking 2 tablets of the supplement daily. Twelve weeks of supplementation led to significant reduction in global lines and wrinkles (13.2%; P=.028) as well as skin dryness and scaling (76%; P=.002). Assessment of collagen content at 6 weeks revealed a significant increase from baseline (6.3%; P=.002), though the difference after 12 weeks was not significant (3.5%; P=.134). The authors concluded that although preliminary data suggested that BioCell Collagen may reduce visible signs of aging, a controlled study was necessary to verify this finding.³⁷

A single-blind, case-controlled study assessed a similar supplement, Celergen, that contained marine collagen peptides.³⁸ Forty-one adults took 2 capsules each day for 60 days. Assessment of their skin physiology was conducted at the enrollment visit, 2 months later, and after the treatment period ended. Skin elasticity, transepidermal water loss, epidermal and dermal thickness, and density were measured. Investigators found that Celergen administration significantly enhanced skin elasticity and sebum production (P<.0001) but did not influence cutaneous moisture. The dermal thickness and homogenous distribution of collagen fibers were enhanced in 11 patients while properties of the epidermis remained unchanged. The study determined that supplementation remarkably improved skin elasticity, sebum production, and dermal ultrasonic markers.³⁸

A double-blind, randomized, placebo-controlled study assessed a collagen- and antioxidant-containing supplement, Gold Collagen Forte, on skin properties.³⁹ The treatment and placebo groups each consisted of 60 patients who consumed 1 bottle (50 mL) of the product each day for 90 days. Patients completed a self-assessment of their skin regarding photoaging, focusing on the crow’s-feet area and nasolabial folds, while skin elasticity was assessed with the SkinLab USB elasticity module. Results showed a significant increase in skin elasticity (+7.5%; P≤.001). Self-assessment results showed improvements in both the treatment and placebo groups, and investigators concluded that Gold Collagen Forte may have photoprotective effects and help improve skin health.³⁹

Safety

Although trials have demonstrated vitamin supplementation to be safe and effective for skin enhancement, it is important to consider potential vitamin toxicities. High doses of vitamin C supplementation have been shown to cause damage via lipid peroxidation.⁴⁰ In a study assessing if high levels of beta-carotene and vitamin E were associated with a lower risk for lung cancer, data showed that these supplements may actually have harmful effects.^40,41 Additionally, consumption of high-dose dietary supplements has been associated with an increased risk for severe medical events, including disability and death among adolescents and young adults.⁴²

Conclusion

Numerous trials have indicated that the use of systemic vitamins can have beneficial effects on the protection and appearance of skin. Photodamage from UV light–induced erythema can be decreased by carotenoids and vitamins C and E. Similarly, supplements that combine multiple nutrients with collagen have been shown to improve the appearance of aging skin by decreasing the prominence of wrinkles. Given the growing number of products and advertisements that exist in the supplement marketplace, it is crucial for clinicians to ground their recommendations to patients in the scientific data of robust studies.

Identification

The South African fattail scorpion (Parabuthus transvaalicus)(Figure) is one of the most poisonous scorpions in southern Africa.¹ A member of the Buthidae scorpion family, it can grow as long as 15 cm and is dark brown-black with lighter red-brown pincers. Similar to other fattail scorpions, it has slender pincers (pedipalps) and a thick square tail (the telson). Parabuthus transvaalicus inhabits hot dry deserts, scrublands, and semiarid regions.^1,2 It also is popular in exotic pet collections, the most common source of stings in the United States.

Stings and Envenomation

Scorpions with thicker tails generally have more potent venom than those with slender tails and thick pincers. Venom is injected by a stinger at the tip of the telson¹; P transvaalicus also can spray venom as far as 3 m.^1,2 Venom is not known to cause toxicity through skin contact but could represent a hazard if sprayed in the eye.

Scorpion toxins are a group of complex neurotoxins that act on sodium channels, either retarding inactivation (α toxin) or enhancing activation (β toxin), causing massive depolarization of excitable cells.^1,3 The toxin causes neurons to fire repetitively.⁴ Neurotransmitters—noradrenaline, adrenaline, and acetylcholine—cause the observed sympathetic, parasympathetic, and skeletal muscle effects.¹

Incidence
Worldwide, more than 1.2 million individuals are stung by a scorpion annually, causing more than 3250 deaths a year.⁵ Adults are stung more often, but children experience more severe envenomation, are more likely to develop severe illness requiring intensive supportive care, and have a higher mortality.⁴

As many as one-third of patients stung by a Parabuthus scorpion develop neuromuscular toxicity, which can be life-threatening.⁶ In a study of 277 envenomations by P transvaalicus, 10% of patients developed severe symptoms and 5 died. Children younger than 10 years and adults older than 50 years are at greatest risk for adverse outcomes.⁶ Children have a case fatality rate as high as 10 times the adult fatality rate.⁷

Clinical Presentation
The clinical presentation of scorpion envenomation varies with the species involved, the amount of venom injected, and the victim’s weight and baseline health.¹ Scorpion envenomation is divided into 4 grades based on the severity of a sting:

• Grade I: pain and paresthesia at the envenomation site; usually, no local inflammation

• Grade II: local symptoms as well as more remote pain and paresthesia; pain can radiate up the affected limb

• Grade III: cranial nerve or somatic skeletal neuromuscular dysfunction; either presentation can have associated autonomic dysfunction

• Grade IV: both cranial nerve and somatic skeletal neuromuscular dysfunction, with associated auto-nomic dysfunction

 

 

The initial symptom of a scorpion sting is intense burning pain. The sting site might be unimpressive, with only a mild local reaction. Symptoms usually progress to maximum severity within 5 hours.¹ Muscle pain, cramps, and weakness are prominent. The patient might have difficulty walking and swallowing, with increased salivation and drooling, and visual disturbance with abnormal eye movements. Pulse, blood pressure, and temperature often are elevated. The patient might be hyperreflexic with clonus.^1,6

Symptoms of increased sympathetic activity are hypertension, tachycardia, cardiac dysrhythmia, perspiration, hyperglycemia, and restlessness.^1,2 Parasympathetic effects are increased salivation, hypotension, bradycardia, and gastric distension. Skeletal muscle effects include tremors and involuntary muscle movement, which can be severe. Cranial nerve dysfunction may manifest as dysphagia, drooling, abnormal eye movements, blurred vision, slurred speech, and tongue fasciculations. Subsequent development of muscle weakness, bulbar paralysis, and difficulty breathing may be caused by depletion of neurotransmitters after prolonged excessive neuronal activity.¹

Distinctive Signs in Younger Patients
A child who is stung by a scorpion might have symptoms similar to those seen in an adult victim but can also experience an extreme form of restlessness that indicates severe envenomation characterized by inability to lay still, violent muscle twitching, and uncontrollable flailing of extremities. The child might have facial grimacing, with lip-smacking and chewing motions. In addition, bulbar paralysis and respiratory distress are more likely in children who have been stung than in adults.^1,2

Management

Treatment of a P transvaalicus sting is directed at “scorpionism,” envenomation that is associated with systemic symptoms that can be life-threatening. Treatment comprises support of vital functions, symptomatic measures, and injection of antivenin.⁸

Support of Vital Functions
In adults, systemic symptoms can be delayed as long as 8 hours after the sting. However, most severe cases usually are evident within 60 minutes; infants can reach grade IV as quickly as 15 to 30 minutes.^9,10 Loss of pharyngeal reflexes and development of respiratory distress are ominous warning signs requiring immediate respiratory support. Respiratory failure is the most common cause of death.¹ An asymptomatic child should be admitted to a hospital for observation for a minimum of 12 hours if the species of scorpion was not identified.²

Pain Relief
Most patients cannot tolerate an ice pack because of severe hyperesthesia. Infiltration of the local sting site with an anesthetic generally is safe and can provide some local pain relief. Intravenous fentanyl has been used in closely monitored patients because the drug is not associated with histamine release. Medications that cause release of histamine, such as morphine, can exacerbate or confuse the clinical picture.

Antivenin
Scorpion antivenin contains purified IgG fragments; allergic reactions are now rare. The sooner antivenin is administered, the greater the benefit. When administered early, it can prevent many of the most serious complications.⁷ In a randomized, double-blind study of critically ill children with clinically significant signs of scorpion envenomation, intravenous administration of scorpion-specific fragment antigen-binding 2 (F[(ab’]₂) antivenin resulted in resolution of clinical symptoms within 4 hours.¹¹

When managing grade III or IV scorpion envenomation, all patients should be admitted to a medical facility equipped to provide intensive supportive care; consider consultation with a regional poison control center. The World Health Organization maintains an international poison control center (at https://www.who.int/ipcs/poisons/centre/en/) with regional telephone numbers; alternatively, in the United States, call the nationwide telephone number of the Poison Control Center (800-222-1222).

The World Health Organization has identified declining production of antivenin as a crisis.¹²

Resolution
Symptoms of envenomation typically resolve 9 to 30 hours after a sting in a patient with grade III or IV envenomation not treated with antivenin.⁴ However, pain and paresthesia occasionally last as long as 2 weeks. In rare cases, more long-term sequelae of burning paresthesia persist for months.⁴

Conclusion

It is important for dermatologists to be aware of the potential for life-threatening envenomation by certain scorpion species native to southern Africa. In the United States, stings of these species most often are seen in patients with a pet collection, but late sequelae also can be seen in travelers returning from an endemic region. The site of a sting often appears unimpressive initially, but severe hyperesthesia is common. Patients with cardiac, neurologic, or respiratory symptoms require intensive supportive care. Proper care can be lifesaving.

Identification

The South African fattail scorpion (Parabuthus transvaalicus)(Figure) is one of the most poisonous scorpions in southern Africa.¹ A member of the Buthidae scorpion family, it can grow as long as 15 cm and is dark brown-black with lighter red-brown pincers. Similar to other fattail scorpions, it has slender pincers (pedipalps) and a thick square tail (the telson). Parabuthus transvaalicus inhabits hot dry deserts, scrublands, and semiarid regions.^1,2 It also is popular in exotic pet collections, the most common source of stings in the United States.

Stings and Envenomation

Scorpions with thicker tails generally have more potent venom than those with slender tails and thick pincers. Venom is injected by a stinger at the tip of the telson¹; P transvaalicus also can spray venom as far as 3 m.^1,2 Venom is not known to cause toxicity through skin contact but could represent a hazard if sprayed in the eye.

Scorpion toxins are a group of complex neurotoxins that act on sodium channels, either retarding inactivation (α toxin) or enhancing activation (β toxin), causing massive depolarization of excitable cells.^1,3 The toxin causes neurons to fire repetitively.⁴ Neurotransmitters—noradrenaline, adrenaline, and acetylcholine—cause the observed sympathetic, parasympathetic, and skeletal muscle effects.¹

Incidence
Worldwide, more than 1.2 million individuals are stung by a scorpion annually, causing more than 3250 deaths a year.⁵ Adults are stung more often, but children experience more severe envenomation, are more likely to develop severe illness requiring intensive supportive care, and have a higher mortality.⁴

As many as one-third of patients stung by a Parabuthus scorpion develop neuromuscular toxicity, which can be life-threatening.⁶ In a study of 277 envenomations by P transvaalicus, 10% of patients developed severe symptoms and 5 died. Children younger than 10 years and adults older than 50 years are at greatest risk for adverse outcomes.⁶ Children have a case fatality rate as high as 10 times the adult fatality rate.⁷

Clinical Presentation
The clinical presentation of scorpion envenomation varies with the species involved, the amount of venom injected, and the victim’s weight and baseline health.¹ Scorpion envenomation is divided into 4 grades based on the severity of a sting:

• Grade I: pain and paresthesia at the envenomation site; usually, no local inflammation

• Grade II: local symptoms as well as more remote pain and paresthesia; pain can radiate up the affected limb

• Grade III: cranial nerve or somatic skeletal neuromuscular dysfunction; either presentation can have associated autonomic dysfunction

• Grade IV: both cranial nerve and somatic skeletal neuromuscular dysfunction, with associated auto-nomic dysfunction

 

 

The initial symptom of a scorpion sting is intense burning pain. The sting site might be unimpressive, with only a mild local reaction. Symptoms usually progress to maximum severity within 5 hours.¹ Muscle pain, cramps, and weakness are prominent. The patient might have difficulty walking and swallowing, with increased salivation and drooling, and visual disturbance with abnormal eye movements. Pulse, blood pressure, and temperature often are elevated. The patient might be hyperreflexic with clonus.^1,6

Symptoms of increased sympathetic activity are hypertension, tachycardia, cardiac dysrhythmia, perspiration, hyperglycemia, and restlessness.^1,2 Parasympathetic effects are increased salivation, hypotension, bradycardia, and gastric distension. Skeletal muscle effects include tremors and involuntary muscle movement, which can be severe. Cranial nerve dysfunction may manifest as dysphagia, drooling, abnormal eye movements, blurred vision, slurred speech, and tongue fasciculations. Subsequent development of muscle weakness, bulbar paralysis, and difficulty breathing may be caused by depletion of neurotransmitters after prolonged excessive neuronal activity.¹

Distinctive Signs in Younger Patients
A child who is stung by a scorpion might have symptoms similar to those seen in an adult victim but can also experience an extreme form of restlessness that indicates severe envenomation characterized by inability to lay still, violent muscle twitching, and uncontrollable flailing of extremities. The child might have facial grimacing, with lip-smacking and chewing motions. In addition, bulbar paralysis and respiratory distress are more likely in children who have been stung than in adults.^1,2

Management

Treatment of a P transvaalicus sting is directed at “scorpionism,” envenomation that is associated with systemic symptoms that can be life-threatening. Treatment comprises support of vital functions, symptomatic measures, and injection of antivenin.⁸

Support of Vital Functions
In adults, systemic symptoms can be delayed as long as 8 hours after the sting. However, most severe cases usually are evident within 60 minutes; infants can reach grade IV as quickly as 15 to 30 minutes.^9,10 Loss of pharyngeal reflexes and development of respiratory distress are ominous warning signs requiring immediate respiratory support. Respiratory failure is the most common cause of death.¹ An asymptomatic child should be admitted to a hospital for observation for a minimum of 12 hours if the species of scorpion was not identified.²

Pain Relief
Most patients cannot tolerate an ice pack because of severe hyperesthesia. Infiltration of the local sting site with an anesthetic generally is safe and can provide some local pain relief. Intravenous fentanyl has been used in closely monitored patients because the drug is not associated with histamine release. Medications that cause release of histamine, such as morphine, can exacerbate or confuse the clinical picture.

Antivenin
Scorpion antivenin contains purified IgG fragments; allergic reactions are now rare. The sooner antivenin is administered, the greater the benefit. When administered early, it can prevent many of the most serious complications.⁷ In a randomized, double-blind study of critically ill children with clinically significant signs of scorpion envenomation, intravenous administration of scorpion-specific fragment antigen-binding 2 (F[(ab’]₂) antivenin resulted in resolution of clinical symptoms within 4 hours.¹¹

When managing grade III or IV scorpion envenomation, all patients should be admitted to a medical facility equipped to provide intensive supportive care; consider consultation with a regional poison control center. The World Health Organization maintains an international poison control center (at https://www.who.int/ipcs/poisons/centre/en/) with regional telephone numbers; alternatively, in the United States, call the nationwide telephone number of the Poison Control Center (800-222-1222).

The World Health Organization has identified declining production of antivenin as a crisis.¹²

Resolution
Symptoms of envenomation typically resolve 9 to 30 hours after a sting in a patient with grade III or IV envenomation not treated with antivenin.⁴ However, pain and paresthesia occasionally last as long as 2 weeks. In rare cases, more long-term sequelae of burning paresthesia persist for months.⁴

Conclusion

It is important for dermatologists to be aware of the potential for life-threatening envenomation by certain scorpion species native to southern Africa. In the United States, stings of these species most often are seen in patients with a pet collection, but late sequelae also can be seen in travelers returning from an endemic region. The site of a sting often appears unimpressive initially, but severe hyperesthesia is common. Patients with cardiac, neurologic, or respiratory symptoms require intensive supportive care. Proper care can be lifesaving.

Identification

The South African fattail scorpion (Parabuthus transvaalicus)(Figure) is one of the most poisonous scorpions in southern Africa.¹ A member of the Buthidae scorpion family, it can grow as long as 15 cm and is dark brown-black with lighter red-brown pincers. Similar to other fattail scorpions, it has slender pincers (pedipalps) and a thick square tail (the telson). Parabuthus transvaalicus inhabits hot dry deserts, scrublands, and semiarid regions.^1,2 It also is popular in exotic pet collections, the most common source of stings in the United States.

Stings and Envenomation

Scorpions with thicker tails generally have more potent venom than those with slender tails and thick pincers. Venom is injected by a stinger at the tip of the telson¹; P transvaalicus also can spray venom as far as 3 m.^1,2 Venom is not known to cause toxicity through skin contact but could represent a hazard if sprayed in the eye.

Scorpion toxins are a group of complex neurotoxins that act on sodium channels, either retarding inactivation (α toxin) or enhancing activation (β toxin), causing massive depolarization of excitable cells.^1,3 The toxin causes neurons to fire repetitively.⁴ Neurotransmitters—noradrenaline, adrenaline, and acetylcholine—cause the observed sympathetic, parasympathetic, and skeletal muscle effects.¹

Incidence
Worldwide, more than 1.2 million individuals are stung by a scorpion annually, causing more than 3250 deaths a year.⁵ Adults are stung more often, but children experience more severe envenomation, are more likely to develop severe illness requiring intensive supportive care, and have a higher mortality.⁴

As many as one-third of patients stung by a Parabuthus scorpion develop neuromuscular toxicity, which can be life-threatening.⁶ In a study of 277 envenomations by P transvaalicus, 10% of patients developed severe symptoms and 5 died. Children younger than 10 years and adults older than 50 years are at greatest risk for adverse outcomes.⁶ Children have a case fatality rate as high as 10 times the adult fatality rate.⁷

Clinical Presentation
The clinical presentation of scorpion envenomation varies with the species involved, the amount of venom injected, and the victim’s weight and baseline health.¹ Scorpion envenomation is divided into 4 grades based on the severity of a sting:

• Grade I: pain and paresthesia at the envenomation site; usually, no local inflammation

• Grade II: local symptoms as well as more remote pain and paresthesia; pain can radiate up the affected limb

• Grade III: cranial nerve or somatic skeletal neuromuscular dysfunction; either presentation can have associated autonomic dysfunction

• Grade IV: both cranial nerve and somatic skeletal neuromuscular dysfunction, with associated auto-nomic dysfunction

 

 

The initial symptom of a scorpion sting is intense burning pain. The sting site might be unimpressive, with only a mild local reaction. Symptoms usually progress to maximum severity within 5 hours.¹ Muscle pain, cramps, and weakness are prominent. The patient might have difficulty walking and swallowing, with increased salivation and drooling, and visual disturbance with abnormal eye movements. Pulse, blood pressure, and temperature often are elevated. The patient might be hyperreflexic with clonus.^1,6

Symptoms of increased sympathetic activity are hypertension, tachycardia, cardiac dysrhythmia, perspiration, hyperglycemia, and restlessness.^1,2 Parasympathetic effects are increased salivation, hypotension, bradycardia, and gastric distension. Skeletal muscle effects include tremors and involuntary muscle movement, which can be severe. Cranial nerve dysfunction may manifest as dysphagia, drooling, abnormal eye movements, blurred vision, slurred speech, and tongue fasciculations. Subsequent development of muscle weakness, bulbar paralysis, and difficulty breathing may be caused by depletion of neurotransmitters after prolonged excessive neuronal activity.¹

Distinctive Signs in Younger Patients
A child who is stung by a scorpion might have symptoms similar to those seen in an adult victim but can also experience an extreme form of restlessness that indicates severe envenomation characterized by inability to lay still, violent muscle twitching, and uncontrollable flailing of extremities. The child might have facial grimacing, with lip-smacking and chewing motions. In addition, bulbar paralysis and respiratory distress are more likely in children who have been stung than in adults.^1,2

Management

Treatment of a P transvaalicus sting is directed at “scorpionism,” envenomation that is associated with systemic symptoms that can be life-threatening. Treatment comprises support of vital functions, symptomatic measures, and injection of antivenin.⁸

Support of Vital Functions
In adults, systemic symptoms can be delayed as long as 8 hours after the sting. However, most severe cases usually are evident within 60 minutes; infants can reach grade IV as quickly as 15 to 30 minutes.^9,10 Loss of pharyngeal reflexes and development of respiratory distress are ominous warning signs requiring immediate respiratory support. Respiratory failure is the most common cause of death.¹ An asymptomatic child should be admitted to a hospital for observation for a minimum of 12 hours if the species of scorpion was not identified.²

Pain Relief
Most patients cannot tolerate an ice pack because of severe hyperesthesia. Infiltration of the local sting site with an anesthetic generally is safe and can provide some local pain relief. Intravenous fentanyl has been used in closely monitored patients because the drug is not associated with histamine release. Medications that cause release of histamine, such as morphine, can exacerbate or confuse the clinical picture.

Antivenin
Scorpion antivenin contains purified IgG fragments; allergic reactions are now rare. The sooner antivenin is administered, the greater the benefit. When administered early, it can prevent many of the most serious complications.⁷ In a randomized, double-blind study of critically ill children with clinically significant signs of scorpion envenomation, intravenous administration of scorpion-specific fragment antigen-binding 2 (F[(ab’]₂) antivenin resulted in resolution of clinical symptoms within 4 hours.¹¹

When managing grade III or IV scorpion envenomation, all patients should be admitted to a medical facility equipped to provide intensive supportive care; consider consultation with a regional poison control center. The World Health Organization maintains an international poison control center (at https://www.who.int/ipcs/poisons/centre/en/) with regional telephone numbers; alternatively, in the United States, call the nationwide telephone number of the Poison Control Center (800-222-1222).

The World Health Organization has identified declining production of antivenin as a crisis.¹²

Resolution
Symptoms of envenomation typically resolve 9 to 30 hours after a sting in a patient with grade III or IV envenomation not treated with antivenin.⁴ However, pain and paresthesia occasionally last as long as 2 weeks. In rare cases, more long-term sequelae of burning paresthesia persist for months.⁴

Conclusion

It is important for dermatologists to be aware of the potential for life-threatening envenomation by certain scorpion species native to southern Africa. In the United States, stings of these species most often are seen in patients with a pet collection, but late sequelae also can be seen in travelers returning from an endemic region. The site of a sting often appears unimpressive initially, but severe hyperesthesia is common. Patients with cardiac, neurologic, or respiratory symptoms require intensive supportive care. Proper care can be lifesaving.

Practice Gap

Management of nonmelanoma skin cancer (NMSC) in elderly patients can cause morbidity because these patients frequently struggle to care for their biopsy sites and experience biopsy- and surgery-related complications. To minimize this treatment-related morbidity, we designed a knifeless treatment approach that employs reflectance confocal microscopy (RCM) in lieu of skin biopsy to establish the diagnosis of NMSC, then uses either intralesional or topical chemotherapy or immunotherapy (as appropriate, depending on depth of invasion) to cure the NMSC. With this approach, the patient is spared both biopsy- and surgery-related difficulties, though both intralesional and topical chemotherapy are accompanied by their own risks for adverse effects.

The Technique

Elderly patients, diabetic patients, and patients with lesions suspicious for NMSC on areas prone to poor wound healing or to notable treatment-related morbidity (eg, lower legs, genitals, the face of younger patients) are offered skin biopsy or RCM; the latter is performed during the appointment by an RCM-trained medical assistant. Patients who elect to undergo RCM and who have a diagnosis of superficial basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) in situ are then treated with topical imiquimod or 5-fluorouracil. Patients with an invasive subtype of either BCC, SCC, or keratoacanthoma receive intralesional 5-fluorouracil injected at a concentration of 50 mg/cc at weekly intervals until the lesion blanches, with ongoing follow-up until the lesion is observed to have resolved under dermoscopic inspection.

When resolution is uncertain, RCM is repeated to assess for tumor clearance. Repeat RCM is performed at least 4 weeks after termination of treatment to avoid misinterpretation caused by treatment-related tissue inflammation. Patients who are not cured using this management approach are offered appropriate surgical management.

Practice Implications

Reflectance confocal microscopy has emerged as an effective modality for confirming the diagnosis of NMSC with high sensitivity and specificity.^1,2 Emergence of this technology presents an opportunity for improving the way the NMSC is managed because RCM allows dermatologists to confirm the diagnosis of BCC and SCC by interpretation of RCM mosaics rather than by histopathologic examination of biopsied tissue. Our knifeless approach to skin cancer management is especially beneficial when biopsy and dermatologic surgery are likely to confer notable morbidity, such as managing NMSC on the face of a young adult, in the frail elderly population, or in diabetic patients, and when treating sites on the lower extremity prone to poor wound healing.

Practice Gap

Management of nonmelanoma skin cancer (NMSC) in elderly patients can cause morbidity because these patients frequently struggle to care for their biopsy sites and experience biopsy- and surgery-related complications. To minimize this treatment-related morbidity, we designed a knifeless treatment approach that employs reflectance confocal microscopy (RCM) in lieu of skin biopsy to establish the diagnosis of NMSC, then uses either intralesional or topical chemotherapy or immunotherapy (as appropriate, depending on depth of invasion) to cure the NMSC. With this approach, the patient is spared both biopsy- and surgery-related difficulties, though both intralesional and topical chemotherapy are accompanied by their own risks for adverse effects.

The Technique

Elderly patients, diabetic patients, and patients with lesions suspicious for NMSC on areas prone to poor wound healing or to notable treatment-related morbidity (eg, lower legs, genitals, the face of younger patients) are offered skin biopsy or RCM; the latter is performed during the appointment by an RCM-trained medical assistant. Patients who elect to undergo RCM and who have a diagnosis of superficial basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) in situ are then treated with topical imiquimod or 5-fluorouracil. Patients with an invasive subtype of either BCC, SCC, or keratoacanthoma receive intralesional 5-fluorouracil injected at a concentration of 50 mg/cc at weekly intervals until the lesion blanches, with ongoing follow-up until the lesion is observed to have resolved under dermoscopic inspection.

When resolution is uncertain, RCM is repeated to assess for tumor clearance. Repeat RCM is performed at least 4 weeks after termination of treatment to avoid misinterpretation caused by treatment-related tissue inflammation. Patients who are not cured using this management approach are offered appropriate surgical management.

Practice Implications

Reflectance confocal microscopy has emerged as an effective modality for confirming the diagnosis of NMSC with high sensitivity and specificity.^1,2 Emergence of this technology presents an opportunity for improving the way the NMSC is managed because RCM allows dermatologists to confirm the diagnosis of BCC and SCC by interpretation of RCM mosaics rather than by histopathologic examination of biopsied tissue. Our knifeless approach to skin cancer management is especially beneficial when biopsy and dermatologic surgery are likely to confer notable morbidity, such as managing NMSC on the face of a young adult, in the frail elderly population, or in diabetic patients, and when treating sites on the lower extremity prone to poor wound healing.

Practice Gap

Management of nonmelanoma skin cancer (NMSC) in elderly patients can cause morbidity because these patients frequently struggle to care for their biopsy sites and experience biopsy- and surgery-related complications. To minimize this treatment-related morbidity, we designed a knifeless treatment approach that employs reflectance confocal microscopy (RCM) in lieu of skin biopsy to establish the diagnosis of NMSC, then uses either intralesional or topical chemotherapy or immunotherapy (as appropriate, depending on depth of invasion) to cure the NMSC. With this approach, the patient is spared both biopsy- and surgery-related difficulties, though both intralesional and topical chemotherapy are accompanied by their own risks for adverse effects.

The Technique

Elderly patients, diabetic patients, and patients with lesions suspicious for NMSC on areas prone to poor wound healing or to notable treatment-related morbidity (eg, lower legs, genitals, the face of younger patients) are offered skin biopsy or RCM; the latter is performed during the appointment by an RCM-trained medical assistant. Patients who elect to undergo RCM and who have a diagnosis of superficial basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) in situ are then treated with topical imiquimod or 5-fluorouracil. Patients with an invasive subtype of either BCC, SCC, or keratoacanthoma receive intralesional 5-fluorouracil injected at a concentration of 50 mg/cc at weekly intervals until the lesion blanches, with ongoing follow-up until the lesion is observed to have resolved under dermoscopic inspection.

When resolution is uncertain, RCM is repeated to assess for tumor clearance. Repeat RCM is performed at least 4 weeks after termination of treatment to avoid misinterpretation caused by treatment-related tissue inflammation. Patients who are not cured using this management approach are offered appropriate surgical management.

Practice Implications

Reflectance confocal microscopy has emerged as an effective modality for confirming the diagnosis of NMSC with high sensitivity and specificity.^1,2 Emergence of this technology presents an opportunity for improving the way the NMSC is managed because RCM allows dermatologists to confirm the diagnosis of BCC and SCC by interpretation of RCM mosaics rather than by histopathologic examination of biopsied tissue. Our knifeless approach to skin cancer management is especially beneficial when biopsy and dermatologic surgery are likely to confer notable morbidity, such as managing NMSC on the face of a young adult, in the frail elderly population, or in diabetic patients, and when treating sites on the lower extremity prone to poor wound healing.

Neglected tropical diseases (NTDs) are a group of 20 diseases that typically are chronic and cause long-term disability, which negatively impacts work productivity, child survival, and school performance and attendance with adverse effect on future earnings.¹ Data from the 2013 Global Burden of Disease study revealed that half of the world’s NTDs occur in poor populations living in wealthy countries.² Neglected tropical diseases with skin manifestations include parasitic infections (eg, American trypanosomiasis, African trypanosomiasis, dracunculiasis, echinococcosis, foodborne trematodiases, leishmaniasis, lymphatic filariasis, onchocerciasis, scabies and other ectoparasites, schistosomiasis, soil-transmitted helminths, taeniasis/cysticercosis), bacterial infections (eg, Buruli ulcer, leprosy, yaws), fungal infections (eg, mycetoma, chromoblastomycosis, deep mycoses), and viral infections (eg, dengue, chikungunya). Rabies and snakebite envenomization involve the skin through inoculation. Within the larger group of NTDs, the World Health Organization has identified “skin NTDs” as a subgroup of NTDs that present primarily with changes in the skin.³ In the absence of early diagnosis and treatment of these diseases, chronic and lifelong disfigurement, disability, stigma, and socioeconomic losses ensue.

The Department of Health of the Government of Western Australia stated:

Stigma is a mark of disgrace that sets a person apart from others. When a person is labeled by their illness they are no longer seen as an individual but as part of a stereotyped group. Negative attitudes and beliefs toward this group create prejudice which leads to negative actions and discrimination.⁴

Stigma associated with skin NTDs exemplifies how skin diseases can have enduring impact on individuals.⁵ For example, scarring from inactive cutaneous leishmaniasis carries heavy psychosocial burden. Young women reported that facial scarring from cutaneous leishmaniasis led to marriage rejections.⁶ Some even reported extreme suicidal ideations.⁷ Recently, major depressive disorder associated with scarring from inactive cutaneous leishmaniasis has been recognized as a notable contributor to disease burden from cutaneous leishmaniasis.⁸

Lymphatic filariasis is a major cause of leg and scrotal lymphedema worldwide. Even when the condition is treated, lymphedema often persists due to chronic irreversible lymphatic damage. A systematic review of 18 stigma studies in lymphatic filariasis found common themes related to the deleterious consequences of stigma on social relationships; work and education opportunities; health outcomes from reduced treatment-seeking behavior; and mental health, including anxiety, depression, and suicidal tendencies.⁹ In one subdistrict in India, implementation of a community-based lymphedema management program that consisted of teaching hygiene and limb care for more than 20,000 lymphedema patients and performing community outreach activities (eg, street plays, radio programs, informational brochures) to teach people about lymphatic filariasis and lymphedema care was associated with community members being accepting of patients and an improvement in their understanding of disease etiology.¹⁰

Skin involvement from onchocerciasis infection (onchocercal skin disease) is another condition associated with notable stigma.⁹ Through the African Programme for Onchocerciasis Control, annual mass drug administration of ivermectin in onchocerciasis-endemic communities has reduced the rate of onchocercal skin disease in these communities. In looking at perception of stigma in onchocercal skin diseases before community-directed ivermectin therapy and 7 to 10 years after, avoidance of people with onchocercal skin disease decreased from 32.7% to 4.3%. There also was an improvement in relationships between healthy people and those with onchocercal skin disease.¹¹

One of the most stigmatizing conditions is leprosy, often referred to as Hansen disease to give credit to the person who discovered that leprosy was caused by Mycobacterium leprae and not from sin, being cursed, or genetic inheritance. Even with this knowledge, stigma persists that can lead to family abandonment and social isolation, which further impacts afflicted individuals’ willingness to seek care, thus leading to disease progression. More recently, there has been research looking at interventions to reduce the stigma that individuals afflicted with leprosy face. In a study from Indonesia where individuals with leprosy were randomized to counseling, socioeconomic development, or contact between community members and affected people, all interventions were associated with a reduction in stigma.¹² A rights-based counseling module integrated individual, family, and group forms of counseling and consisted of 5 sessions that focused on medical knowledge of leprosy and rights of individuals with leprosy, along with elements of cognitive behavioral therapy. Socioeconomic development involved opportunities for business training, creation of community groups through which microfinance services were administered, and other assistance to improve livelihood. Informed by evidence from the field of human immunodeficiency virus and mental health that contact with affected people reduces negative attitudes and behavior among those participating in the intervention, contact between community members and persons affected by leprosy occurred through dialogue and interaction at events held in schools, village halls, and mosques. Furthermore, early detection and subsequent early treatment of leprosy can prevent individuals from the disability and disfigurement that we commonly associate with the disease, which often is not the message that afflicted individuals and their communities are hearing and seeing. Targeting media portrayal, the New Face of Leprosy project seeks to shift the messaging around leprosy to one of hope and positivity by promoting positive images—not presenting severe disfigurement as the representative image of leprosy—and strong messaging that the disease is curable.¹³

Although steps are being taken to address the psychosocial burden of skin NTDs, there is still much work to be done. From the public health lens that largely governs the policies and approaches toward addressing NTDs, the focus often is on interrupting and eliminating disease transmission. Morbidity management, including reduction in stigma and functional impairment, is not always the priority. It is in this space that dermatologists are uniquely positioned to advocate for management approaches that address the morbidity associated with skin NTDs. We have an intimate understanding of how impactful skin diseases can be, even if they are not commonly fatal. Globally, skin diseases are the fourth leading cause of nonfatal disease burden,¹⁴ yet dermatology lacks effective evidence-based interventions for reducing stigma in our patients with visible chronic diseases.¹⁵

Every day, we see firsthand how skin diseases affect not only our patients but also their families, friends, and caregivers. Although we may not see skin NTDs on a regular basis in our clinics, we can understand almost intuitively how devastating skin NTDs could be on individuals, families, and communities. For patients with skin NTDs, receiving medical therapy is only one component of treatment. In addition to optimizing early diagnosis and treatment, interventions taken to educate families and communities affected by skin NTDs are vitally important. Stigma reduction is possible, as we have seen from the aforementioned interventions used in communities with lymphatic filariasis, onchocerciasis, and leprosy. We call upon our fellow dermatologists to take interest in creating, evaluating, and promoting interventions that address stigma in skin NTDs; it is critical in achieving and maintaining health and well-being for our patients.

Neglected tropical diseases (NTDs) are a group of 20 diseases that typically are chronic and cause long-term disability, which negatively impacts work productivity, child survival, and school performance and attendance with adverse effect on future earnings.¹ Data from the 2013 Global Burden of Disease study revealed that half of the world’s NTDs occur in poor populations living in wealthy countries.² Neglected tropical diseases with skin manifestations include parasitic infections (eg, American trypanosomiasis, African trypanosomiasis, dracunculiasis, echinococcosis, foodborne trematodiases, leishmaniasis, lymphatic filariasis, onchocerciasis, scabies and other ectoparasites, schistosomiasis, soil-transmitted helminths, taeniasis/cysticercosis), bacterial infections (eg, Buruli ulcer, leprosy, yaws), fungal infections (eg, mycetoma, chromoblastomycosis, deep mycoses), and viral infections (eg, dengue, chikungunya). Rabies and snakebite envenomization involve the skin through inoculation. Within the larger group of NTDs, the World Health Organization has identified “skin NTDs” as a subgroup of NTDs that present primarily with changes in the skin.³ In the absence of early diagnosis and treatment of these diseases, chronic and lifelong disfigurement, disability, stigma, and socioeconomic losses ensue.

The Department of Health of the Government of Western Australia stated:

Stigma is a mark of disgrace that sets a person apart from others. When a person is labeled by their illness they are no longer seen as an individual but as part of a stereotyped group. Negative attitudes and beliefs toward this group create prejudice which leads to negative actions and discrimination.⁴

Stigma associated with skin NTDs exemplifies how skin diseases can have enduring impact on individuals.⁵ For example, scarring from inactive cutaneous leishmaniasis carries heavy psychosocial burden. Young women reported that facial scarring from cutaneous leishmaniasis led to marriage rejections.⁶ Some even reported extreme suicidal ideations.⁷ Recently, major depressive disorder associated with scarring from inactive cutaneous leishmaniasis has been recognized as a notable contributor to disease burden from cutaneous leishmaniasis.⁸

Lymphatic filariasis is a major cause of leg and scrotal lymphedema worldwide. Even when the condition is treated, lymphedema often persists due to chronic irreversible lymphatic damage. A systematic review of 18 stigma studies in lymphatic filariasis found common themes related to the deleterious consequences of stigma on social relationships; work and education opportunities; health outcomes from reduced treatment-seeking behavior; and mental health, including anxiety, depression, and suicidal tendencies.⁹ In one subdistrict in India, implementation of a community-based lymphedema management program that consisted of teaching hygiene and limb care for more than 20,000 lymphedema patients and performing community outreach activities (eg, street plays, radio programs, informational brochures) to teach people about lymphatic filariasis and lymphedema care was associated with community members being accepting of patients and an improvement in their understanding of disease etiology.¹⁰

Skin involvement from onchocerciasis infection (onchocercal skin disease) is another condition associated with notable stigma.⁹ Through the African Programme for Onchocerciasis Control, annual mass drug administration of ivermectin in onchocerciasis-endemic communities has reduced the rate of onchocercal skin disease in these communities. In looking at perception of stigma in onchocercal skin diseases before community-directed ivermectin therapy and 7 to 10 years after, avoidance of people with onchocercal skin disease decreased from 32.7% to 4.3%. There also was an improvement in relationships between healthy people and those with onchocercal skin disease.¹¹

One of the most stigmatizing conditions is leprosy, often referred to as Hansen disease to give credit to the person who discovered that leprosy was caused by Mycobacterium leprae and not from sin, being cursed, or genetic inheritance. Even with this knowledge, stigma persists that can lead to family abandonment and social isolation, which further impacts afflicted individuals’ willingness to seek care, thus leading to disease progression. More recently, there has been research looking at interventions to reduce the stigma that individuals afflicted with leprosy face. In a study from Indonesia where individuals with leprosy were randomized to counseling, socioeconomic development, or contact between community members and affected people, all interventions were associated with a reduction in stigma.¹² A rights-based counseling module integrated individual, family, and group forms of counseling and consisted of 5 sessions that focused on medical knowledge of leprosy and rights of individuals with leprosy, along with elements of cognitive behavioral therapy. Socioeconomic development involved opportunities for business training, creation of community groups through which microfinance services were administered, and other assistance to improve livelihood. Informed by evidence from the field of human immunodeficiency virus and mental health that contact with affected people reduces negative attitudes and behavior among those participating in the intervention, contact between community members and persons affected by leprosy occurred through dialogue and interaction at events held in schools, village halls, and mosques. Furthermore, early detection and subsequent early treatment of leprosy can prevent individuals from the disability and disfigurement that we commonly associate with the disease, which often is not the message that afflicted individuals and their communities are hearing and seeing. Targeting media portrayal, the New Face of Leprosy project seeks to shift the messaging around leprosy to one of hope and positivity by promoting positive images—not presenting severe disfigurement as the representative image of leprosy—and strong messaging that the disease is curable.¹³

Although steps are being taken to address the psychosocial burden of skin NTDs, there is still much work to be done. From the public health lens that largely governs the policies and approaches toward addressing NTDs, the focus often is on interrupting and eliminating disease transmission. Morbidity management, including reduction in stigma and functional impairment, is not always the priority. It is in this space that dermatologists are uniquely positioned to advocate for management approaches that address the morbidity associated with skin NTDs. We have an intimate understanding of how impactful skin diseases can be, even if they are not commonly fatal. Globally, skin diseases are the fourth leading cause of nonfatal disease burden,¹⁴ yet dermatology lacks effective evidence-based interventions for reducing stigma in our patients with visible chronic diseases.¹⁵

Every day, we see firsthand how skin diseases affect not only our patients but also their families, friends, and caregivers. Although we may not see skin NTDs on a regular basis in our clinics, we can understand almost intuitively how devastating skin NTDs could be on individuals, families, and communities. For patients with skin NTDs, receiving medical therapy is only one component of treatment. In addition to optimizing early diagnosis and treatment, interventions taken to educate families and communities affected by skin NTDs are vitally important. Stigma reduction is possible, as we have seen from the aforementioned interventions used in communities with lymphatic filariasis, onchocerciasis, and leprosy. We call upon our fellow dermatologists to take interest in creating, evaluating, and promoting interventions that address stigma in skin NTDs; it is critical in achieving and maintaining health and well-being for our patients.

Neglected tropical diseases (NTDs) are a group of 20 diseases that typically are chronic and cause long-term disability, which negatively impacts work productivity, child survival, and school performance and attendance with adverse effect on future earnings.¹ Data from the 2013 Global Burden of Disease study revealed that half of the world’s NTDs occur in poor populations living in wealthy countries.² Neglected tropical diseases with skin manifestations include parasitic infections (eg, American trypanosomiasis, African trypanosomiasis, dracunculiasis, echinococcosis, foodborne trematodiases, leishmaniasis, lymphatic filariasis, onchocerciasis, scabies and other ectoparasites, schistosomiasis, soil-transmitted helminths, taeniasis/cysticercosis), bacterial infections (eg, Buruli ulcer, leprosy, yaws), fungal infections (eg, mycetoma, chromoblastomycosis, deep mycoses), and viral infections (eg, dengue, chikungunya). Rabies and snakebite envenomization involve the skin through inoculation. Within the larger group of NTDs, the World Health Organization has identified “skin NTDs” as a subgroup of NTDs that present primarily with changes in the skin.³ In the absence of early diagnosis and treatment of these diseases, chronic and lifelong disfigurement, disability, stigma, and socioeconomic losses ensue.

The Department of Health of the Government of Western Australia stated:

Stigma is a mark of disgrace that sets a person apart from others. When a person is labeled by their illness they are no longer seen as an individual but as part of a stereotyped group. Negative attitudes and beliefs toward this group create prejudice which leads to negative actions and discrimination.⁴

Stigma associated with skin NTDs exemplifies how skin diseases can have enduring impact on individuals.⁵ For example, scarring from inactive cutaneous leishmaniasis carries heavy psychosocial burden. Young women reported that facial scarring from cutaneous leishmaniasis led to marriage rejections.⁶ Some even reported extreme suicidal ideations.⁷ Recently, major depressive disorder associated with scarring from inactive cutaneous leishmaniasis has been recognized as a notable contributor to disease burden from cutaneous leishmaniasis.⁸

Lymphatic filariasis is a major cause of leg and scrotal lymphedema worldwide. Even when the condition is treated, lymphedema often persists due to chronic irreversible lymphatic damage. A systematic review of 18 stigma studies in lymphatic filariasis found common themes related to the deleterious consequences of stigma on social relationships; work and education opportunities; health outcomes from reduced treatment-seeking behavior; and mental health, including anxiety, depression, and suicidal tendencies.⁹ In one subdistrict in India, implementation of a community-based lymphedema management program that consisted of teaching hygiene and limb care for more than 20,000 lymphedema patients and performing community outreach activities (eg, street plays, radio programs, informational brochures) to teach people about lymphatic filariasis and lymphedema care was associated with community members being accepting of patients and an improvement in their understanding of disease etiology.¹⁰

Skin involvement from onchocerciasis infection (onchocercal skin disease) is another condition associated with notable stigma.⁹ Through the African Programme for Onchocerciasis Control, annual mass drug administration of ivermectin in onchocerciasis-endemic communities has reduced the rate of onchocercal skin disease in these communities. In looking at perception of stigma in onchocercal skin diseases before community-directed ivermectin therapy and 7 to 10 years after, avoidance of people with onchocercal skin disease decreased from 32.7% to 4.3%. There also was an improvement in relationships between healthy people and those with onchocercal skin disease.¹¹

One of the most stigmatizing conditions is leprosy, often referred to as Hansen disease to give credit to the person who discovered that leprosy was caused by Mycobacterium leprae and not from sin, being cursed, or genetic inheritance. Even with this knowledge, stigma persists that can lead to family abandonment and social isolation, which further impacts afflicted individuals’ willingness to seek care, thus leading to disease progression. More recently, there has been research looking at interventions to reduce the stigma that individuals afflicted with leprosy face. In a study from Indonesia where individuals with leprosy were randomized to counseling, socioeconomic development, or contact between community members and affected people, all interventions were associated with a reduction in stigma.¹² A rights-based counseling module integrated individual, family, and group forms of counseling and consisted of 5 sessions that focused on medical knowledge of leprosy and rights of individuals with leprosy, along with elements of cognitive behavioral therapy. Socioeconomic development involved opportunities for business training, creation of community groups through which microfinance services were administered, and other assistance to improve livelihood. Informed by evidence from the field of human immunodeficiency virus and mental health that contact with affected people reduces negative attitudes and behavior among those participating in the intervention, contact between community members and persons affected by leprosy occurred through dialogue and interaction at events held in schools, village halls, and mosques. Furthermore, early detection and subsequent early treatment of leprosy can prevent individuals from the disability and disfigurement that we commonly associate with the disease, which often is not the message that afflicted individuals and their communities are hearing and seeing. Targeting media portrayal, the New Face of Leprosy project seeks to shift the messaging around leprosy to one of hope and positivity by promoting positive images—not presenting severe disfigurement as the representative image of leprosy—and strong messaging that the disease is curable.¹³

Although steps are being taken to address the psychosocial burden of skin NTDs, there is still much work to be done. From the public health lens that largely governs the policies and approaches toward addressing NTDs, the focus often is on interrupting and eliminating disease transmission. Morbidity management, including reduction in stigma and functional impairment, is not always the priority. It is in this space that dermatologists are uniquely positioned to advocate for management approaches that address the morbidity associated with skin NTDs. We have an intimate understanding of how impactful skin diseases can be, even if they are not commonly fatal. Globally, skin diseases are the fourth leading cause of nonfatal disease burden,¹⁴ yet dermatology lacks effective evidence-based interventions for reducing stigma in our patients with visible chronic diseases.¹⁵

Every day, we see firsthand how skin diseases affect not only our patients but also their families, friends, and caregivers. Although we may not see skin NTDs on a regular basis in our clinics, we can understand almost intuitively how devastating skin NTDs could be on individuals, families, and communities. For patients with skin NTDs, receiving medical therapy is only one component of treatment. In addition to optimizing early diagnosis and treatment, interventions taken to educate families and communities affected by skin NTDs are vitally important. Stigma reduction is possible, as we have seen from the aforementioned interventions used in communities with lymphatic filariasis, onchocerciasis, and leprosy. We call upon our fellow dermatologists to take interest in creating, evaluating, and promoting interventions that address stigma in skin NTDs; it is critical in achieving and maintaining health and well-being for our patients.

Nearly 2.7 million veterans who rely on the Veterans Health Administration (VHA) for their health care live in rural communities.¹ Of these, more than half are aged ≥ 65 years. Rural veterans have greater rates of service-related disability and chronic medical conditions than do their urban counterparts.^1,2 Yet because of their rural location, they face unique challenges, including long travel times and distances to health care services, lack of public transportation options, and limited availability of specialized medical and social support services.

Compounding these geographic barriers is a more general lack of workforce infrastructure and a dearth of clinical health care providers (HCPs) skilled in geriatric medicine. The demand for geriatricians is projected to outpace supply and result in a national shortage of nearly 27 000 geriatricians by 2025.³ Moreover, the overwhelming majority (90%) of HCPs identifying as geriatric specialists reside in urban areas.⁴ This creates tremendous pressure on the health care system to provide remote care for older veterans contending with complex conditions, and ultimately these veterans may not receive the specialized care they need.

Telehealth modalities bridge these gaps by bringing health care to veterans in rural communities. They may also hold promise for strengthening community care in rural areas through workforce development and dissemination of educational resources. The VHA has been recognized as a leader in the field of telehealth since it began offering telehealth services to veterans in 1977^5-8 and served more than 677 000 Veterans via telehealth in fiscal year (FY) 2015.⁹ The VHA currently employs multiple modes of telehealth to increase veterans’ access to health care, including: (1) synchronous technology like clinical video telehealth (CVT), which provides live encounters between HCPs and patients using videoconferencing software; and (2) asynchronous technology, such as store-and-forward communication that offers remote transmission and clinical interpretation of veteran health data. The VHA has also strengthened its broad telehealth infrastructure by staffing VHA clinical sites with telehealth clinical technicians and providing telehealth hardware throughout.

The Department of Veterans Affairs (VA) Office of Geriatrics and Extended Care (GEC) and Office of Rural Health (ORH) established the Geriatric Research Education and Clinical Centers (GRECC) Connect project in 2014 to leverage the existing telehealth technologies at the VA to meet the health care needs of older veterans. GRECC Connect builds on the VHA network of geriatrics expertise in GRECCs by providing telehealth-based consultative support for rural primary care provider (PCP) teams, older veterans, and their families. This program profile describes this project’s mission, structure, and activities.

Program Overview

GRECC Connect leverages the clinical expertise and administrative infrastructure of participating GRECCs in order to reach clinicians and veterans in primarily rural communities.¹⁰ GRECCs are VA centers of excellence focused on aging and comprise a large network of interdisciplinary geriatrics expertise. All GRECCs have strong affiliations with local universities and are located in urban VA medical centers (VAMCs). GRECC Connect is based on a hub-and-spoke model in which urban GRECC hub sites are connected to community-based outpatient clinic (CBOC) and VAMC spokes that primarily serve veterans in other communities. CBOCs are stand-alone clinics that are geographically separate from a related VA medical center and provide outpatient primary care, mental health care services, and some specialty care services such as cardiology or neurology. They range in size from small, mainly telehealth clinics with 1 technician to large clinics with several specialty providers. Each GRECC hub site partners with an average of 6 CBOCs (range 3-16), each of which is an average distance of 92.8 miles from the related VA medical center (range 20-406 miles).

GRECC Connect was established under the umbrella of the VA Geriatric Scholars Program, which since 2008 integrates geriatrics into rural primary care practices through tailored education for continuing professional development.¹¹ Through intensive courses in geriatrics and quality improvement methods and through participation in local quality improvement projects benefiting older veterans, the Geriatric Scholars Program trains rural PCPs so that they can more effectively and independently diagnose and manage common geriatric syndromes.¹² The network of clinician scholars developed by the Geriatric Scholars Program, all rural frontline clinicians at VA clinics, has given the GRECC Connect project a well-prepared, geriatrics-trained workforce to act as project champions at rural CBOCs and VAMCs. The GRECC Connect project’s goals are to enhance access to geriatric specialty care among older veterans with complex medical problems, geriatric syndromes, and increased risk for institutionalization, and to provide geriatrics-focused educational support to rural HCP teams.

Geriatric Provider Consultations

The first overarching goal of the GRECC Connect project is to improve access to geriatrics specialty care by facilitating linkages between GRECC hub sites and the CBOCs and VAMCs that primarily serve veterans in rural communities. GRECC hub sites offer consultative support from geriatrics specialty team members (eg, geriatricians, nurse practitioners, pharmacists, gero- or neuropsychologists, registered nurses [RNs], and social workers) to rural PCP in their catchment area. This support is offered through a variety of telehealth modalities readily available in the VA (Table 1). These include CVT, in which a veteran located at a rural CBOC is seen using videoconferencing software by a geriatrics specialty provider who is located at a GRECC hub site. At some GRECC hub sites, CVT has also been used to conduct group visits between a GRECC provider at the hub site and several veterans who participate from a rural CBOC. Electronic consultations, or e-consults, involve a rural provider entering a clinical question in the VA Computerized Patient Record System. The question is then triaged, and a geriatrics provider at a GRECC responds, based on review of that veteran’s chart. At some GRECC hub sites, the e-consults are more extensive and may include telephone contact with the veteran or their caregiver.

Consultations between GRECC-based teams and rural PCPs may cover any aspect of geriatrics care, ranging from broad concerns to subspecialty areas of geriatric medicine. For instance, general geriatrics consultation may address polypharmacy, during either care transitions or ongoing care. Consultation may also reflect the specific focus area of a particular GRECC, such as cognitive assessment (eg, Pittsburgh GRECC), management of osteoporosis to address falls (eg, Durham GRECC, Miami GRECC), and continence care (eg, Birmingham/Atlanta GRECC).¹³ Most consultations are initiated by a remote HCP who is seeking geriatrics expertise from the GRECC team.

Some GRECC hub sites, however, employ case finding strategies, or detailed chart reviews, in order to identify older veterans who may benefit from geriatrics consultation. For veterans identified through those mechanisms, the GRECC clinicians suggest that the rural HCP either request or allow an e-consult or evaluation via CVT for those veterans. The geriatric consultations may help identify additional care needs for older veterans and lead to recommendations, orders, or remote provision of a variety of other actions, including VA or non-VA services (eg, home-based primary care, home nursing service, respite service, social support services such as Meals on Wheels); neuropsychological testing; physical or occupational therapy; audiology or optometry referral; falls and fracture risk assessment and interventions to reduce falls (eg, home safety evaluation, physical therapy); osteoporosis risk assessments (eg, densitometry, recommendations for pharmacologic therapy) to reduce the risk of injury or nontraumatic fractures from falls; palliative care for incontinence and hospice; and counseling on geriatric issues such as dementia caregiving, advanced directives, and driving cessation.

More recently, the Miami GRECC has begun evaluating rural veterans at risk for hypoglycemia, providing patient education and counseling about hypoglycemia, and making recommendations to the veterans’ primary care teams.¹⁴ Consultations may also lead to the appropriate use or discontinuation of medications, related to polypharmacy. GRECC-based teams, for example, have helped rural HCPs modify medication doses, start appropriate medications for dementia and depression, and identify and stop potentially inappropriate medications (eg, those that increase fall risk or that have significant anticholinergic properties).¹⁵

GRECC Connect Geriatric Case Conference Series

The second overarching goal of the GRECC Connect project is to provide geriatrics-focused educational support to equip PCPs to better serve their aging veteran patients. This is achieved through twice-monthly, case-based conferences supported by the VA Employee Education System (EES) and delivered through a webinar interface. Case conferences are targeted to members of the health care team who may provide care for rural older adults, including physicians, nurse practitioners, physician assistants, RNs, psychologists, social workers, physical and occupational therapists, and pharmacists. The format of these sessions includes a clinical case presentation, a didactic portion to enhance knowledge of participants, and an open question/answer period. The conferences focus on discussions of challenging clinical cases, addressing common problems (eg, driving concerns), and the assessment/management of geriatric syndromes (eg, cognitive decline, falls, polypharmacy). These conferences aim to improve the knowledge and skills of rural clinical teams in taking care of older veterans and to disseminate best practices in geriatric medicine, using case discussions to highlight practical applications of practices to clinical care. Recent GRECC Connect geriatric case conferences are listed in Table 2 and are recorded and archived to ensure that busy clinicians may access these trainings at the time of their choosing. These materials are catalogued and archived on the EES server.

Early Experience

GRECC Connect tracks on an annual basis the number of unique veterans served, number of participating GRECC hub sites and CBOCs, mileage from veteran homes to teleconsultation sites, and number of clinicians and staff engaged in GRECC Connect education programs.¹⁶ Since its inception in 2014, the GRECC Connect project has provided direct clinical support to more than 4000 unique veterans (eFigure), of whom half were seen for a cognition-related issue. Consultations were made on behalf of 1,622 veterans in FY 2018, of whom 60% were from rural or highly rural communities and 56.8% were served by CVT visits. The number of GRECC hub sites has increased from 4 in FY 2014 to 12 (of 20 total GRECCs) in FY 2018. The locations of current GRECC hub sites can be found on the Geriatric Scholars website: www.gerischolars.org. Through this expansion, GRECC Connect provides geriatric consultative and educational support to > 70 rural VA clinics in 10 of the 18 Veterans Integrated Service Networks (VISNs).

To assess the reduction in commute times from teleconsultation, we calculated the difference between the mileage from veteran homes to teleconsultation sites (ie, rural clinics) and the mileage from veteran homes to VAMCs where geriatric teams are located. We estimate that the 1622 veterans served in FY 2018 saved a total of 179 121 miles in travel through GRECC Connect. Veterans traveled 106 fewer miles and on average saved $58 in out-of-pocket savings (based on US General Services Administration 2018 standard mileage reimbursement rate of $0.545 per mile). However, many of the veterans have reported anecdotally that the reduction in mileage traveled was less important than the elimination of stress involved in urban navigating, driving, and parking.

More difficult to measure, GRECC Connect seeks to enhance veteran safety by reducing driving distances for older veterans whose driving abilities may be influenced by many age-related health conditions (eg, visual changes, cognitive impairment). For these and other reasons, surveyed veterans overwhelmingly reported that they would be likely to recommend teleconsultation services to other veterans, and that they preferred telemedicine consultation over traveling long distances for in-person clinical consultations.¹⁶

Since its inception in 2014, GRECC Connect has provided case-based education to a total of 2335 unique clinicians and staff. Participants have included physicians, nurse practitioners, RNs, social workers, and pharmacists. This distribution reflects the interdisciplinary nature of geriatric care. A plurality of participants (39%) were RNs. Surveyed participants in the GRECC Connect geriatrics case conference series report high overall satisfaction with the learning activity, acquisition of new knowledge and skills, and intention to apply new knowledge and skills to improve job performance.¹⁰ In addition, participants agreed that the online training platform was effective for learning and that they would recommend the education series to other HCPs.^10,16

Discussion

During its rapid 4-year scale up, GRECC Connect has established a national network and enhanced relationships between GRECC-based clinical teams and rural provider teams. In doing so, the program has begun to improve rural veterans’ access to geriatric specialty care. By providing continuing education to members of the interprofessional health care team, GRECC Connect develops rural providers’ clinical competency and promotes geriatrics skills and expertise. These activities are synergistic: Clinical support enables rural HCPs to become better at managing their own patients, while formal educational activities highlight the availability of specialized consultation available through GRECC Connect. Through ongoing creation of handbooks, workflows, and data analytic strategies, GRECC Connect aims to disseminate this model to additional GRECCs as well as other GEC programs to promote “anywhere to anywhere” VA health care.¹⁷

Barriers and Facilitators

GRECC Connect has had notable implementation challenges while new consultation relationships have been forged in order to provide geriatric expertise to rural areas where it is not otherwise available. Many GRECCs had already established connections with rural CBOCs. Among GRECCs that had previously established consultative relationships with rural clinics, the use of telehealth modalities to provide geriatric clinical resources has been a natural extension of these partnerships. GRECCs that lacked these connections, however, often had to obtain buy-in from multiple stakeholders, including rural HCPs and teams, administrative leads, and local telehealth coordinators, and they required VISN- and facility-level leadership to encourage and sustain rural team participation.

Depending on the distance of the GRECC hub-site to the CBOC, efforts to establish and sustain partnerships may require multiple contacts over time (eg, via face-to-face meetings, one-on-one outreach) and large-scale advertising of consultative services. Continuous engagement with CBOC-based teams also involves development of case finding strategies (eg, hospital discharge information, diagnoses, clinical criteria) to better identify veterans who may benefit from GRECC Connect consultation. Owing to the heterogeneity of technological resources, space, scheduling capacity, and staffing at CBOCs, GRECC sites continue to have variable engagement with their CBOC partners.

The inclusion of GRECC Connect within the Geriatric Scholars Program helps ensure that clinician scholars can serve as project champions at their respective rural sites. Rural HCPs with full-time clinical duties initially had difficulty carving out time to participate in GRECC Connect’s case-based conferences. However, the webinar platform has improved and sustained provider participation, and enduring recordings of the presentations allow clinicians to participate in the conferences at their convenience. Finally, the project experienced delays in taking certain administrative steps and hiring staff needed to support the establishment of telehealth modalities—even within a single health care system like the VA, each medical center and regional system has unique policies that complicate how telehealth modalities can be set up.

Conclusion and Future Directions

The GRECC Connect project aims to establish and support meaningful partnerships between urban geriatric specialists and rural HCPs to facilitate veterans’ increased access to geriatric specialty care. VA ORH has recognized it as a Rural Promising Practice, and GRECC Connect is currently being disseminated through an enterprise-wide initiative. Early evidence demonstrates that over 4 years, the expansion of GRECC Connect has helped meet critical aims of improving provider confidence and skills in geriatric management, and of increasing direct service provision. We have also used nationwide education platforms (eg, VA EES) to deliver geriatrics-focused education to health care teams.

Older rural veterans and their caregivers may benefit from this program through decreased travel-associated burden and report high satisfaction with these programs. Through a recently established collaboration with the GEC Data Analysis Center, we will use national data to refine our ability to identify at-risk, older rural veterans and to better evaluate their service needs and the GRECC Connect clinical impact. Because the VA is rapidly expanding use of telehealth and other virtual and digital methods to increase access to care, continued investments in telehealth are central to the VA 5-year strategic plan.¹⁸ In this spirit, GRECC Connect will continue to expand its program offerings and to leverage telehealth technologies to meet the needs of older veterans.

Acknowledgments

The authors wish to acknowledge Lisa Tenover, MD, PhD, (Palo Alto GRECC) for her contributions to this manuscript; the VA Rural Health Resource Center–Western Region; and GRECC Connect team members for their tireless work to ensure this project’s success. The GRECC Teams include Atlanta/Birmingham (Julia [Annette] Tedford, RN; Marquitta Cox, LMSW; Lisa Welch, LMSW; Mark Phillips; Lanie Walters, PharmD; Kroshona Tabb, PhD; Robert Langford, and Jason [Thomas] Sanders, HT, TCT); Bronx/NY Harbor (Ab Brody, RN; PhD, GNP-BC; Nick Koufacos, LMSW; and Shatice Jones); Canandaigua (Gary Kochersberger, MD; Suzanne Gillespie, MD; Gary Warner, PhD; Christie Hylwa, RPh CCP; Sharon Fell, LMSW; and Dorian Savino, MPA); Durham (Mamata Yanamadala, MBBS; Christy Knight, LCSW, MSW; and Julie Vognsen); Eastern Colorado (Larry Bourg, MD; Skotti Church, MD; Morgan Elmore, DO; Stephanie Hartz, LCSW; Carolyn Horney, MD; Steven Huart, AuD; Kathryn Nearing, PhD; Elizabeth O’Brien, PharmD; Laurence Robbins, MD; Robert Schwartz, MD; Karen Shea, MD; and Joleen Sussman, PhD); Little Rock (Prasad Padala, MD; and Tanya Taylor, RN); Madison (Ryan Bartkus, MD; Timothy Howell, MD; Lindsay Clark, PhD; Lauren Welch, PharmD, BCGP; Ellen Wanninger, MSW, CAPSW; Stacie Monson, RN, BSN; and Teresa Swader, MSW, LCSW); Miami (Carlos Gomez Orozo); New England (Malissa Kraft, PsyD); Palo Alto (Terri Huh, PhD, ABPP; Philip Choe, DO; Dawna Dougherty, LCSW; Ashley Scales, MPH); Pittsburgh (Stacey Shaffer, MD; Carol Dolbee, CRNP; Nancy Kovell, LCSW; Paul Bulgarelli, DO; Lauren Jost, PsyD; and Marcia Homer, RN-BC); and San Antonio (Becky Powers, MD; Che Kelly, RN, BSN; Cynthia Stewart, LCSW; Rebecca Rottman-Sagebiel, PharmD, BCPS, CGP; Melody Moris; Daniel MacCarthy; and Chen-pin Wang, PhD).

Nearly 2.7 million veterans who rely on the Veterans Health Administration (VHA) for their health care live in rural communities.¹ Of these, more than half are aged ≥ 65 years. Rural veterans have greater rates of service-related disability and chronic medical conditions than do their urban counterparts.^1,2 Yet because of their rural location, they face unique challenges, including long travel times and distances to health care services, lack of public transportation options, and limited availability of specialized medical and social support services.

Compounding these geographic barriers is a more general lack of workforce infrastructure and a dearth of clinical health care providers (HCPs) skilled in geriatric medicine. The demand for geriatricians is projected to outpace supply and result in a national shortage of nearly 27 000 geriatricians by 2025.³ Moreover, the overwhelming majority (90%) of HCPs identifying as geriatric specialists reside in urban areas.⁴ This creates tremendous pressure on the health care system to provide remote care for older veterans contending with complex conditions, and ultimately these veterans may not receive the specialized care they need.

Telehealth modalities bridge these gaps by bringing health care to veterans in rural communities. They may also hold promise for strengthening community care in rural areas through workforce development and dissemination of educational resources. The VHA has been recognized as a leader in the field of telehealth since it began offering telehealth services to veterans in 1977^5-8 and served more than 677 000 Veterans via telehealth in fiscal year (FY) 2015.⁹ The VHA currently employs multiple modes of telehealth to increase veterans’ access to health care, including: (1) synchronous technology like clinical video telehealth (CVT), which provides live encounters between HCPs and patients using videoconferencing software; and (2) asynchronous technology, such as store-and-forward communication that offers remote transmission and clinical interpretation of veteran health data. The VHA has also strengthened its broad telehealth infrastructure by staffing VHA clinical sites with telehealth clinical technicians and providing telehealth hardware throughout.

The Department of Veterans Affairs (VA) Office of Geriatrics and Extended Care (GEC) and Office of Rural Health (ORH) established the Geriatric Research Education and Clinical Centers (GRECC) Connect project in 2014 to leverage the existing telehealth technologies at the VA to meet the health care needs of older veterans. GRECC Connect builds on the VHA network of geriatrics expertise in GRECCs by providing telehealth-based consultative support for rural primary care provider (PCP) teams, older veterans, and their families. This program profile describes this project’s mission, structure, and activities.

Program Overview

GRECC Connect leverages the clinical expertise and administrative infrastructure of participating GRECCs in order to reach clinicians and veterans in primarily rural communities.¹⁰ GRECCs are VA centers of excellence focused on aging and comprise a large network of interdisciplinary geriatrics expertise. All GRECCs have strong affiliations with local universities and are located in urban VA medical centers (VAMCs). GRECC Connect is based on a hub-and-spoke model in which urban GRECC hub sites are connected to community-based outpatient clinic (CBOC) and VAMC spokes that primarily serve veterans in other communities. CBOCs are stand-alone clinics that are geographically separate from a related VA medical center and provide outpatient primary care, mental health care services, and some specialty care services such as cardiology or neurology. They range in size from small, mainly telehealth clinics with 1 technician to large clinics with several specialty providers. Each GRECC hub site partners with an average of 6 CBOCs (range 3-16), each of which is an average distance of 92.8 miles from the related VA medical center (range 20-406 miles).

GRECC Connect was established under the umbrella of the VA Geriatric Scholars Program, which since 2008 integrates geriatrics into rural primary care practices through tailored education for continuing professional development.¹¹ Through intensive courses in geriatrics and quality improvement methods and through participation in local quality improvement projects benefiting older veterans, the Geriatric Scholars Program trains rural PCPs so that they can more effectively and independently diagnose and manage common geriatric syndromes.¹² The network of clinician scholars developed by the Geriatric Scholars Program, all rural frontline clinicians at VA clinics, has given the GRECC Connect project a well-prepared, geriatrics-trained workforce to act as project champions at rural CBOCs and VAMCs. The GRECC Connect project’s goals are to enhance access to geriatric specialty care among older veterans with complex medical problems, geriatric syndromes, and increased risk for institutionalization, and to provide geriatrics-focused educational support to rural HCP teams.

Geriatric Provider Consultations

The first overarching goal of the GRECC Connect project is to improve access to geriatrics specialty care by facilitating linkages between GRECC hub sites and the CBOCs and VAMCs that primarily serve veterans in rural communities. GRECC hub sites offer consultative support from geriatrics specialty team members (eg, geriatricians, nurse practitioners, pharmacists, gero- or neuropsychologists, registered nurses [RNs], and social workers) to rural PCP in their catchment area. This support is offered through a variety of telehealth modalities readily available in the VA (Table 1). These include CVT, in which a veteran located at a rural CBOC is seen using videoconferencing software by a geriatrics specialty provider who is located at a GRECC hub site. At some GRECC hub sites, CVT has also been used to conduct group visits between a GRECC provider at the hub site and several veterans who participate from a rural CBOC. Electronic consultations, or e-consults, involve a rural provider entering a clinical question in the VA Computerized Patient Record System. The question is then triaged, and a geriatrics provider at a GRECC responds, based on review of that veteran’s chart. At some GRECC hub sites, the e-consults are more extensive and may include telephone contact with the veteran or their caregiver.

Consultations between GRECC-based teams and rural PCPs may cover any aspect of geriatrics care, ranging from broad concerns to subspecialty areas of geriatric medicine. For instance, general geriatrics consultation may address polypharmacy, during either care transitions or ongoing care. Consultation may also reflect the specific focus area of a particular GRECC, such as cognitive assessment (eg, Pittsburgh GRECC), management of osteoporosis to address falls (eg, Durham GRECC, Miami GRECC), and continence care (eg, Birmingham/Atlanta GRECC).¹³ Most consultations are initiated by a remote HCP who is seeking geriatrics expertise from the GRECC team.

Some GRECC hub sites, however, employ case finding strategies, or detailed chart reviews, in order to identify older veterans who may benefit from geriatrics consultation. For veterans identified through those mechanisms, the GRECC clinicians suggest that the rural HCP either request or allow an e-consult or evaluation via CVT for those veterans. The geriatric consultations may help identify additional care needs for older veterans and lead to recommendations, orders, or remote provision of a variety of other actions, including VA or non-VA services (eg, home-based primary care, home nursing service, respite service, social support services such as Meals on Wheels); neuropsychological testing; physical or occupational therapy; audiology or optometry referral; falls and fracture risk assessment and interventions to reduce falls (eg, home safety evaluation, physical therapy); osteoporosis risk assessments (eg, densitometry, recommendations for pharmacologic therapy) to reduce the risk of injury or nontraumatic fractures from falls; palliative care for incontinence and hospice; and counseling on geriatric issues such as dementia caregiving, advanced directives, and driving cessation.

More recently, the Miami GRECC has begun evaluating rural veterans at risk for hypoglycemia, providing patient education and counseling about hypoglycemia, and making recommendations to the veterans’ primary care teams.¹⁴ Consultations may also lead to the appropriate use or discontinuation of medications, related to polypharmacy. GRECC-based teams, for example, have helped rural HCPs modify medication doses, start appropriate medications for dementia and depression, and identify and stop potentially inappropriate medications (eg, those that increase fall risk or that have significant anticholinergic properties).¹⁵

GRECC Connect Geriatric Case Conference Series

The second overarching goal of the GRECC Connect project is to provide geriatrics-focused educational support to equip PCPs to better serve their aging veteran patients. This is achieved through twice-monthly, case-based conferences supported by the VA Employee Education System (EES) and delivered through a webinar interface. Case conferences are targeted to members of the health care team who may provide care for rural older adults, including physicians, nurse practitioners, physician assistants, RNs, psychologists, social workers, physical and occupational therapists, and pharmacists. The format of these sessions includes a clinical case presentation, a didactic portion to enhance knowledge of participants, and an open question/answer period. The conferences focus on discussions of challenging clinical cases, addressing common problems (eg, driving concerns), and the assessment/management of geriatric syndromes (eg, cognitive decline, falls, polypharmacy). These conferences aim to improve the knowledge and skills of rural clinical teams in taking care of older veterans and to disseminate best practices in geriatric medicine, using case discussions to highlight practical applications of practices to clinical care. Recent GRECC Connect geriatric case conferences are listed in Table 2 and are recorded and archived to ensure that busy clinicians may access these trainings at the time of their choosing. These materials are catalogued and archived on the EES server.

Early Experience

GRECC Connect tracks on an annual basis the number of unique veterans served, number of participating GRECC hub sites and CBOCs, mileage from veteran homes to teleconsultation sites, and number of clinicians and staff engaged in GRECC Connect education programs.¹⁶ Since its inception in 2014, the GRECC Connect project has provided direct clinical support to more than 4000 unique veterans (eFigure), of whom half were seen for a cognition-related issue. Consultations were made on behalf of 1,622 veterans in FY 2018, of whom 60% were from rural or highly rural communities and 56.8% were served by CVT visits. The number of GRECC hub sites has increased from 4 in FY 2014 to 12 (of 20 total GRECCs) in FY 2018. The locations of current GRECC hub sites can be found on the Geriatric Scholars website: www.gerischolars.org. Through this expansion, GRECC Connect provides geriatric consultative and educational support to > 70 rural VA clinics in 10 of the 18 Veterans Integrated Service Networks (VISNs).

To assess the reduction in commute times from teleconsultation, we calculated the difference between the mileage from veteran homes to teleconsultation sites (ie, rural clinics) and the mileage from veteran homes to VAMCs where geriatric teams are located. We estimate that the 1622 veterans served in FY 2018 saved a total of 179 121 miles in travel through GRECC Connect. Veterans traveled 106 fewer miles and on average saved $58 in out-of-pocket savings (based on US General Services Administration 2018 standard mileage reimbursement rate of $0.545 per mile). However, many of the veterans have reported anecdotally that the reduction in mileage traveled was less important than the elimination of stress involved in urban navigating, driving, and parking.

More difficult to measure, GRECC Connect seeks to enhance veteran safety by reducing driving distances for older veterans whose driving abilities may be influenced by many age-related health conditions (eg, visual changes, cognitive impairment). For these and other reasons, surveyed veterans overwhelmingly reported that they would be likely to recommend teleconsultation services to other veterans, and that they preferred telemedicine consultation over traveling long distances for in-person clinical consultations.¹⁶

Since its inception in 2014, GRECC Connect has provided case-based education to a total of 2335 unique clinicians and staff. Participants have included physicians, nurse practitioners, RNs, social workers, and pharmacists. This distribution reflects the interdisciplinary nature of geriatric care. A plurality of participants (39%) were RNs. Surveyed participants in the GRECC Connect geriatrics case conference series report high overall satisfaction with the learning activity, acquisition of new knowledge and skills, and intention to apply new knowledge and skills to improve job performance.¹⁰ In addition, participants agreed that the online training platform was effective for learning and that they would recommend the education series to other HCPs.^10,16

Discussion

During its rapid 4-year scale up, GRECC Connect has established a national network and enhanced relationships between GRECC-based clinical teams and rural provider teams. In doing so, the program has begun to improve rural veterans’ access to geriatric specialty care. By providing continuing education to members of the interprofessional health care team, GRECC Connect develops rural providers’ clinical competency and promotes geriatrics skills and expertise. These activities are synergistic: Clinical support enables rural HCPs to become better at managing their own patients, while formal educational activities highlight the availability of specialized consultation available through GRECC Connect. Through ongoing creation of handbooks, workflows, and data analytic strategies, GRECC Connect aims to disseminate this model to additional GRECCs as well as other GEC programs to promote “anywhere to anywhere” VA health care.¹⁷

Barriers and Facilitators

GRECC Connect has had notable implementation challenges while new consultation relationships have been forged in order to provide geriatric expertise to rural areas where it is not otherwise available. Many GRECCs had already established connections with rural CBOCs. Among GRECCs that had previously established consultative relationships with rural clinics, the use of telehealth modalities to provide geriatric clinical resources has been a natural extension of these partnerships. GRECCs that lacked these connections, however, often had to obtain buy-in from multiple stakeholders, including rural HCPs and teams, administrative leads, and local telehealth coordinators, and they required VISN- and facility-level leadership to encourage and sustain rural team participation.

Depending on the distance of the GRECC hub-site to the CBOC, efforts to establish and sustain partnerships may require multiple contacts over time (eg, via face-to-face meetings, one-on-one outreach) and large-scale advertising of consultative services. Continuous engagement with CBOC-based teams also involves development of case finding strategies (eg, hospital discharge information, diagnoses, clinical criteria) to better identify veterans who may benefit from GRECC Connect consultation. Owing to the heterogeneity of technological resources, space, scheduling capacity, and staffing at CBOCs, GRECC sites continue to have variable engagement with their CBOC partners.

The inclusion of GRECC Connect within the Geriatric Scholars Program helps ensure that clinician scholars can serve as project champions at their respective rural sites. Rural HCPs with full-time clinical duties initially had difficulty carving out time to participate in GRECC Connect’s case-based conferences. However, the webinar platform has improved and sustained provider participation, and enduring recordings of the presentations allow clinicians to participate in the conferences at their convenience. Finally, the project experienced delays in taking certain administrative steps and hiring staff needed to support the establishment of telehealth modalities—even within a single health care system like the VA, each medical center and regional system has unique policies that complicate how telehealth modalities can be set up.

Conclusion and Future Directions

The GRECC Connect project aims to establish and support meaningful partnerships between urban geriatric specialists and rural HCPs to facilitate veterans’ increased access to geriatric specialty care. VA ORH has recognized it as a Rural Promising Practice, and GRECC Connect is currently being disseminated through an enterprise-wide initiative. Early evidence demonstrates that over 4 years, the expansion of GRECC Connect has helped meet critical aims of improving provider confidence and skills in geriatric management, and of increasing direct service provision. We have also used nationwide education platforms (eg, VA EES) to deliver geriatrics-focused education to health care teams.

Older rural veterans and their caregivers may benefit from this program through decreased travel-associated burden and report high satisfaction with these programs. Through a recently established collaboration with the GEC Data Analysis Center, we will use national data to refine our ability to identify at-risk, older rural veterans and to better evaluate their service needs and the GRECC Connect clinical impact. Because the VA is rapidly expanding use of telehealth and other virtual and digital methods to increase access to care, continued investments in telehealth are central to the VA 5-year strategic plan.¹⁸ In this spirit, GRECC Connect will continue to expand its program offerings and to leverage telehealth technologies to meet the needs of older veterans.

Acknowledgments

The authors wish to acknowledge Lisa Tenover, MD, PhD, (Palo Alto GRECC) for her contributions to this manuscript; the VA Rural Health Resource Center–Western Region; and GRECC Connect team members for their tireless work to ensure this project’s success. The GRECC Teams include Atlanta/Birmingham (Julia [Annette] Tedford, RN; Marquitta Cox, LMSW; Lisa Welch, LMSW; Mark Phillips; Lanie Walters, PharmD; Kroshona Tabb, PhD; Robert Langford, and Jason [Thomas] Sanders, HT, TCT); Bronx/NY Harbor (Ab Brody, RN; PhD, GNP-BC; Nick Koufacos, LMSW; and Shatice Jones); Canandaigua (Gary Kochersberger, MD; Suzanne Gillespie, MD; Gary Warner, PhD; Christie Hylwa, RPh CCP; Sharon Fell, LMSW; and Dorian Savino, MPA); Durham (Mamata Yanamadala, MBBS; Christy Knight, LCSW, MSW; and Julie Vognsen); Eastern Colorado (Larry Bourg, MD; Skotti Church, MD; Morgan Elmore, DO; Stephanie Hartz, LCSW; Carolyn Horney, MD; Steven Huart, AuD; Kathryn Nearing, PhD; Elizabeth O’Brien, PharmD; Laurence Robbins, MD; Robert Schwartz, MD; Karen Shea, MD; and Joleen Sussman, PhD); Little Rock (Prasad Padala, MD; and Tanya Taylor, RN); Madison (Ryan Bartkus, MD; Timothy Howell, MD; Lindsay Clark, PhD; Lauren Welch, PharmD, BCGP; Ellen Wanninger, MSW, CAPSW; Stacie Monson, RN, BSN; and Teresa Swader, MSW, LCSW); Miami (Carlos Gomez Orozo); New England (Malissa Kraft, PsyD); Palo Alto (Terri Huh, PhD, ABPP; Philip Choe, DO; Dawna Dougherty, LCSW; Ashley Scales, MPH); Pittsburgh (Stacey Shaffer, MD; Carol Dolbee, CRNP; Nancy Kovell, LCSW; Paul Bulgarelli, DO; Lauren Jost, PsyD; and Marcia Homer, RN-BC); and San Antonio (Becky Powers, MD; Che Kelly, RN, BSN; Cynthia Stewart, LCSW; Rebecca Rottman-Sagebiel, PharmD, BCPS, CGP; Melody Moris; Daniel MacCarthy; and Chen-pin Wang, PhD).

Nearly 2.7 million veterans who rely on the Veterans Health Administration (VHA) for their health care live in rural communities.¹ Of these, more than half are aged ≥ 65 years. Rural veterans have greater rates of service-related disability and chronic medical conditions than do their urban counterparts.^1,2 Yet because of their rural location, they face unique challenges, including long travel times and distances to health care services, lack of public transportation options, and limited availability of specialized medical and social support services.

Compounding these geographic barriers is a more general lack of workforce infrastructure and a dearth of clinical health care providers (HCPs) skilled in geriatric medicine. The demand for geriatricians is projected to outpace supply and result in a national shortage of nearly 27 000 geriatricians by 2025.³ Moreover, the overwhelming majority (90%) of HCPs identifying as geriatric specialists reside in urban areas.⁴ This creates tremendous pressure on the health care system to provide remote care for older veterans contending with complex conditions, and ultimately these veterans may not receive the specialized care they need.

Telehealth modalities bridge these gaps by bringing health care to veterans in rural communities. They may also hold promise for strengthening community care in rural areas through workforce development and dissemination of educational resources. The VHA has been recognized as a leader in the field of telehealth since it began offering telehealth services to veterans in 1977^5-8 and served more than 677 000 Veterans via telehealth in fiscal year (FY) 2015.⁹ The VHA currently employs multiple modes of telehealth to increase veterans’ access to health care, including: (1) synchronous technology like clinical video telehealth (CVT), which provides live encounters between HCPs and patients using videoconferencing software; and (2) asynchronous technology, such as store-and-forward communication that offers remote transmission and clinical interpretation of veteran health data. The VHA has also strengthened its broad telehealth infrastructure by staffing VHA clinical sites with telehealth clinical technicians and providing telehealth hardware throughout.

The Department of Veterans Affairs (VA) Office of Geriatrics and Extended Care (GEC) and Office of Rural Health (ORH) established the Geriatric Research Education and Clinical Centers (GRECC) Connect project in 2014 to leverage the existing telehealth technologies at the VA to meet the health care needs of older veterans. GRECC Connect builds on the VHA network of geriatrics expertise in GRECCs by providing telehealth-based consultative support for rural primary care provider (PCP) teams, older veterans, and their families. This program profile describes this project’s mission, structure, and activities.

Program Overview

GRECC Connect leverages the clinical expertise and administrative infrastructure of participating GRECCs in order to reach clinicians and veterans in primarily rural communities.¹⁰ GRECCs are VA centers of excellence focused on aging and comprise a large network of interdisciplinary geriatrics expertise. All GRECCs have strong affiliations with local universities and are located in urban VA medical centers (VAMCs). GRECC Connect is based on a hub-and-spoke model in which urban GRECC hub sites are connected to community-based outpatient clinic (CBOC) and VAMC spokes that primarily serve veterans in other communities. CBOCs are stand-alone clinics that are geographically separate from a related VA medical center and provide outpatient primary care, mental health care services, and some specialty care services such as cardiology or neurology. They range in size from small, mainly telehealth clinics with 1 technician to large clinics with several specialty providers. Each GRECC hub site partners with an average of 6 CBOCs (range 3-16), each of which is an average distance of 92.8 miles from the related VA medical center (range 20-406 miles).

GRECC Connect was established under the umbrella of the VA Geriatric Scholars Program, which since 2008 integrates geriatrics into rural primary care practices through tailored education for continuing professional development.¹¹ Through intensive courses in geriatrics and quality improvement methods and through participation in local quality improvement projects benefiting older veterans, the Geriatric Scholars Program trains rural PCPs so that they can more effectively and independently diagnose and manage common geriatric syndromes.¹² The network of clinician scholars developed by the Geriatric Scholars Program, all rural frontline clinicians at VA clinics, has given the GRECC Connect project a well-prepared, geriatrics-trained workforce to act as project champions at rural CBOCs and VAMCs. The GRECC Connect project’s goals are to enhance access to geriatric specialty care among older veterans with complex medical problems, geriatric syndromes, and increased risk for institutionalization, and to provide geriatrics-focused educational support to rural HCP teams.

Geriatric Provider Consultations

The first overarching goal of the GRECC Connect project is to improve access to geriatrics specialty care by facilitating linkages between GRECC hub sites and the CBOCs and VAMCs that primarily serve veterans in rural communities. GRECC hub sites offer consultative support from geriatrics specialty team members (eg, geriatricians, nurse practitioners, pharmacists, gero- or neuropsychologists, registered nurses [RNs], and social workers) to rural PCP in their catchment area. This support is offered through a variety of telehealth modalities readily available in the VA (Table 1). These include CVT, in which a veteran located at a rural CBOC is seen using videoconferencing software by a geriatrics specialty provider who is located at a GRECC hub site. At some GRECC hub sites, CVT has also been used to conduct group visits between a GRECC provider at the hub site and several veterans who participate from a rural CBOC. Electronic consultations, or e-consults, involve a rural provider entering a clinical question in the VA Computerized Patient Record System. The question is then triaged, and a geriatrics provider at a GRECC responds, based on review of that veteran’s chart. At some GRECC hub sites, the e-consults are more extensive and may include telephone contact with the veteran or their caregiver.

Consultations between GRECC-based teams and rural PCPs may cover any aspect of geriatrics care, ranging from broad concerns to subspecialty areas of geriatric medicine. For instance, general geriatrics consultation may address polypharmacy, during either care transitions or ongoing care. Consultation may also reflect the specific focus area of a particular GRECC, such as cognitive assessment (eg, Pittsburgh GRECC), management of osteoporosis to address falls (eg, Durham GRECC, Miami GRECC), and continence care (eg, Birmingham/Atlanta GRECC).¹³ Most consultations are initiated by a remote HCP who is seeking geriatrics expertise from the GRECC team.

Some GRECC hub sites, however, employ case finding strategies, or detailed chart reviews, in order to identify older veterans who may benefit from geriatrics consultation. For veterans identified through those mechanisms, the GRECC clinicians suggest that the rural HCP either request or allow an e-consult or evaluation via CVT for those veterans. The geriatric consultations may help identify additional care needs for older veterans and lead to recommendations, orders, or remote provision of a variety of other actions, including VA or non-VA services (eg, home-based primary care, home nursing service, respite service, social support services such as Meals on Wheels); neuropsychological testing; physical or occupational therapy; audiology or optometry referral; falls and fracture risk assessment and interventions to reduce falls (eg, home safety evaluation, physical therapy); osteoporosis risk assessments (eg, densitometry, recommendations for pharmacologic therapy) to reduce the risk of injury or nontraumatic fractures from falls; palliative care for incontinence and hospice; and counseling on geriatric issues such as dementia caregiving, advanced directives, and driving cessation.

More recently, the Miami GRECC has begun evaluating rural veterans at risk for hypoglycemia, providing patient education and counseling about hypoglycemia, and making recommendations to the veterans’ primary care teams.¹⁴ Consultations may also lead to the appropriate use or discontinuation of medications, related to polypharmacy. GRECC-based teams, for example, have helped rural HCPs modify medication doses, start appropriate medications for dementia and depression, and identify and stop potentially inappropriate medications (eg, those that increase fall risk or that have significant anticholinergic properties).¹⁵

GRECC Connect Geriatric Case Conference Series

The second overarching goal of the GRECC Connect project is to provide geriatrics-focused educational support to equip PCPs to better serve their aging veteran patients. This is achieved through twice-monthly, case-based conferences supported by the VA Employee Education System (EES) and delivered through a webinar interface. Case conferences are targeted to members of the health care team who may provide care for rural older adults, including physicians, nurse practitioners, physician assistants, RNs, psychologists, social workers, physical and occupational therapists, and pharmacists. The format of these sessions includes a clinical case presentation, a didactic portion to enhance knowledge of participants, and an open question/answer period. The conferences focus on discussions of challenging clinical cases, addressing common problems (eg, driving concerns), and the assessment/management of geriatric syndromes (eg, cognitive decline, falls, polypharmacy). These conferences aim to improve the knowledge and skills of rural clinical teams in taking care of older veterans and to disseminate best practices in geriatric medicine, using case discussions to highlight practical applications of practices to clinical care. Recent GRECC Connect geriatric case conferences are listed in Table 2 and are recorded and archived to ensure that busy clinicians may access these trainings at the time of their choosing. These materials are catalogued and archived on the EES server.

Early Experience

GRECC Connect tracks on an annual basis the number of unique veterans served, number of participating GRECC hub sites and CBOCs, mileage from veteran homes to teleconsultation sites, and number of clinicians and staff engaged in GRECC Connect education programs.¹⁶ Since its inception in 2014, the GRECC Connect project has provided direct clinical support to more than 4000 unique veterans (eFigure), of whom half were seen for a cognition-related issue. Consultations were made on behalf of 1,622 veterans in FY 2018, of whom 60% were from rural or highly rural communities and 56.8% were served by CVT visits. The number of GRECC hub sites has increased from 4 in FY 2014 to 12 (of 20 total GRECCs) in FY 2018. The locations of current GRECC hub sites can be found on the Geriatric Scholars website: www.gerischolars.org. Through this expansion, GRECC Connect provides geriatric consultative and educational support to > 70 rural VA clinics in 10 of the 18 Veterans Integrated Service Networks (VISNs).

To assess the reduction in commute times from teleconsultation, we calculated the difference between the mileage from veteran homes to teleconsultation sites (ie, rural clinics) and the mileage from veteran homes to VAMCs where geriatric teams are located. We estimate that the 1622 veterans served in FY 2018 saved a total of 179 121 miles in travel through GRECC Connect. Veterans traveled 106 fewer miles and on average saved $58 in out-of-pocket savings (based on US General Services Administration 2018 standard mileage reimbursement rate of $0.545 per mile). However, many of the veterans have reported anecdotally that the reduction in mileage traveled was less important than the elimination of stress involved in urban navigating, driving, and parking.

More difficult to measure, GRECC Connect seeks to enhance veteran safety by reducing driving distances for older veterans whose driving abilities may be influenced by many age-related health conditions (eg, visual changes, cognitive impairment). For these and other reasons, surveyed veterans overwhelmingly reported that they would be likely to recommend teleconsultation services to other veterans, and that they preferred telemedicine consultation over traveling long distances for in-person clinical consultations.¹⁶

Since its inception in 2014, GRECC Connect has provided case-based education to a total of 2335 unique clinicians and staff. Participants have included physicians, nurse practitioners, RNs, social workers, and pharmacists. This distribution reflects the interdisciplinary nature of geriatric care. A plurality of participants (39%) were RNs. Surveyed participants in the GRECC Connect geriatrics case conference series report high overall satisfaction with the learning activity, acquisition of new knowledge and skills, and intention to apply new knowledge and skills to improve job performance.¹⁰ In addition, participants agreed that the online training platform was effective for learning and that they would recommend the education series to other HCPs.^10,16

Discussion

During its rapid 4-year scale up, GRECC Connect has established a national network and enhanced relationships between GRECC-based clinical teams and rural provider teams. In doing so, the program has begun to improve rural veterans’ access to geriatric specialty care. By providing continuing education to members of the interprofessional health care team, GRECC Connect develops rural providers’ clinical competency and promotes geriatrics skills and expertise. These activities are synergistic: Clinical support enables rural HCPs to become better at managing their own patients, while formal educational activities highlight the availability of specialized consultation available through GRECC Connect. Through ongoing creation of handbooks, workflows, and data analytic strategies, GRECC Connect aims to disseminate this model to additional GRECCs as well as other GEC programs to promote “anywhere to anywhere” VA health care.¹⁷

Barriers and Facilitators

GRECC Connect has had notable implementation challenges while new consultation relationships have been forged in order to provide geriatric expertise to rural areas where it is not otherwise available. Many GRECCs had already established connections with rural CBOCs. Among GRECCs that had previously established consultative relationships with rural clinics, the use of telehealth modalities to provide geriatric clinical resources has been a natural extension of these partnerships. GRECCs that lacked these connections, however, often had to obtain buy-in from multiple stakeholders, including rural HCPs and teams, administrative leads, and local telehealth coordinators, and they required VISN- and facility-level leadership to encourage and sustain rural team participation.

Depending on the distance of the GRECC hub-site to the CBOC, efforts to establish and sustain partnerships may require multiple contacts over time (eg, via face-to-face meetings, one-on-one outreach) and large-scale advertising of consultative services. Continuous engagement with CBOC-based teams also involves development of case finding strategies (eg, hospital discharge information, diagnoses, clinical criteria) to better identify veterans who may benefit from GRECC Connect consultation. Owing to the heterogeneity of technological resources, space, scheduling capacity, and staffing at CBOCs, GRECC sites continue to have variable engagement with their CBOC partners.

The inclusion of GRECC Connect within the Geriatric Scholars Program helps ensure that clinician scholars can serve as project champions at their respective rural sites. Rural HCPs with full-time clinical duties initially had difficulty carving out time to participate in GRECC Connect’s case-based conferences. However, the webinar platform has improved and sustained provider participation, and enduring recordings of the presentations allow clinicians to participate in the conferences at their convenience. Finally, the project experienced delays in taking certain administrative steps and hiring staff needed to support the establishment of telehealth modalities—even within a single health care system like the VA, each medical center and regional system has unique policies that complicate how telehealth modalities can be set up.

Conclusion and Future Directions

The GRECC Connect project aims to establish and support meaningful partnerships between urban geriatric specialists and rural HCPs to facilitate veterans’ increased access to geriatric specialty care. VA ORH has recognized it as a Rural Promising Practice, and GRECC Connect is currently being disseminated through an enterprise-wide initiative. Early evidence demonstrates that over 4 years, the expansion of GRECC Connect has helped meet critical aims of improving provider confidence and skills in geriatric management, and of increasing direct service provision. We have also used nationwide education platforms (eg, VA EES) to deliver geriatrics-focused education to health care teams.

Older rural veterans and their caregivers may benefit from this program through decreased travel-associated burden and report high satisfaction with these programs. Through a recently established collaboration with the GEC Data Analysis Center, we will use national data to refine our ability to identify at-risk, older rural veterans and to better evaluate their service needs and the GRECC Connect clinical impact. Because the VA is rapidly expanding use of telehealth and other virtual and digital methods to increase access to care, continued investments in telehealth are central to the VA 5-year strategic plan.¹⁸ In this spirit, GRECC Connect will continue to expand its program offerings and to leverage telehealth technologies to meet the needs of older veterans.

Acknowledgments

The authors wish to acknowledge Lisa Tenover, MD, PhD, (Palo Alto GRECC) for her contributions to this manuscript; the VA Rural Health Resource Center–Western Region; and GRECC Connect team members for their tireless work to ensure this project’s success. The GRECC Teams include Atlanta/Birmingham (Julia [Annette] Tedford, RN; Marquitta Cox, LMSW; Lisa Welch, LMSW; Mark Phillips; Lanie Walters, PharmD; Kroshona Tabb, PhD; Robert Langford, and Jason [Thomas] Sanders, HT, TCT); Bronx/NY Harbor (Ab Brody, RN; PhD, GNP-BC; Nick Koufacos, LMSW; and Shatice Jones); Canandaigua (Gary Kochersberger, MD; Suzanne Gillespie, MD; Gary Warner, PhD; Christie Hylwa, RPh CCP; Sharon Fell, LMSW; and Dorian Savino, MPA); Durham (Mamata Yanamadala, MBBS; Christy Knight, LCSW, MSW; and Julie Vognsen); Eastern Colorado (Larry Bourg, MD; Skotti Church, MD; Morgan Elmore, DO; Stephanie Hartz, LCSW; Carolyn Horney, MD; Steven Huart, AuD; Kathryn Nearing, PhD; Elizabeth O’Brien, PharmD; Laurence Robbins, MD; Robert Schwartz, MD; Karen Shea, MD; and Joleen Sussman, PhD); Little Rock (Prasad Padala, MD; and Tanya Taylor, RN); Madison (Ryan Bartkus, MD; Timothy Howell, MD; Lindsay Clark, PhD; Lauren Welch, PharmD, BCGP; Ellen Wanninger, MSW, CAPSW; Stacie Monson, RN, BSN; and Teresa Swader, MSW, LCSW); Miami (Carlos Gomez Orozo); New England (Malissa Kraft, PsyD); Palo Alto (Terri Huh, PhD, ABPP; Philip Choe, DO; Dawna Dougherty, LCSW; Ashley Scales, MPH); Pittsburgh (Stacey Shaffer, MD; Carol Dolbee, CRNP; Nancy Kovell, LCSW; Paul Bulgarelli, DO; Lauren Jost, PsyD; and Marcia Homer, RN-BC); and San Antonio (Becky Powers, MD; Che Kelly, RN, BSN; Cynthia Stewart, LCSW; Rebecca Rottman-Sagebiel, PharmD, BCPS, CGP; Melody Moris; Daniel MacCarthy; and Chen-pin Wang, PhD).

Asthma attacks account for 1.8 million emergency department (ED) visits each year in the US and for 10 deaths daily.¹ Management of asthma attacks includes administration of inhaled ß₂ adrenergic agonists, inhaled anticholinergic agents, IV magnesium sulfate, and corticosteroids.² Status asthmaticus is an intense acute exacerbation of asthma that does not respond to repeated treatments of bronchodilators and corticosteroids.³ It is a medical emergency requiring immediate recognition and treatment. The decision to intubate a patient with status asthmaticus is a clinical decision based on work of breathing, respiratory acidosis, and failure to respond to medical interventions.

In refractory cases of status asthmaticus, intubation and mechanical ventilation are undertaken to provide oxygenation and ventilation until the bronchospasm resolves. However, mechanical ventilation is associated with significant risks, including high end-inspiratory pressures, barotrauma, and volutrauma.⁴ Rescue therapies include muscle relaxation, infusion of ketamine (central acting nonopioid analgesic with bronchodilatory properties), heliox, and general anesthesia.^2,4 We report a case of a patient with life-threatening asthma and status asthmaticus treated with sevoflurane general anesthesia.

Case Presentation

A 55-year-old woman whose medical history was notable for asthma, psoriasis, hypothyroidism, tobacco, and alcohol abuse, and posttraumatic stress disorder (PTSD) presented to the ED. The patient had rarely sought medical attention and had no prior ED visits or hospitalizations in the electronic health record. Her home regimen included an albuterol inhaler used as needed. Her family reported that they had found her in distress in bed in a tripod position, unable to speak and struggling to breath.

Emergency medical services found the patient cyanotic, apneic, and pulseless. She received cardiopulmonary resuscitation for 30 seconds and 1-mg IV epinephrine, and spontaneous circulation returned. The patient arrived in the ED with an oral airway in place receiving bag valve mask ventilation. The patient expelled the oral airway. She was unable to speak due to dyspnea, exhibited persistent cyanosis, fatigue due to work of breathing, and failed to respond to nebulized albuterol/ipratropium bromide, IV methylprednisolone, and magnesium sulfate. The patient met criteria for acute severe asthma, or status asthmaticus. Thus, the patient received rapid sequence induction with rocuronium and ketamine and was intubated.

According to her family, the patient had no previous intensive care unit (ICU) admissions or prior intubations. Her only asthma medication was an albuterol inhaler as needed. The patient worked as a supervisor at a window blind manufacturing company. She lived alone, smoked 2 packs of cigarettes a day for more than 30 years, had no pets, drank unknown quantities of beer, wine, and hard liquor daily, and had smoked marijuana for several years.

The patient’s physical examination was notable for diffuse expiratory wheezes. Laboratory analysis revealed white blood cell count of 13.7 k/mcL, sodium 140 mmol/L, potassium 4.9 mmol/L, chloride 105 mmol/L, CO₂ 17 mmol/L, creatinine 0.98 mg/dL, troponin 0.03 ng/mL, lactate 7.2 mmol/L. Her chest X-ray showed hyperinflation but no focal opacities, pneumothorax, or pulmonary edema. Her endotracheal tube was in good position (Figure 1). A computed tomography pulmonary angiogram showed no pulmonary embolus or emphysema. There were atelectatic changes in the dependent portion of the right lower lobe, central bronchial wall thickening, and no stigmata of air trapping (Figure 2). An echocardiogram revealed a left ventricular ejection fraction of 45%, normal right ventricle and right ventricular size and function with an estimated right ventricular systolic pressure of 40 mm Hg.

The patient was admitted to the ICU and started on continuous infusion cisatracurium for paralysis and deep sedation to improve ventilatory synchrony and decrease auto positive end-expiratory pressure (PEEP). Mechanical ventilation was initiated with volume-cycled assist control ventilation, 6 mL/kg/ideal body weight (IBW) at 5-cm H₂O PEEP, and 1 minute ventilation of 10 liters. The patient had severe air trapping and high airway pressures. The dynamic PEEP was 22-cm H₂O (normal PEEP of 5-cm H₂O), peak airway pressure (PAP) 41-cm H₂O, and plateau pressure 31-cm H₂O. In addition, the arterial blood gas (ABG) showed severe hypercapnic respiratory acidosis without significant hypoxemia with pH 7.15, PaCO₂ 90 mm Hg, and PaO₂ 150 mm Hg.

Pressure controlled ventilation was attempted unsuccessfully due to high airway resistance. Ultimately, the patient was set on volume control with low tidal volume, 6 mL/kg/IBW, high flow 90 L/min, PEEP 0 cm of H₂O, and a low respiratory rate of 10 to achieve an inspiratory to expiratory (I:E) ratio of 1:7. Managing the ventilator to avoid dynamic hyperinflation and auto-PEEP, she remained relatively stable and improved.

By day 4 the patient’s ventilator was set to volume assist control with respiratory rate of 16, tidal volume, 6 mL/kg/IBW, PEEP 5-cm H₂O with auto PEEP of 3-cm H₂O, and fraction of inspired ABG O₂ (FiO₂) 0.35 with PAP of 46-cm H₂O and plateau pressure of 17-cm H₂O. The ABG was pH 7.32, PaCO₂ 65 mm Hg, and PaO₂ 74 mm Hg. However, on hospital day 5, she developed worsening PAP 60 to 77-cm H₂O, plateau pressures 17-cm H₂O, and a dynamic PEEP 16-cm H₂O and was unresponsive to ventilator maneuvers to lower airway pressures and improve ventilation.

The patient had been receiving continuous albuterol and ipratropium nebulizer treatments. Ketamine infusion was considered fraught with potential for a dissociative reaction due to the patient’s significant PTSD. The patient’s family requested avoidance of ketamine infusion since the patient was paralyzed and psychiatric effects could not be monitored. Heliox 80/20 mixture was considered; however, it is incompatible with the ventilator that was being used since it could not account for the density of the helium gas flow in the tidal volumes. Extracorporeal membrane oxygenation (ECMO) was not available at our facility, and the patient was not a candidate for the regional ECMO center.

On hospital day 8, the patient developed worsening respiratory acidosis. The patient’s PAP increased to > 77-cm H₂O, and her ABG revealed pH 7.22, PaCO₂ 90 mm Hg, and PaO₂ 77 mm Hg with FiO₂ 0.4. A chest X-ray demonstrated a new left lower lobe infiltrate. Fiber optic bronchoscopy was notable for scattered thick secretions throughout both lungs without obstructing mucus plug. Removal of airway secretions did not improve airway pressures or dynamic hyperinflation.

After consultation and discussion with the chief of anesthesia, the patient was placed on an anesthesia ventilator and started on sevoflurane 1.5% in the ICU. Anesthesiology was available 24 hours a day, and the anesthesiologist rounded with the intensivist frequently for this patient. The anesthesia technician worked closely with respiratory therapy regarding ventilator setting and changing the anesthesia gas scavenging charcoal canister. Within 4 hours, her gas exchange normalized (Table). The patient’s ABG was pH 7.44, PaCO₂ 52 mm Hg, and PaO₂ 69 mm Hg on FiO₂ 0.4. On volume cycled ventilation with a rate of 12, flow rate of 40 L/min, and tidal volume 6 mL/kg/IBW, the PAP decreased to 41-cm H₂O.

Within 24 hours bronchospasm improved as evidenced by decreased airway pressures, resolution of wheezing, and decreased CO₂ retention. The sevoflurane was easily weaned over the next 48 hours by decreasing the dose by 25% every 12-hour shift without rebound bronchospasm. Airway pressures and ABGs were frequently monitored during the weaning process. The patient resumed conventional mechanical ventilation, cisatracurium was discontinued, and she underwent a percutaneous tracheostomy for critical illness polymyopathy. Her respiratory muscle strength recovered more robustly than anticipated. Prior to discharge to a skilled nursing facility for continued rehabilitation, she was removed from mechanical ventilation and decannulated.

Discussion

This case illustrates the successful treatment of a patient with extreme status asthmaticus given inhalational anesthesia as supportive care while the bronchospasm and status asthmaticus abated. This is an unusual treatment in an ominous situation. Inhalational anesthetics are potent bronchodilators and have been successfully used in the management of status asthmaticus refractory to conventional therapy.⁴ Inhalational anesthetics have been shown to decrease airway resistance, dynamic hyperinflation, and intrinsic PEEP.⁵ These agents result in rapid bronchodilation by relaxing the smooth muscle and are associated with early liberation from mechanical ventilation.^5,6 Although there are no guidelines regarding which inhalational agent is best, specific dosing, duration, or titration, case reports in the literature regarding the successful use of inhalational agents in life-threatening status asthmaticus exist.^2,5,7

Caveats regarding the use of inhalational anesthetics in status asthmaticus include proarrhythmias, severe hepatic and renal toxicity. Although isoflurane is less likely to cause arrhythmia, both isoflurane and sevoflurane can cause dose-dependent hypotension by peripheral vasodilatation.⁷ Ourpatient did not manifest any adverse effects.

Additional challenges regarding the use of inhalational anesthetics for status asthmaticus include differences in ventilators and occupational hazards.⁸ Anesthesia or operating room ventilators differ from ICU ventilators in flow and pressure capabilities.⁷ The anesthesia ventilator is not capable of generating inspiratory pressures sufficient to ventilate patients with severely elevated airway resistance. Thus, the decrease inspiratory flow that occurs with increasing airway pressure limits the tidal volume delivered and consequently the minute volume. Although newer anesthesia ventilators have increased flow capabilities, they require a fully trained staff.⁸

Potential occupational exposure to these volatile anesthetic gases occurs as patients being treated may exhale considerable amounts of volatile anesthetics.⁸ An anesthesia gas scavenging device, such as a charcoal canister, must be attached to the ventilator to capture the exhaled anesthetic gases and should be changed every 12 hours.⁸ Finally, there is a potential for rebound bronchospasm as the anesthetic agent is tapered.^6,7,9-11

Conclusion

Inhalational anesthetics are an option as rescue therapy for severe life-threatening asthma when all other therapies have failed. Use of inhalational anesthetics in status asthmaticus consists of case reports of which half are in children.^2,5,7 Our patient contributes to the literature of case reports regarding using sevoflurane in refractory status asthmaticus. A decision to choose them must be a collaborative team approach with anesthesiology, pulmonary/critical care medicine, respiratory therapy, and ICU nurses, and the risks and benefits should be discussed with decision-making family members. Since there are no specific guidelines for the use of inhalational agents in status asthmaticus, close attention to inspiratory flows, gas scavenging devices, and clinical response is required. Additionally, the team must be comfortable with the plan to use an anesthesia ventilator and trained on its limitations.

Asthma attacks account for 1.8 million emergency department (ED) visits each year in the US and for 10 deaths daily.¹ Management of asthma attacks includes administration of inhaled ß₂ adrenergic agonists, inhaled anticholinergic agents, IV magnesium sulfate, and corticosteroids.² Status asthmaticus is an intense acute exacerbation of asthma that does not respond to repeated treatments of bronchodilators and corticosteroids.³ It is a medical emergency requiring immediate recognition and treatment. The decision to intubate a patient with status asthmaticus is a clinical decision based on work of breathing, respiratory acidosis, and failure to respond to medical interventions.

In refractory cases of status asthmaticus, intubation and mechanical ventilation are undertaken to provide oxygenation and ventilation until the bronchospasm resolves. However, mechanical ventilation is associated with significant risks, including high end-inspiratory pressures, barotrauma, and volutrauma.⁴ Rescue therapies include muscle relaxation, infusion of ketamine (central acting nonopioid analgesic with bronchodilatory properties), heliox, and general anesthesia.^2,4 We report a case of a patient with life-threatening asthma and status asthmaticus treated with sevoflurane general anesthesia.

Case Presentation

A 55-year-old woman whose medical history was notable for asthma, psoriasis, hypothyroidism, tobacco, and alcohol abuse, and posttraumatic stress disorder (PTSD) presented to the ED. The patient had rarely sought medical attention and had no prior ED visits or hospitalizations in the electronic health record. Her home regimen included an albuterol inhaler used as needed. Her family reported that they had found her in distress in bed in a tripod position, unable to speak and struggling to breath.

Emergency medical services found the patient cyanotic, apneic, and pulseless. She received cardiopulmonary resuscitation for 30 seconds and 1-mg IV epinephrine, and spontaneous circulation returned. The patient arrived in the ED with an oral airway in place receiving bag valve mask ventilation. The patient expelled the oral airway. She was unable to speak due to dyspnea, exhibited persistent cyanosis, fatigue due to work of breathing, and failed to respond to nebulized albuterol/ipratropium bromide, IV methylprednisolone, and magnesium sulfate. The patient met criteria for acute severe asthma, or status asthmaticus. Thus, the patient received rapid sequence induction with rocuronium and ketamine and was intubated.

According to her family, the patient had no previous intensive care unit (ICU) admissions or prior intubations. Her only asthma medication was an albuterol inhaler as needed. The patient worked as a supervisor at a window blind manufacturing company. She lived alone, smoked 2 packs of cigarettes a day for more than 30 years, had no pets, drank unknown quantities of beer, wine, and hard liquor daily, and had smoked marijuana for several years.

The patient’s physical examination was notable for diffuse expiratory wheezes. Laboratory analysis revealed white blood cell count of 13.7 k/mcL, sodium 140 mmol/L, potassium 4.9 mmol/L, chloride 105 mmol/L, CO₂ 17 mmol/L, creatinine 0.98 mg/dL, troponin 0.03 ng/mL, lactate 7.2 mmol/L. Her chest X-ray showed hyperinflation but no focal opacities, pneumothorax, or pulmonary edema. Her endotracheal tube was in good position (Figure 1). A computed tomography pulmonary angiogram showed no pulmonary embolus or emphysema. There were atelectatic changes in the dependent portion of the right lower lobe, central bronchial wall thickening, and no stigmata of air trapping (Figure 2). An echocardiogram revealed a left ventricular ejection fraction of 45%, normal right ventricle and right ventricular size and function with an estimated right ventricular systolic pressure of 40 mm Hg.

The patient was admitted to the ICU and started on continuous infusion cisatracurium for paralysis and deep sedation to improve ventilatory synchrony and decrease auto positive end-expiratory pressure (PEEP). Mechanical ventilation was initiated with volume-cycled assist control ventilation, 6 mL/kg/ideal body weight (IBW) at 5-cm H₂O PEEP, and 1 minute ventilation of 10 liters. The patient had severe air trapping and high airway pressures. The dynamic PEEP was 22-cm H₂O (normal PEEP of 5-cm H₂O), peak airway pressure (PAP) 41-cm H₂O, and plateau pressure 31-cm H₂O. In addition, the arterial blood gas (ABG) showed severe hypercapnic respiratory acidosis without significant hypoxemia with pH 7.15, PaCO₂ 90 mm Hg, and PaO₂ 150 mm Hg.

Pressure controlled ventilation was attempted unsuccessfully due to high airway resistance. Ultimately, the patient was set on volume control with low tidal volume, 6 mL/kg/IBW, high flow 90 L/min, PEEP 0 cm of H₂O, and a low respiratory rate of 10 to achieve an inspiratory to expiratory (I:E) ratio of 1:7. Managing the ventilator to avoid dynamic hyperinflation and auto-PEEP, she remained relatively stable and improved.

By day 4 the patient’s ventilator was set to volume assist control with respiratory rate of 16, tidal volume, 6 mL/kg/IBW, PEEP 5-cm H₂O with auto PEEP of 3-cm H₂O, and fraction of inspired ABG O₂ (FiO₂) 0.35 with PAP of 46-cm H₂O and plateau pressure of 17-cm H₂O. The ABG was pH 7.32, PaCO₂ 65 mm Hg, and PaO₂ 74 mm Hg. However, on hospital day 5, she developed worsening PAP 60 to 77-cm H₂O, plateau pressures 17-cm H₂O, and a dynamic PEEP 16-cm H₂O and was unresponsive to ventilator maneuvers to lower airway pressures and improve ventilation.

The patient had been receiving continuous albuterol and ipratropium nebulizer treatments. Ketamine infusion was considered fraught with potential for a dissociative reaction due to the patient’s significant PTSD. The patient’s family requested avoidance of ketamine infusion since the patient was paralyzed and psychiatric effects could not be monitored. Heliox 80/20 mixture was considered; however, it is incompatible with the ventilator that was being used since it could not account for the density of the helium gas flow in the tidal volumes. Extracorporeal membrane oxygenation (ECMO) was not available at our facility, and the patient was not a candidate for the regional ECMO center.

On hospital day 8, the patient developed worsening respiratory acidosis. The patient’s PAP increased to > 77-cm H₂O, and her ABG revealed pH 7.22, PaCO₂ 90 mm Hg, and PaO₂ 77 mm Hg with FiO₂ 0.4. A chest X-ray demonstrated a new left lower lobe infiltrate. Fiber optic bronchoscopy was notable for scattered thick secretions throughout both lungs without obstructing mucus plug. Removal of airway secretions did not improve airway pressures or dynamic hyperinflation.

After consultation and discussion with the chief of anesthesia, the patient was placed on an anesthesia ventilator and started on sevoflurane 1.5% in the ICU. Anesthesiology was available 24 hours a day, and the anesthesiologist rounded with the intensivist frequently for this patient. The anesthesia technician worked closely with respiratory therapy regarding ventilator setting and changing the anesthesia gas scavenging charcoal canister. Within 4 hours, her gas exchange normalized (Table). The patient’s ABG was pH 7.44, PaCO₂ 52 mm Hg, and PaO₂ 69 mm Hg on FiO₂ 0.4. On volume cycled ventilation with a rate of 12, flow rate of 40 L/min, and tidal volume 6 mL/kg/IBW, the PAP decreased to 41-cm H₂O.

Within 24 hours bronchospasm improved as evidenced by decreased airway pressures, resolution of wheezing, and decreased CO₂ retention. The sevoflurane was easily weaned over the next 48 hours by decreasing the dose by 25% every 12-hour shift without rebound bronchospasm. Airway pressures and ABGs were frequently monitored during the weaning process. The patient resumed conventional mechanical ventilation, cisatracurium was discontinued, and she underwent a percutaneous tracheostomy for critical illness polymyopathy. Her respiratory muscle strength recovered more robustly than anticipated. Prior to discharge to a skilled nursing facility for continued rehabilitation, she was removed from mechanical ventilation and decannulated.

Discussion

This case illustrates the successful treatment of a patient with extreme status asthmaticus given inhalational anesthesia as supportive care while the bronchospasm and status asthmaticus abated. This is an unusual treatment in an ominous situation. Inhalational anesthetics are potent bronchodilators and have been successfully used in the management of status asthmaticus refractory to conventional therapy.⁴ Inhalational anesthetics have been shown to decrease airway resistance, dynamic hyperinflation, and intrinsic PEEP.⁵ These agents result in rapid bronchodilation by relaxing the smooth muscle and are associated with early liberation from mechanical ventilation.^5,6 Although there are no guidelines regarding which inhalational agent is best, specific dosing, duration, or titration, case reports in the literature regarding the successful use of inhalational agents in life-threatening status asthmaticus exist.^2,5,7

Caveats regarding the use of inhalational anesthetics in status asthmaticus include proarrhythmias, severe hepatic and renal toxicity. Although isoflurane is less likely to cause arrhythmia, both isoflurane and sevoflurane can cause dose-dependent hypotension by peripheral vasodilatation.⁷ Ourpatient did not manifest any adverse effects.

Additional challenges regarding the use of inhalational anesthetics for status asthmaticus include differences in ventilators and occupational hazards.⁸ Anesthesia or operating room ventilators differ from ICU ventilators in flow and pressure capabilities.⁷ The anesthesia ventilator is not capable of generating inspiratory pressures sufficient to ventilate patients with severely elevated airway resistance. Thus, the decrease inspiratory flow that occurs with increasing airway pressure limits the tidal volume delivered and consequently the minute volume. Although newer anesthesia ventilators have increased flow capabilities, they require a fully trained staff.⁸

Potential occupational exposure to these volatile anesthetic gases occurs as patients being treated may exhale considerable amounts of volatile anesthetics.⁸ An anesthesia gas scavenging device, such as a charcoal canister, must be attached to the ventilator to capture the exhaled anesthetic gases and should be changed every 12 hours.⁸ Finally, there is a potential for rebound bronchospasm as the anesthetic agent is tapered.^6,7,9-11

Conclusion

Inhalational anesthetics are an option as rescue therapy for severe life-threatening asthma when all other therapies have failed. Use of inhalational anesthetics in status asthmaticus consists of case reports of which half are in children.^2,5,7 Our patient contributes to the literature of case reports regarding using sevoflurane in refractory status asthmaticus. A decision to choose them must be a collaborative team approach with anesthesiology, pulmonary/critical care medicine, respiratory therapy, and ICU nurses, and the risks and benefits should be discussed with decision-making family members. Since there are no specific guidelines for the use of inhalational agents in status asthmaticus, close attention to inspiratory flows, gas scavenging devices, and clinical response is required. Additionally, the team must be comfortable with the plan to use an anesthesia ventilator and trained on its limitations.

Asthma attacks account for 1.8 million emergency department (ED) visits each year in the US and for 10 deaths daily.¹ Management of asthma attacks includes administration of inhaled ß₂ adrenergic agonists, inhaled anticholinergic agents, IV magnesium sulfate, and corticosteroids.² Status asthmaticus is an intense acute exacerbation of asthma that does not respond to repeated treatments of bronchodilators and corticosteroids.³ It is a medical emergency requiring immediate recognition and treatment. The decision to intubate a patient with status asthmaticus is a clinical decision based on work of breathing, respiratory acidosis, and failure to respond to medical interventions.

In refractory cases of status asthmaticus, intubation and mechanical ventilation are undertaken to provide oxygenation and ventilation until the bronchospasm resolves. However, mechanical ventilation is associated with significant risks, including high end-inspiratory pressures, barotrauma, and volutrauma.⁴ Rescue therapies include muscle relaxation, infusion of ketamine (central acting nonopioid analgesic with bronchodilatory properties), heliox, and general anesthesia.^2,4 We report a case of a patient with life-threatening asthma and status asthmaticus treated with sevoflurane general anesthesia.

Case Presentation

A 55-year-old woman whose medical history was notable for asthma, psoriasis, hypothyroidism, tobacco, and alcohol abuse, and posttraumatic stress disorder (PTSD) presented to the ED. The patient had rarely sought medical attention and had no prior ED visits or hospitalizations in the electronic health record. Her home regimen included an albuterol inhaler used as needed. Her family reported that they had found her in distress in bed in a tripod position, unable to speak and struggling to breath.

Emergency medical services found the patient cyanotic, apneic, and pulseless. She received cardiopulmonary resuscitation for 30 seconds and 1-mg IV epinephrine, and spontaneous circulation returned. The patient arrived in the ED with an oral airway in place receiving bag valve mask ventilation. The patient expelled the oral airway. She was unable to speak due to dyspnea, exhibited persistent cyanosis, fatigue due to work of breathing, and failed to respond to nebulized albuterol/ipratropium bromide, IV methylprednisolone, and magnesium sulfate. The patient met criteria for acute severe asthma, or status asthmaticus. Thus, the patient received rapid sequence induction with rocuronium and ketamine and was intubated.

According to her family, the patient had no previous intensive care unit (ICU) admissions or prior intubations. Her only asthma medication was an albuterol inhaler as needed. The patient worked as a supervisor at a window blind manufacturing company. She lived alone, smoked 2 packs of cigarettes a day for more than 30 years, had no pets, drank unknown quantities of beer, wine, and hard liquor daily, and had smoked marijuana for several years.

The patient’s physical examination was notable for diffuse expiratory wheezes. Laboratory analysis revealed white blood cell count of 13.7 k/mcL, sodium 140 mmol/L, potassium 4.9 mmol/L, chloride 105 mmol/L, CO₂ 17 mmol/L, creatinine 0.98 mg/dL, troponin 0.03 ng/mL, lactate 7.2 mmol/L. Her chest X-ray showed hyperinflation but no focal opacities, pneumothorax, or pulmonary edema. Her endotracheal tube was in good position (Figure 1). A computed tomography pulmonary angiogram showed no pulmonary embolus or emphysema. There were atelectatic changes in the dependent portion of the right lower lobe, central bronchial wall thickening, and no stigmata of air trapping (Figure 2). An echocardiogram revealed a left ventricular ejection fraction of 45%, normal right ventricle and right ventricular size and function with an estimated right ventricular systolic pressure of 40 mm Hg.

The patient was admitted to the ICU and started on continuous infusion cisatracurium for paralysis and deep sedation to improve ventilatory synchrony and decrease auto positive end-expiratory pressure (PEEP). Mechanical ventilation was initiated with volume-cycled assist control ventilation, 6 mL/kg/ideal body weight (IBW) at 5-cm H₂O PEEP, and 1 minute ventilation of 10 liters. The patient had severe air trapping and high airway pressures. The dynamic PEEP was 22-cm H₂O (normal PEEP of 5-cm H₂O), peak airway pressure (PAP) 41-cm H₂O, and plateau pressure 31-cm H₂O. In addition, the arterial blood gas (ABG) showed severe hypercapnic respiratory acidosis without significant hypoxemia with pH 7.15, PaCO₂ 90 mm Hg, and PaO₂ 150 mm Hg.

Pressure controlled ventilation was attempted unsuccessfully due to high airway resistance. Ultimately, the patient was set on volume control with low tidal volume, 6 mL/kg/IBW, high flow 90 L/min, PEEP 0 cm of H₂O, and a low respiratory rate of 10 to achieve an inspiratory to expiratory (I:E) ratio of 1:7. Managing the ventilator to avoid dynamic hyperinflation and auto-PEEP, she remained relatively stable and improved.

By day 4 the patient’s ventilator was set to volume assist control with respiratory rate of 16, tidal volume, 6 mL/kg/IBW, PEEP 5-cm H₂O with auto PEEP of 3-cm H₂O, and fraction of inspired ABG O₂ (FiO₂) 0.35 with PAP of 46-cm H₂O and plateau pressure of 17-cm H₂O. The ABG was pH 7.32, PaCO₂ 65 mm Hg, and PaO₂ 74 mm Hg. However, on hospital day 5, she developed worsening PAP 60 to 77-cm H₂O, plateau pressures 17-cm H₂O, and a dynamic PEEP 16-cm H₂O and was unresponsive to ventilator maneuvers to lower airway pressures and improve ventilation.

The patient had been receiving continuous albuterol and ipratropium nebulizer treatments. Ketamine infusion was considered fraught with potential for a dissociative reaction due to the patient’s significant PTSD. The patient’s family requested avoidance of ketamine infusion since the patient was paralyzed and psychiatric effects could not be monitored. Heliox 80/20 mixture was considered; however, it is incompatible with the ventilator that was being used since it could not account for the density of the helium gas flow in the tidal volumes. Extracorporeal membrane oxygenation (ECMO) was not available at our facility, and the patient was not a candidate for the regional ECMO center.

On hospital day 8, the patient developed worsening respiratory acidosis. The patient’s PAP increased to > 77-cm H₂O, and her ABG revealed pH 7.22, PaCO₂ 90 mm Hg, and PaO₂ 77 mm Hg with FiO₂ 0.4. A chest X-ray demonstrated a new left lower lobe infiltrate. Fiber optic bronchoscopy was notable for scattered thick secretions throughout both lungs without obstructing mucus plug. Removal of airway secretions did not improve airway pressures or dynamic hyperinflation.

After consultation and discussion with the chief of anesthesia, the patient was placed on an anesthesia ventilator and started on sevoflurane 1.5% in the ICU. Anesthesiology was available 24 hours a day, and the anesthesiologist rounded with the intensivist frequently for this patient. The anesthesia technician worked closely with respiratory therapy regarding ventilator setting and changing the anesthesia gas scavenging charcoal canister. Within 4 hours, her gas exchange normalized (Table). The patient’s ABG was pH 7.44, PaCO₂ 52 mm Hg, and PaO₂ 69 mm Hg on FiO₂ 0.4. On volume cycled ventilation with a rate of 12, flow rate of 40 L/min, and tidal volume 6 mL/kg/IBW, the PAP decreased to 41-cm H₂O.

Within 24 hours bronchospasm improved as evidenced by decreased airway pressures, resolution of wheezing, and decreased CO₂ retention. The sevoflurane was easily weaned over the next 48 hours by decreasing the dose by 25% every 12-hour shift without rebound bronchospasm. Airway pressures and ABGs were frequently monitored during the weaning process. The patient resumed conventional mechanical ventilation, cisatracurium was discontinued, and she underwent a percutaneous tracheostomy for critical illness polymyopathy. Her respiratory muscle strength recovered more robustly than anticipated. Prior to discharge to a skilled nursing facility for continued rehabilitation, she was removed from mechanical ventilation and decannulated.

Discussion

This case illustrates the successful treatment of a patient with extreme status asthmaticus given inhalational anesthesia as supportive care while the bronchospasm and status asthmaticus abated. This is an unusual treatment in an ominous situation. Inhalational anesthetics are potent bronchodilators and have been successfully used in the management of status asthmaticus refractory to conventional therapy.⁴ Inhalational anesthetics have been shown to decrease airway resistance, dynamic hyperinflation, and intrinsic PEEP.⁵ These agents result in rapid bronchodilation by relaxing the smooth muscle and are associated with early liberation from mechanical ventilation.^5,6 Although there are no guidelines regarding which inhalational agent is best, specific dosing, duration, or titration, case reports in the literature regarding the successful use of inhalational agents in life-threatening status asthmaticus exist.^2,5,7

Caveats regarding the use of inhalational anesthetics in status asthmaticus include proarrhythmias, severe hepatic and renal toxicity. Although isoflurane is less likely to cause arrhythmia, both isoflurane and sevoflurane can cause dose-dependent hypotension by peripheral vasodilatation.⁷ Ourpatient did not manifest any adverse effects.

Additional challenges regarding the use of inhalational anesthetics for status asthmaticus include differences in ventilators and occupational hazards.⁸ Anesthesia or operating room ventilators differ from ICU ventilators in flow and pressure capabilities.⁷ The anesthesia ventilator is not capable of generating inspiratory pressures sufficient to ventilate patients with severely elevated airway resistance. Thus, the decrease inspiratory flow that occurs with increasing airway pressure limits the tidal volume delivered and consequently the minute volume. Although newer anesthesia ventilators have increased flow capabilities, they require a fully trained staff.⁸

Potential occupational exposure to these volatile anesthetic gases occurs as patients being treated may exhale considerable amounts of volatile anesthetics.⁸ An anesthesia gas scavenging device, such as a charcoal canister, must be attached to the ventilator to capture the exhaled anesthetic gases and should be changed every 12 hours.⁸ Finally, there is a potential for rebound bronchospasm as the anesthetic agent is tapered.^6,7,9-11

Conclusion

Inhalational anesthetics are an option as rescue therapy for severe life-threatening asthma when all other therapies have failed. Use of inhalational anesthetics in status asthmaticus consists of case reports of which half are in children.^2,5,7 Our patient contributes to the literature of case reports regarding using sevoflurane in refractory status asthmaticus. A decision to choose them must be a collaborative team approach with anesthesiology, pulmonary/critical care medicine, respiratory therapy, and ICU nurses, and the risks and benefits should be discussed with decision-making family members. Since there are no specific guidelines for the use of inhalational agents in status asthmaticus, close attention to inspiratory flows, gas scavenging devices, and clinical response is required. Additionally, the team must be comfortable with the plan to use an anesthesia ventilator and trained on its limitations.

In the current health care environment, hospitals are constantly challenged to improve quality metrics and deliver better health care outcomes. One means to achieving quality improvement is through the use of order sets, groups of related orders that a health care provider (HCP) can place with either a few keystrokes or mouse clicks.¹

Historically, design of order sets has largely focused on clicking checkboxes containing evidence-based practices. According to Bates and colleagues and the Institute for Safe Medication Practices, incorporating evidence-based medicine (EBM) into order sets is not by itself sufficient.^2,3Execution of proper design coupled with simplicity and provider efficiency is paramount to HCP buy-in, increased likelihood of order set adherence, and to potentially better outcomes.

In this article, we outline advancements in order set design. These improvements increase provider efficiency and ease of use; incorporate human factors engineering (HFE); apply failure mode and effects analysis; and include EBM.

Methods

An inpatient nicotine replacement therapy (NRT) order was developed as part of a multifaceted solution to improve tobacco cessation care at the James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida, a complexity level 1a facility. This NRT order set used the 4-step order set design framework the authors’ developed (for additional information about the NRT order set, contact the authors). We distinguish order set design technique between 2 different inpatient NRT order sets. The first order set in the comparison (Figure 1) is an inpatient NRT order set of unknown origin—it is common for US Department of Veterans Affairs (VA) medical facilities to share order sets and other resources. The second order set (Figure 2) is an inpatient NRT order set we designed using our 4-step process for comparison in this article. No institutional review board approval was required as this work met criteria for operational improvement activities exempt from ethics review.

Justin Iannello, DO, MBA, was the team leader and developer of the 4-step order set design technique. The intervention team consisted of 4 internal medicine physicians with expertise in quality improvement and patient safety: 1 certified professional in patient safety and certified as a Lean Six Sigma Black Belt; 2 physicians certified as Lean Six Sigma Black Belts; and 1 physician certified as a Lean Six Sigma Green Belt. Two inpatient clinical pharmacists and 1 quality management specialist also were involved in its development.

Development of a new NRT order set was felt to be an integral part of the tobacco cessation care delivery process. An NRT order set perceived by users as value-added required a solution that merged EBM with standardization and applied quality improvement principles. The result was an approach to order set design that focused on 4 key questions: Is the order set efficient and easy to use/navigate? Is human factors engineering incorporated? Is failure mode and effects analysis applied? Are evidence-based practices included?

Ease of Use and Navigation

Implementing an order set that is efficient and easy to use or navigate seems straightforward but can be difficult to execute. Figure 1 shows many detailed options consisting of different combinations of nicotine patches, lozenges, and gum. Also included are oral tobacco cessation options (bupropion and varenicline). Although more options may seem better, confusion about appropriate medication selection can occur.

According to Heath and Heath, too many options can result in lack of action.⁴ For example, Heath and Heath discuss a food store that offered 6 free samples of different jams on one day and 24 jams the following day. The customers who sampled 6 different types of jam were 10 times more likely to buy jam. The authors concluded that the more options available, the more difficulty a potential buyer has in deciding on a course of action.⁴

In clinical situations where a HCP is using an order set, the number of options can mean the difference between use vs avoidance if the choices are overwhelming. HCPs process layers of detail every day when creating differential diagnoses and treatment plans. While that level of detail is necessary clinically, that same level of detail included in orders sets can create challenges for HCPs.

Figure 2 advances the order set in Figure 1 by providing a simpler and cleaner design, so HCPs can more easily review and process the information. This order set design minimizes the number of options available to help users make the right decision, focusing on value for the appropriate setting and audience. In other words, order sets should not be a “one size fits all” approach.

Order sets should be tailored to the appropriate clinical setting (eg, inpatient acute care, outpatient clinic setting, etc) and HCP (eg, hospitalist, tobacco cessation specialist, etc). We are comparing NRT order sets designed for HCPs who do not routinely prescribe oral tobacco cessation products in the inpatient setting. When possible, autogenerated bundle orders should also be used according to evidence-based recommendations (such as nicotine patch tapers) for ease of use and further simplification of order sets.

Finally, usability testing known as “evaluating a product or service by testing it with representative users” helps further refine an order set.⁵Usability testing should be applied during all phases of order set development with end user(s) as it helps identify problems with order set design prior to implementation. By applying usability testing, the order set becomes more meaningful and valued by the user.

Human Factors Engineering

HFE is “the study of all the factors that make it easier to do the work in the right way.”⁶ HFE seeks to identify, align, and apply processes for people and the world within which they live and work to promote safe and efficient practices, especially in relation to the technology and physical design features in their work environment.⁶

The average American adult makes about 35,000 decisions per day.⁷ Thus, there is potential for error at any moment. Design that does not take HFE into account can be dangerous. For example, when tube feed and IV line connectors look similar and are compatible, patients may inadvertently receive food administered directly into their bloodstream.⁸

HFE can and should be applied to order sets. Everything from the look, feel, and verbiage of an order set affects potential outcomes. For example, consider the impact even seemingly minor modifications can have on outcomes simply by guiding users in a different way: Figure 1 provides NRT options based on cigarette use per day, whereas Figure 2 conveys pack use per day in relation to the equivalent number of cigarettes used daily. These differences may seem small; however, it helps guide users to the right choice when considering that health care providers have been historically trained on social history gathering that emphasizes packs per day and pack-years.

Failure Mode and Effects Analysis

Failure mode and effects analysis (FMEA) is “a structured way to identify and address potential problems, or failures and their resulting effects on the system or process before an adverse event occurs.”⁹ The benefit of an order set must be weighed against the risk during development. FMEA should be applied during order set design to assess and limit risk just as with any other clinical care process.

FMEA examines both level of risk and frequency of risk occurrence associated with a new proposed process. For example, let’s evaluate an order set designed for pain control after surgery that consists of multiple high-risk opioids along with antihistamine medications for as-needed itch relief (a non-life-threatening adverse event (AE) of opioids well known by the medical community). An interdisciplinary FMEA team consisting of subject matter experts may examine how the process should flow in step-by-step detail and then discuss the benefit of a process and risk for potential error. A FMEA team would then analyze what could go wrong with each part of the process and assign a level of risk and risk frequency for various steps in the process, and then decide that certain steps should be modified or eliminated. Perhaps after FMEA, a facility might conclude that the risk of serious complications is high when you combine opioid use with antihistamine medications. The facility could decide to remove antihistamine medications from an order set if it is determined that risks outweigh benefits. While a root cause analysis might identify the cause of an AE after order set use, these situations can be prevented with FMEA.

When applying FMEA to Figure 1, while bupropion is known as an evidence-based oral tobacco cessation option, there is the possibility that bupropion could be inadvertently prescribed from the order set in a hospitalized patient with alcohol withdrawal and withdrawal seizure history. These potentially dangerous situations can be avoided with FMEA. Thus, although bupropion may be evidence-based for NRT, decisions regarding order set design using EBM alone are insufficient.

The practitioner must consider possible unintended consequences within order sets and target treatment options to the appropriate setting and audience. Although Figure 1 may appear to be more inclusive, the interdisciplinary committee designing the inpatient NRT order set felt there was heightened risk with introducing bupropion in Figure 1 and decided the risk would be lowered by removing bupropion from the redesigned NRT order set (Figure 2). In addition to the goal of balancing availability of NRT options with acceptable risk, Figure 2 also focused on building an NRT order set most applicable to the inpatient setting.

Including Evidence-Based Practices

EBM has become a routine part of clinical decision making. Therefore, including EBM in order set design is vital. EBM for NRT has demonstrated that combination therapy is more effective than is monotherapy to help tobacco users quit. Incremental doses of NRT are recommended for patients who use tobacco more frequently.¹⁰

As shown in Figures 1 and 2, both order set designs incorporate EBM for NRT. Although the importance of implementing EBM is evident, critical factors, such as HFE and FMEA make a difference with well-designed order sets.

Results

The 4-step order set design technique was used during development of an inpatient NRT order set at the JAHVH. Results for the inpatient Joint Commission Tobacco Treatment Measures were obtained from the Veterans Health Administration quality metric reporting system known as Strategic Analytics for Improvement and Learning (SAIL). SAIL performance measure outcomes, which include the inpatient Joint Commission Tobacco Treatment Measures, are derived from chart reviews conducted by the External Peer Review Program. Outcomes demonstrated that TOB-2 and TOB-3 (2 inpatient Joint Commission Tobacco Treatment Measures) known as tob20 and tob40, respectively, within SAIL improved by more than 300% after development of an NRT order set using the 4-step order set design framework along with implementation of a multifaceted tobacco cessation care delivery system at JAHVH.

Discussion

While the overall tobacco cessation care delivery system contributed to improved outcomes with the inpatient Joint Commission Tobacco Treatment Measures at JAHVH, the NRT order set was a cornerstone of the design. Although using our order set design technique does not necessarily guarantee successful outcomes, we believe using the 4-step order set design process increases the value of order sets and has potential to improve quality outcomes.

Limitations

Although improved outcomes following implementation of our NRT order set suggest correlation, causation cannot be proven. Also while the NRT order set is believed to have helped tremendously with outcomes, the entire tobacco cessation care delivery system at JAHVH contributed to the results. In addition, the inpatient Joint Commission Tobacco Treatment Measures help improve processes for tobacco cessation care. However, we are uncertain whether the results of our improvement efforts helped patients stop tobacco use. Further studies are needed to determine impact on population health. Finally, our results were based on improvement work done at a single center. Further studies are necessary to see whether results are reproducible.

Conclusion

There was significant improvement with the inpatient Joint Commission Tobacco Treatment Measures outcomes following development of a tobacco cessation care delivery system that included design of an inpatient NRT order set using a 4-step process we developed. This 4-step structure includes emphasis on efficiency and ease of use; human factors engineering; failure mode and effects analysis; and incorporation of evidence-based medicine (Box.) Postimplementation results showed improvement of the inpatient Joint Commission Tobacco Treatment Measures by greater than 3-fold at a single hospital.

The next steps for this initiative include testing the 4-step order set design process in multiple clinical settings to determine the effectiveness of this approach in other areas of clinical care.

In the current health care environment, hospitals are constantly challenged to improve quality metrics and deliver better health care outcomes. One means to achieving quality improvement is through the use of order sets, groups of related orders that a health care provider (HCP) can place with either a few keystrokes or mouse clicks.¹

Historically, design of order sets has largely focused on clicking checkboxes containing evidence-based practices. According to Bates and colleagues and the Institute for Safe Medication Practices, incorporating evidence-based medicine (EBM) into order sets is not by itself sufficient.^2,3Execution of proper design coupled with simplicity and provider efficiency is paramount to HCP buy-in, increased likelihood of order set adherence, and to potentially better outcomes.

In this article, we outline advancements in order set design. These improvements increase provider efficiency and ease of use; incorporate human factors engineering (HFE); apply failure mode and effects analysis; and include EBM.

Methods

An inpatient nicotine replacement therapy (NRT) order was developed as part of a multifaceted solution to improve tobacco cessation care at the James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida, a complexity level 1a facility. This NRT order set used the 4-step order set design framework the authors’ developed (for additional information about the NRT order set, contact the authors). We distinguish order set design technique between 2 different inpatient NRT order sets. The first order set in the comparison (Figure 1) is an inpatient NRT order set of unknown origin—it is common for US Department of Veterans Affairs (VA) medical facilities to share order sets and other resources. The second order set (Figure 2) is an inpatient NRT order set we designed using our 4-step process for comparison in this article. No institutional review board approval was required as this work met criteria for operational improvement activities exempt from ethics review.

Justin Iannello, DO, MBA, was the team leader and developer of the 4-step order set design technique. The intervention team consisted of 4 internal medicine physicians with expertise in quality improvement and patient safety: 1 certified professional in patient safety and certified as a Lean Six Sigma Black Belt; 2 physicians certified as Lean Six Sigma Black Belts; and 1 physician certified as a Lean Six Sigma Green Belt. Two inpatient clinical pharmacists and 1 quality management specialist also were involved in its development.

Development of a new NRT order set was felt to be an integral part of the tobacco cessation care delivery process. An NRT order set perceived by users as value-added required a solution that merged EBM with standardization and applied quality improvement principles. The result was an approach to order set design that focused on 4 key questions: Is the order set efficient and easy to use/navigate? Is human factors engineering incorporated? Is failure mode and effects analysis applied? Are evidence-based practices included?

Ease of Use and Navigation

Implementing an order set that is efficient and easy to use or navigate seems straightforward but can be difficult to execute. Figure 1 shows many detailed options consisting of different combinations of nicotine patches, lozenges, and gum. Also included are oral tobacco cessation options (bupropion and varenicline). Although more options may seem better, confusion about appropriate medication selection can occur.

According to Heath and Heath, too many options can result in lack of action.⁴ For example, Heath and Heath discuss a food store that offered 6 free samples of different jams on one day and 24 jams the following day. The customers who sampled 6 different types of jam were 10 times more likely to buy jam. The authors concluded that the more options available, the more difficulty a potential buyer has in deciding on a course of action.⁴

In clinical situations where a HCP is using an order set, the number of options can mean the difference between use vs avoidance if the choices are overwhelming. HCPs process layers of detail every day when creating differential diagnoses and treatment plans. While that level of detail is necessary clinically, that same level of detail included in orders sets can create challenges for HCPs.

Figure 2 advances the order set in Figure 1 by providing a simpler and cleaner design, so HCPs can more easily review and process the information. This order set design minimizes the number of options available to help users make the right decision, focusing on value for the appropriate setting and audience. In other words, order sets should not be a “one size fits all” approach.

Order sets should be tailored to the appropriate clinical setting (eg, inpatient acute care, outpatient clinic setting, etc) and HCP (eg, hospitalist, tobacco cessation specialist, etc). We are comparing NRT order sets designed for HCPs who do not routinely prescribe oral tobacco cessation products in the inpatient setting. When possible, autogenerated bundle orders should also be used according to evidence-based recommendations (such as nicotine patch tapers) for ease of use and further simplification of order sets.

Finally, usability testing known as “evaluating a product or service by testing it with representative users” helps further refine an order set.⁵Usability testing should be applied during all phases of order set development with end user(s) as it helps identify problems with order set design prior to implementation. By applying usability testing, the order set becomes more meaningful and valued by the user.

Human Factors Engineering

HFE is “the study of all the factors that make it easier to do the work in the right way.”⁶ HFE seeks to identify, align, and apply processes for people and the world within which they live and work to promote safe and efficient practices, especially in relation to the technology and physical design features in their work environment.⁶

The average American adult makes about 35,000 decisions per day.⁷ Thus, there is potential for error at any moment. Design that does not take HFE into account can be dangerous. For example, when tube feed and IV line connectors look similar and are compatible, patients may inadvertently receive food administered directly into their bloodstream.⁸

HFE can and should be applied to order sets. Everything from the look, feel, and verbiage of an order set affects potential outcomes. For example, consider the impact even seemingly minor modifications can have on outcomes simply by guiding users in a different way: Figure 1 provides NRT options based on cigarette use per day, whereas Figure 2 conveys pack use per day in relation to the equivalent number of cigarettes used daily. These differences may seem small; however, it helps guide users to the right choice when considering that health care providers have been historically trained on social history gathering that emphasizes packs per day and pack-years.

Failure Mode and Effects Analysis

Failure mode and effects analysis (FMEA) is “a structured way to identify and address potential problems, or failures and their resulting effects on the system or process before an adverse event occurs.”⁹ The benefit of an order set must be weighed against the risk during development. FMEA should be applied during order set design to assess and limit risk just as with any other clinical care process.

FMEA examines both level of risk and frequency of risk occurrence associated with a new proposed process. For example, let’s evaluate an order set designed for pain control after surgery that consists of multiple high-risk opioids along with antihistamine medications for as-needed itch relief (a non-life-threatening adverse event (AE) of opioids well known by the medical community). An interdisciplinary FMEA team consisting of subject matter experts may examine how the process should flow in step-by-step detail and then discuss the benefit of a process and risk for potential error. A FMEA team would then analyze what could go wrong with each part of the process and assign a level of risk and risk frequency for various steps in the process, and then decide that certain steps should be modified or eliminated. Perhaps after FMEA, a facility might conclude that the risk of serious complications is high when you combine opioid use with antihistamine medications. The facility could decide to remove antihistamine medications from an order set if it is determined that risks outweigh benefits. While a root cause analysis might identify the cause of an AE after order set use, these situations can be prevented with FMEA.

When applying FMEA to Figure 1, while bupropion is known as an evidence-based oral tobacco cessation option, there is the possibility that bupropion could be inadvertently prescribed from the order set in a hospitalized patient with alcohol withdrawal and withdrawal seizure history. These potentially dangerous situations can be avoided with FMEA. Thus, although bupropion may be evidence-based for NRT, decisions regarding order set design using EBM alone are insufficient.

The practitioner must consider possible unintended consequences within order sets and target treatment options to the appropriate setting and audience. Although Figure 1 may appear to be more inclusive, the interdisciplinary committee designing the inpatient NRT order set felt there was heightened risk with introducing bupropion in Figure 1 and decided the risk would be lowered by removing bupropion from the redesigned NRT order set (Figure 2). In addition to the goal of balancing availability of NRT options with acceptable risk, Figure 2 also focused on building an NRT order set most applicable to the inpatient setting.

Including Evidence-Based Practices

EBM has become a routine part of clinical decision making. Therefore, including EBM in order set design is vital. EBM for NRT has demonstrated that combination therapy is more effective than is monotherapy to help tobacco users quit. Incremental doses of NRT are recommended for patients who use tobacco more frequently.¹⁰

As shown in Figures 1 and 2, both order set designs incorporate EBM for NRT. Although the importance of implementing EBM is evident, critical factors, such as HFE and FMEA make a difference with well-designed order sets.

Results

The 4-step order set design technique was used during development of an inpatient NRT order set at the JAHVH. Results for the inpatient Joint Commission Tobacco Treatment Measures were obtained from the Veterans Health Administration quality metric reporting system known as Strategic Analytics for Improvement and Learning (SAIL). SAIL performance measure outcomes, which include the inpatient Joint Commission Tobacco Treatment Measures, are derived from chart reviews conducted by the External Peer Review Program. Outcomes demonstrated that TOB-2 and TOB-3 (2 inpatient Joint Commission Tobacco Treatment Measures) known as tob20 and tob40, respectively, within SAIL improved by more than 300% after development of an NRT order set using the 4-step order set design framework along with implementation of a multifaceted tobacco cessation care delivery system at JAHVH.

Discussion

While the overall tobacco cessation care delivery system contributed to improved outcomes with the inpatient Joint Commission Tobacco Treatment Measures at JAHVH, the NRT order set was a cornerstone of the design. Although using our order set design technique does not necessarily guarantee successful outcomes, we believe using the 4-step order set design process increases the value of order sets and has potential to improve quality outcomes.

Limitations

Although improved outcomes following implementation of our NRT order set suggest correlation, causation cannot be proven. Also while the NRT order set is believed to have helped tremendously with outcomes, the entire tobacco cessation care delivery system at JAHVH contributed to the results. In addition, the inpatient Joint Commission Tobacco Treatment Measures help improve processes for tobacco cessation care. However, we are uncertain whether the results of our improvement efforts helped patients stop tobacco use. Further studies are needed to determine impact on population health. Finally, our results were based on improvement work done at a single center. Further studies are necessary to see whether results are reproducible.

Conclusion

There was significant improvement with the inpatient Joint Commission Tobacco Treatment Measures outcomes following development of a tobacco cessation care delivery system that included design of an inpatient NRT order set using a 4-step process we developed. This 4-step structure includes emphasis on efficiency and ease of use; human factors engineering; failure mode and effects analysis; and incorporation of evidence-based medicine (Box.) Postimplementation results showed improvement of the inpatient Joint Commission Tobacco Treatment Measures by greater than 3-fold at a single hospital.

The next steps for this initiative include testing the 4-step order set design process in multiple clinical settings to determine the effectiveness of this approach in other areas of clinical care.

In the current health care environment, hospitals are constantly challenged to improve quality metrics and deliver better health care outcomes. One means to achieving quality improvement is through the use of order sets, groups of related orders that a health care provider (HCP) can place with either a few keystrokes or mouse clicks.¹

Historically, design of order sets has largely focused on clicking checkboxes containing evidence-based practices. According to Bates and colleagues and the Institute for Safe Medication Practices, incorporating evidence-based medicine (EBM) into order sets is not by itself sufficient.^2,3Execution of proper design coupled with simplicity and provider efficiency is paramount to HCP buy-in, increased likelihood of order set adherence, and to potentially better outcomes.

In this article, we outline advancements in order set design. These improvements increase provider efficiency and ease of use; incorporate human factors engineering (HFE); apply failure mode and effects analysis; and include EBM.

Methods

An inpatient nicotine replacement therapy (NRT) order was developed as part of a multifaceted solution to improve tobacco cessation care at the James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida, a complexity level 1a facility. This NRT order set used the 4-step order set design framework the authors’ developed (for additional information about the NRT order set, contact the authors). We distinguish order set design technique between 2 different inpatient NRT order sets. The first order set in the comparison (Figure 1) is an inpatient NRT order set of unknown origin—it is common for US Department of Veterans Affairs (VA) medical facilities to share order sets and other resources. The second order set (Figure 2) is an inpatient NRT order set we designed using our 4-step process for comparison in this article. No institutional review board approval was required as this work met criteria for operational improvement activities exempt from ethics review.

Justin Iannello, DO, MBA, was the team leader and developer of the 4-step order set design technique. The intervention team consisted of 4 internal medicine physicians with expertise in quality improvement and patient safety: 1 certified professional in patient safety and certified as a Lean Six Sigma Black Belt; 2 physicians certified as Lean Six Sigma Black Belts; and 1 physician certified as a Lean Six Sigma Green Belt. Two inpatient clinical pharmacists and 1 quality management specialist also were involved in its development.

Development of a new NRT order set was felt to be an integral part of the tobacco cessation care delivery process. An NRT order set perceived by users as value-added required a solution that merged EBM with standardization and applied quality improvement principles. The result was an approach to order set design that focused on 4 key questions: Is the order set efficient and easy to use/navigate? Is human factors engineering incorporated? Is failure mode and effects analysis applied? Are evidence-based practices included?

Ease of Use and Navigation

Implementing an order set that is efficient and easy to use or navigate seems straightforward but can be difficult to execute. Figure 1 shows many detailed options consisting of different combinations of nicotine patches, lozenges, and gum. Also included are oral tobacco cessation options (bupropion and varenicline). Although more options may seem better, confusion about appropriate medication selection can occur.

According to Heath and Heath, too many options can result in lack of action.⁴ For example, Heath and Heath discuss a food store that offered 6 free samples of different jams on one day and 24 jams the following day. The customers who sampled 6 different types of jam were 10 times more likely to buy jam. The authors concluded that the more options available, the more difficulty a potential buyer has in deciding on a course of action.⁴

In clinical situations where a HCP is using an order set, the number of options can mean the difference between use vs avoidance if the choices are overwhelming. HCPs process layers of detail every day when creating differential diagnoses and treatment plans. While that level of detail is necessary clinically, that same level of detail included in orders sets can create challenges for HCPs.

Figure 2 advances the order set in Figure 1 by providing a simpler and cleaner design, so HCPs can more easily review and process the information. This order set design minimizes the number of options available to help users make the right decision, focusing on value for the appropriate setting and audience. In other words, order sets should not be a “one size fits all” approach.

Order sets should be tailored to the appropriate clinical setting (eg, inpatient acute care, outpatient clinic setting, etc) and HCP (eg, hospitalist, tobacco cessation specialist, etc). We are comparing NRT order sets designed for HCPs who do not routinely prescribe oral tobacco cessation products in the inpatient setting. When possible, autogenerated bundle orders should also be used according to evidence-based recommendations (such as nicotine patch tapers) for ease of use and further simplification of order sets.

Finally, usability testing known as “evaluating a product or service by testing it with representative users” helps further refine an order set.⁵Usability testing should be applied during all phases of order set development with end user(s) as it helps identify problems with order set design prior to implementation. By applying usability testing, the order set becomes more meaningful and valued by the user.

Human Factors Engineering

HFE is “the study of all the factors that make it easier to do the work in the right way.”⁶ HFE seeks to identify, align, and apply processes for people and the world within which they live and work to promote safe and efficient practices, especially in relation to the technology and physical design features in their work environment.⁶

The average American adult makes about 35,000 decisions per day.⁷ Thus, there is potential for error at any moment. Design that does not take HFE into account can be dangerous. For example, when tube feed and IV line connectors look similar and are compatible, patients may inadvertently receive food administered directly into their bloodstream.⁸

HFE can and should be applied to order sets. Everything from the look, feel, and verbiage of an order set affects potential outcomes. For example, consider the impact even seemingly minor modifications can have on outcomes simply by guiding users in a different way: Figure 1 provides NRT options based on cigarette use per day, whereas Figure 2 conveys pack use per day in relation to the equivalent number of cigarettes used daily. These differences may seem small; however, it helps guide users to the right choice when considering that health care providers have been historically trained on social history gathering that emphasizes packs per day and pack-years.

Failure Mode and Effects Analysis

Failure mode and effects analysis (FMEA) is “a structured way to identify and address potential problems, or failures and their resulting effects on the system or process before an adverse event occurs.”⁹ The benefit of an order set must be weighed against the risk during development. FMEA should be applied during order set design to assess and limit risk just as with any other clinical care process.

FMEA examines both level of risk and frequency of risk occurrence associated with a new proposed process. For example, let’s evaluate an order set designed for pain control after surgery that consists of multiple high-risk opioids along with antihistamine medications for as-needed itch relief (a non-life-threatening adverse event (AE) of opioids well known by the medical community). An interdisciplinary FMEA team consisting of subject matter experts may examine how the process should flow in step-by-step detail and then discuss the benefit of a process and risk for potential error. A FMEA team would then analyze what could go wrong with each part of the process and assign a level of risk and risk frequency for various steps in the process, and then decide that certain steps should be modified or eliminated. Perhaps after FMEA, a facility might conclude that the risk of serious complications is high when you combine opioid use with antihistamine medications. The facility could decide to remove antihistamine medications from an order set if it is determined that risks outweigh benefits. While a root cause analysis might identify the cause of an AE after order set use, these situations can be prevented with FMEA.

When applying FMEA to Figure 1, while bupropion is known as an evidence-based oral tobacco cessation option, there is the possibility that bupropion could be inadvertently prescribed from the order set in a hospitalized patient with alcohol withdrawal and withdrawal seizure history. These potentially dangerous situations can be avoided with FMEA. Thus, although bupropion may be evidence-based for NRT, decisions regarding order set design using EBM alone are insufficient.

The practitioner must consider possible unintended consequences within order sets and target treatment options to the appropriate setting and audience. Although Figure 1 may appear to be more inclusive, the interdisciplinary committee designing the inpatient NRT order set felt there was heightened risk with introducing bupropion in Figure 1 and decided the risk would be lowered by removing bupropion from the redesigned NRT order set (Figure 2). In addition to the goal of balancing availability of NRT options with acceptable risk, Figure 2 also focused on building an NRT order set most applicable to the inpatient setting.

Including Evidence-Based Practices

EBM has become a routine part of clinical decision making. Therefore, including EBM in order set design is vital. EBM for NRT has demonstrated that combination therapy is more effective than is monotherapy to help tobacco users quit. Incremental doses of NRT are recommended for patients who use tobacco more frequently.¹⁰

As shown in Figures 1 and 2, both order set designs incorporate EBM for NRT. Although the importance of implementing EBM is evident, critical factors, such as HFE and FMEA make a difference with well-designed order sets.

Results

The 4-step order set design technique was used during development of an inpatient NRT order set at the JAHVH. Results for the inpatient Joint Commission Tobacco Treatment Measures were obtained from the Veterans Health Administration quality metric reporting system known as Strategic Analytics for Improvement and Learning (SAIL). SAIL performance measure outcomes, which include the inpatient Joint Commission Tobacco Treatment Measures, are derived from chart reviews conducted by the External Peer Review Program. Outcomes demonstrated that TOB-2 and TOB-3 (2 inpatient Joint Commission Tobacco Treatment Measures) known as tob20 and tob40, respectively, within SAIL improved by more than 300% after development of an NRT order set using the 4-step order set design framework along with implementation of a multifaceted tobacco cessation care delivery system at JAHVH.

Discussion

While the overall tobacco cessation care delivery system contributed to improved outcomes with the inpatient Joint Commission Tobacco Treatment Measures at JAHVH, the NRT order set was a cornerstone of the design. Although using our order set design technique does not necessarily guarantee successful outcomes, we believe using the 4-step order set design process increases the value of order sets and has potential to improve quality outcomes.

Limitations

Although improved outcomes following implementation of our NRT order set suggest correlation, causation cannot be proven. Also while the NRT order set is believed to have helped tremendously with outcomes, the entire tobacco cessation care delivery system at JAHVH contributed to the results. In addition, the inpatient Joint Commission Tobacco Treatment Measures help improve processes for tobacco cessation care. However, we are uncertain whether the results of our improvement efforts helped patients stop tobacco use. Further studies are needed to determine impact on population health. Finally, our results were based on improvement work done at a single center. Further studies are necessary to see whether results are reproducible.

Conclusion

There was significant improvement with the inpatient Joint Commission Tobacco Treatment Measures outcomes following development of a tobacco cessation care delivery system that included design of an inpatient NRT order set using a 4-step process we developed. This 4-step structure includes emphasis on efficiency and ease of use; human factors engineering; failure mode and effects analysis; and incorporation of evidence-based medicine (Box.) Postimplementation results showed improvement of the inpatient Joint Commission Tobacco Treatment Measures by greater than 3-fold at a single hospital.

The next steps for this initiative include testing the 4-step order set design process in multiple clinical settings to determine the effectiveness of this approach in other areas of clinical care.