Atopic dermatitis (AD) is the most common inflammatory skin condition, affecting approximately 15% to 20% of the global population.^1,2 Atopic dermatitis is characterized by a chronic relapsing dermatitis with pruritus, often beginning in infancy or childhood. Atopic dermatitis is caused by a defect in epidermal barrier function, which results in increased transepidermal water loss.¹ The criteria for AD include a pruritic skin condition plus 3 or more of the following: history of involvement of the skin creases, history of asthma or hay fever, history of AD in a first-degree relative (in children), 1-year history of generally dry skin, visible flexural eczema, and an age of onset of less than 2 years. Adults with AD frequently present with hand or facial dermatitis.¹

UV light therapies including narrowband UVB (NB-UVB), UVA1, and psoralen plus UVA (PUVA) have all been used as effective treatments of AD.^3,4 UV light is beneficial for AD patients due to its immunomodulatory effects, thickening of the stratum corneum, and the reduction of Staphylococcus aureus in the skin.² Most patients with AD improve with light therapy; however, it is estimated that 1% to 3% of patients with AD will experience a paradoxical worsening of their AD after exposure to UV light.^2,5 This condition is referred to as photosensitive AD and is characterized by a photodistributed rash in patients who fulfill the criteria of AD. Photosensitive AD has a female predominance and generally affects patients with late-onset disease with development of AD after puberty.^2,5 The pathogenesis for the development of photosensitivity in patients with AD who previously tolerated exposure to sunlight is unknown.⁵ We describe a case of photosensitive AD exacerbated by UVB exposure.

Case Report

A 55-year-old Asian woman presented for evaluation of a rash on the head, neck, and arms. She reported that she had developed a pruritic rash with edema after sun exposure at 16 years of age. Since then, the rash has been intermittent and completely resolved at times with periods of decreased sun exposure; however, the rash recently had been persistent and worsening despite practicing strict sun protection with daily sunscreen application, protective clothing, and sun avoidance. She was not taking systemic medications or supplements at the time but was applying high-potency topical corticosteroids and calcineurin inhibitors with minimal improvement under the care of a dermatologist.

On physical examination the patient had thin, well-demarcated, erythematous papules and plaques with scaling, primarily on sun-exposed skin on the forehead (Figure 1A), cheeks (Figure 1B), eyelids, upper lip, neck (Figures 1B and 1C), upper chest (Figure 1C), and dorsal aspect of the hands, with excoriated pink papules on the forearms, shoulders, and back. A punch biopsy of the right neck showed spongiotic dermatitis with a perivascular lymphohistiocytic infiltrate (Figure 2). Further workup was pursued including complete blood cell count, comprehensive metabolic profile, liver function panel, Sjögren syndrome antigen A/Sjögren syndrome antigen B test, antinuclear antibody test, human immunodeficiency virus 1/2 antigen/antibody test, hepatitis panel, and mycobacterium tuberculosis test, which were all within reference range. Photodermatosis was suspected and she underwent phototesting including UVA, NB-UVB, and visible light. Phototesting confirmed she had a UVB photosensitivity with a markedly decreased minimal erythema dose (MED) to NB-UVB. The MED to NB-UVB was positive at 24 hours to all tested sites, the lowest of which was 0.135 J/cm². Eczematous changes began to develop at day 6 at doses of 0.945 and 1.080 J/cm². The patient also underwent visible light testing, which was negative. The patient was patch tested for multiple standardized agents as well as personal products, all of which were negative. Subsequent photopatch testing revealed a slightly positive reaction to benzophenone 4, a common ingredient in sunscreens.

The patient was then started on mycophenolate mofetil and prednisone. Repeat MED testing to NB-UVB was performed. Her repeat MED to NB-UVB was determined to be 0.405 J/cm², and hardening commenced at 3 times per week at 70% of the MED (0.2835 J/cm²). She began to flare and develop an eczematous reaction, thus the dose was decreased to 50% of the MED (0.2025 J/cm²), which she tolerated.

Comment

Classification and Clinical Presentation
The literature on photosensitive AD is scant, and this disease entity is rare. Alternative names include photoaggravated AD, photosensitive eczema, and light-exacerbated eczema.⁵ Two main studies have been conducted in recent years that were intended to characterize photosensitive AD. ten Berge et al⁵ conducted a retrospective study of 145 patients with AD that were phototested in 2009. They found that 3% of their total AD patient population had photosensitive AD.⁵ In 2016, Ellenbogen et al² performed a similar single-center retrospective analysis of 17 patients with long-standing AD who suddenly developed photosensitivity.

Patients with photosensitive AD typically present with lesions on sun-exposed skin with coexisting eczematous lesions in sites with a predilection for AD.² In the study conducted by ten Berge et al,⁵ 2 main reaction patterns were observed: erythematous papules with pruritus and an eczematous reaction. The authors suggested one subset of patients demonstrated polymorphous light eruption (PMLE), a common photoinduced eruption thought to represent a delayed-type hypersensitivity, coexisting with AD while the other subset had true photosensitive AD.^5,6 Ellenbogen et al² also found 2 reaction patterns, which they labeled papular (PMLE type) and eczematous (photosensitive AD type). The authors contested the theory of coexisting PMLE in AD because PMLE gets better in the summer with UV radiation hardening.² On the contrary, photosensitive AD worsens with uncontrolled exposure to sunlight. Only with controlled exposure to small doses of UV radiation at a time does this condition improve. Ellenbogen et al² believe both reaction patterns are consistent with photosensitive AD and the PMLE type should be termed papular photosensitive AD type.

Histopathology
The histopathologic findings of photosensitive AD are nonspecific but are characterized by spongiotic dermatitis with a perivascular lymphohistiocytic infiltrate.²

Diagnosis With Phototesting
Phototesting of patients with AD should be considered if there is a suspicion for photosensitivity based on persistent disease despite use of photoprotection and local treatment.^5-7 Patients may not notice a correlation of skin exacerbations with UV exposure, especially if they are only sensitive to UVA, as it is still present on cloudy days and can penetrate glass windows.⁸ Phototesting evaluates the degree of sensitivity to UV light and the specific wavelength eliciting the cutaneous response. Phototesting consists of determining the MED to UVA and UVB, the minimal phototoxic dose for PUVA, and visible light exposure. Further evaluation may include photoprovocation testing or photopatch testing, as these patients can have coexisting photocontact allergies.

The MED is defined as the minimal dose of UV light needed to induce perceptible erythema in exposed skin.⁵ It is dependent on the light source and patient’s skin type, and individual units may vary. To determine the MED to UVA or UVB, 2×2-cm skin fields are irradiated with increasing cumulative UVA/UVB. The dose varies by skin type and it is then read at 24 hours. The majority of patients with photosensitive AD are reported to have a normal MED; however, some studies have reported the MED to be decreased.^5,7-9 ten Berge et al⁵ found 7% of their study participants exhibited a lower MED, as seen in our patient.

The minimal phototoxic dose for PUVA is defined as the least exposure dose of UVA 1 hour after ingestion of 0.4 mg/kg of methoxsalen that produces pink erythema with 4 distinct borders at 48, 72, or 96 hours after ingestion.¹⁰ Visible light exposure is tested using a slide projector as the light source to an approximately 10×5-cm area of skin for 45 minutes. Any immediate or delayed reaction is abnormal and considered positive.¹⁰

Photoprovocation testing has been performed in several studies.^2,5 It consists of exposing an 8-cm area of skin to 80 J/cm² UVA and 10 mJ/cm² UVB, which is read at 24, 48, or 72 hours. A papular or eczematous reaction is considered positive.^2,11

The results of phototesting have varied between studies. ten Berge et al⁵ phototested 107 patients with AD and photosensitivity and 17% were found to be solely sensitive to UVA whereas 67% were found to be sensitive to UVA and UVB. In contrast, Ellenbogen et al² only tested 17 patients with AD and photosensitivity and they found that 56% (9/16) were sensitive to UVA alone while only 44% (7/16) were sensitive to UVA and UVB.

Photopatch testing can help to rule out photosensitivity due to a substance in the presence of UV light. In studies of patients with photosensitive AD (N=125), photocontact reactions occurred in 23% and were predominantly associated with sunscreens, skin care products, and fragrances.^5,12 Photopatch testing is done by placing duplicate sets of patches on nonlesional skin using the Finn Chamber technique. A published list of allergens, which were agreed upon by the European Society of Contact Dermatitis and the European Society for Photodermatology in 2000 are seen in Table 1.¹³ The list contains mainly UV filters and drugs. The patients’ own products also should be tested in addition to the published list of allergens, but a maximum of 30 patches should be placed at one time. The patches are removed at either 24 or 48 hours; some researchers have found greater sensitivity with the 48-hour time period, while others have not found a significant difference.¹⁰ One set of skin fields then is covered with an impermeable occlusive dressing as a control while the other is irradiated with 5 J/cm² of a broad-spectrum UVA light source. UVA fluorescent lamps are the light source of choice because of their widespread availability, reproducible broad spectrum, and beam uniformity.¹⁰ In the study conducted by ten Berge et al,⁵ photopatch testing was performed on 125 patients, and 29 patients were found to be positive to one or more substances. Ellenbogen et al² photopatch tested 5 patients with photosensitive AD and a clinical suspicion of photoallergy; however, all 5 were negative. Our patient underwent traditional patch testing due to clinical suspicion of a coexisting contact allergy, which was negative.

Conclusion

Photosensitive AD is a rare entity characterized by a photodistributed rash and involvement of non–sun-exposed skin. Patients will either have a history of AD or fulfill the criteria of AD. They have positive photoprovocation testing and generally have a normal MED. They may have positive photopatch testing with coexisting photoallergies. Histopathology is nonspecific but shows spongiotic dermatitis with perivascular lymphohistiocytic infiltrate. Diagnosis is essential, as this disease can be life altering and affect quality of life. Effective treatment options are available, and the therapeutic ladder is based on severity of disease.^2,5

Atopic dermatitis (AD) is the most common inflammatory skin condition, affecting approximately 15% to 20% of the global population.^1,2 Atopic dermatitis is characterized by a chronic relapsing dermatitis with pruritus, often beginning in infancy or childhood. Atopic dermatitis is caused by a defect in epidermal barrier function, which results in increased transepidermal water loss.¹ The criteria for AD include a pruritic skin condition plus 3 or more of the following: history of involvement of the skin creases, history of asthma or hay fever, history of AD in a first-degree relative (in children), 1-year history of generally dry skin, visible flexural eczema, and an age of onset of less than 2 years. Adults with AD frequently present with hand or facial dermatitis.¹

UV light therapies including narrowband UVB (NB-UVB), UVA1, and psoralen plus UVA (PUVA) have all been used as effective treatments of AD.^3,4 UV light is beneficial for AD patients due to its immunomodulatory effects, thickening of the stratum corneum, and the reduction of Staphylococcus aureus in the skin.² Most patients with AD improve with light therapy; however, it is estimated that 1% to 3% of patients with AD will experience a paradoxical worsening of their AD after exposure to UV light.^2,5 This condition is referred to as photosensitive AD and is characterized by a photodistributed rash in patients who fulfill the criteria of AD. Photosensitive AD has a female predominance and generally affects patients with late-onset disease with development of AD after puberty.^2,5 The pathogenesis for the development of photosensitivity in patients with AD who previously tolerated exposure to sunlight is unknown.⁵ We describe a case of photosensitive AD exacerbated by UVB exposure.

Case Report

A 55-year-old Asian woman presented for evaluation of a rash on the head, neck, and arms. She reported that she had developed a pruritic rash with edema after sun exposure at 16 years of age. Since then, the rash has been intermittent and completely resolved at times with periods of decreased sun exposure; however, the rash recently had been persistent and worsening despite practicing strict sun protection with daily sunscreen application, protective clothing, and sun avoidance. She was not taking systemic medications or supplements at the time but was applying high-potency topical corticosteroids and calcineurin inhibitors with minimal improvement under the care of a dermatologist.

On physical examination the patient had thin, well-demarcated, erythematous papules and plaques with scaling, primarily on sun-exposed skin on the forehead (Figure 1A), cheeks (Figure 1B), eyelids, upper lip, neck (Figures 1B and 1C), upper chest (Figure 1C), and dorsal aspect of the hands, with excoriated pink papules on the forearms, shoulders, and back. A punch biopsy of the right neck showed spongiotic dermatitis with a perivascular lymphohistiocytic infiltrate (Figure 2). Further workup was pursued including complete blood cell count, comprehensive metabolic profile, liver function panel, Sjögren syndrome antigen A/Sjögren syndrome antigen B test, antinuclear antibody test, human immunodeficiency virus 1/2 antigen/antibody test, hepatitis panel, and mycobacterium tuberculosis test, which were all within reference range. Photodermatosis was suspected and she underwent phototesting including UVA, NB-UVB, and visible light. Phototesting confirmed she had a UVB photosensitivity with a markedly decreased minimal erythema dose (MED) to NB-UVB. The MED to NB-UVB was positive at 24 hours to all tested sites, the lowest of which was 0.135 J/cm². Eczematous changes began to develop at day 6 at doses of 0.945 and 1.080 J/cm². The patient also underwent visible light testing, which was negative. The patient was patch tested for multiple standardized agents as well as personal products, all of which were negative. Subsequent photopatch testing revealed a slightly positive reaction to benzophenone 4, a common ingredient in sunscreens.

The patient was then started on mycophenolate mofetil and prednisone. Repeat MED testing to NB-UVB was performed. Her repeat MED to NB-UVB was determined to be 0.405 J/cm², and hardening commenced at 3 times per week at 70% of the MED (0.2835 J/cm²). She began to flare and develop an eczematous reaction, thus the dose was decreased to 50% of the MED (0.2025 J/cm²), which she tolerated.

Comment

Classification and Clinical Presentation
The literature on photosensitive AD is scant, and this disease entity is rare. Alternative names include photoaggravated AD, photosensitive eczema, and light-exacerbated eczema.⁵ Two main studies have been conducted in recent years that were intended to characterize photosensitive AD. ten Berge et al⁵ conducted a retrospective study of 145 patients with AD that were phototested in 2009. They found that 3% of their total AD patient population had photosensitive AD.⁵ In 2016, Ellenbogen et al² performed a similar single-center retrospective analysis of 17 patients with long-standing AD who suddenly developed photosensitivity.

Patients with photosensitive AD typically present with lesions on sun-exposed skin with coexisting eczematous lesions in sites with a predilection for AD.² In the study conducted by ten Berge et al,⁵ 2 main reaction patterns were observed: erythematous papules with pruritus and an eczematous reaction. The authors suggested one subset of patients demonstrated polymorphous light eruption (PMLE), a common photoinduced eruption thought to represent a delayed-type hypersensitivity, coexisting with AD while the other subset had true photosensitive AD.^5,6 Ellenbogen et al² also found 2 reaction patterns, which they labeled papular (PMLE type) and eczematous (photosensitive AD type). The authors contested the theory of coexisting PMLE in AD because PMLE gets better in the summer with UV radiation hardening.² On the contrary, photosensitive AD worsens with uncontrolled exposure to sunlight. Only with controlled exposure to small doses of UV radiation at a time does this condition improve. Ellenbogen et al² believe both reaction patterns are consistent with photosensitive AD and the PMLE type should be termed papular photosensitive AD type.

Histopathology
The histopathologic findings of photosensitive AD are nonspecific but are characterized by spongiotic dermatitis with a perivascular lymphohistiocytic infiltrate.²

Diagnosis With Phototesting
Phototesting of patients with AD should be considered if there is a suspicion for photosensitivity based on persistent disease despite use of photoprotection and local treatment.^5-7 Patients may not notice a correlation of skin exacerbations with UV exposure, especially if they are only sensitive to UVA, as it is still present on cloudy days and can penetrate glass windows.⁸ Phototesting evaluates the degree of sensitivity to UV light and the specific wavelength eliciting the cutaneous response. Phototesting consists of determining the MED to UVA and UVB, the minimal phototoxic dose for PUVA, and visible light exposure. Further evaluation may include photoprovocation testing or photopatch testing, as these patients can have coexisting photocontact allergies.

The MED is defined as the minimal dose of UV light needed to induce perceptible erythema in exposed skin.⁵ It is dependent on the light source and patient’s skin type, and individual units may vary. To determine the MED to UVA or UVB, 2×2-cm skin fields are irradiated with increasing cumulative UVA/UVB. The dose varies by skin type and it is then read at 24 hours. The majority of patients with photosensitive AD are reported to have a normal MED; however, some studies have reported the MED to be decreased.^5,7-9 ten Berge et al⁵ found 7% of their study participants exhibited a lower MED, as seen in our patient.

The minimal phototoxic dose for PUVA is defined as the least exposure dose of UVA 1 hour after ingestion of 0.4 mg/kg of methoxsalen that produces pink erythema with 4 distinct borders at 48, 72, or 96 hours after ingestion.¹⁰ Visible light exposure is tested using a slide projector as the light source to an approximately 10×5-cm area of skin for 45 minutes. Any immediate or delayed reaction is abnormal and considered positive.¹⁰

Photoprovocation testing has been performed in several studies.^2,5 It consists of exposing an 8-cm area of skin to 80 J/cm² UVA and 10 mJ/cm² UVB, which is read at 24, 48, or 72 hours. A papular or eczematous reaction is considered positive.^2,11

The results of phototesting have varied between studies. ten Berge et al⁵ phototested 107 patients with AD and photosensitivity and 17% were found to be solely sensitive to UVA whereas 67% were found to be sensitive to UVA and UVB. In contrast, Ellenbogen et al² only tested 17 patients with AD and photosensitivity and they found that 56% (9/16) were sensitive to UVA alone while only 44% (7/16) were sensitive to UVA and UVB.

Photopatch testing can help to rule out photosensitivity due to a substance in the presence of UV light. In studies of patients with photosensitive AD (N=125), photocontact reactions occurred in 23% and were predominantly associated with sunscreens, skin care products, and fragrances.^5,12 Photopatch testing is done by placing duplicate sets of patches on nonlesional skin using the Finn Chamber technique. A published list of allergens, which were agreed upon by the European Society of Contact Dermatitis and the European Society for Photodermatology in 2000 are seen in Table 1.¹³ The list contains mainly UV filters and drugs. The patients’ own products also should be tested in addition to the published list of allergens, but a maximum of 30 patches should be placed at one time. The patches are removed at either 24 or 48 hours; some researchers have found greater sensitivity with the 48-hour time period, while others have not found a significant difference.¹⁰ One set of skin fields then is covered with an impermeable occlusive dressing as a control while the other is irradiated with 5 J/cm² of a broad-spectrum UVA light source. UVA fluorescent lamps are the light source of choice because of their widespread availability, reproducible broad spectrum, and beam uniformity.¹⁰ In the study conducted by ten Berge et al,⁵ photopatch testing was performed on 125 patients, and 29 patients were found to be positive to one or more substances. Ellenbogen et al² photopatch tested 5 patients with photosensitive AD and a clinical suspicion of photoallergy; however, all 5 were negative. Our patient underwent traditional patch testing due to clinical suspicion of a coexisting contact allergy, which was negative.

Conclusion

Photosensitive AD is a rare entity characterized by a photodistributed rash and involvement of non–sun-exposed skin. Patients will either have a history of AD or fulfill the criteria of AD. They have positive photoprovocation testing and generally have a normal MED. They may have positive photopatch testing with coexisting photoallergies. Histopathology is nonspecific but shows spongiotic dermatitis with perivascular lymphohistiocytic infiltrate. Diagnosis is essential, as this disease can be life altering and affect quality of life. Effective treatment options are available, and the therapeutic ladder is based on severity of disease.^2,5

Atopic dermatitis (AD) is the most common inflammatory skin condition, affecting approximately 15% to 20% of the global population.^1,2 Atopic dermatitis is characterized by a chronic relapsing dermatitis with pruritus, often beginning in infancy or childhood. Atopic dermatitis is caused by a defect in epidermal barrier function, which results in increased transepidermal water loss.¹ The criteria for AD include a pruritic skin condition plus 3 or more of the following: history of involvement of the skin creases, history of asthma or hay fever, history of AD in a first-degree relative (in children), 1-year history of generally dry skin, visible flexural eczema, and an age of onset of less than 2 years. Adults with AD frequently present with hand or facial dermatitis.¹

UV light therapies including narrowband UVB (NB-UVB), UVA1, and psoralen plus UVA (PUVA) have all been used as effective treatments of AD.^3,4 UV light is beneficial for AD patients due to its immunomodulatory effects, thickening of the stratum corneum, and the reduction of Staphylococcus aureus in the skin.² Most patients with AD improve with light therapy; however, it is estimated that 1% to 3% of patients with AD will experience a paradoxical worsening of their AD after exposure to UV light.^2,5 This condition is referred to as photosensitive AD and is characterized by a photodistributed rash in patients who fulfill the criteria of AD. Photosensitive AD has a female predominance and generally affects patients with late-onset disease with development of AD after puberty.^2,5 The pathogenesis for the development of photosensitivity in patients with AD who previously tolerated exposure to sunlight is unknown.⁵ We describe a case of photosensitive AD exacerbated by UVB exposure.

Case Report

A 55-year-old Asian woman presented for evaluation of a rash on the head, neck, and arms. She reported that she had developed a pruritic rash with edema after sun exposure at 16 years of age. Since then, the rash has been intermittent and completely resolved at times with periods of decreased sun exposure; however, the rash recently had been persistent and worsening despite practicing strict sun protection with daily sunscreen application, protective clothing, and sun avoidance. She was not taking systemic medications or supplements at the time but was applying high-potency topical corticosteroids and calcineurin inhibitors with minimal improvement under the care of a dermatologist.

On physical examination the patient had thin, well-demarcated, erythematous papules and plaques with scaling, primarily on sun-exposed skin on the forehead (Figure 1A), cheeks (Figure 1B), eyelids, upper lip, neck (Figures 1B and 1C), upper chest (Figure 1C), and dorsal aspect of the hands, with excoriated pink papules on the forearms, shoulders, and back. A punch biopsy of the right neck showed spongiotic dermatitis with a perivascular lymphohistiocytic infiltrate (Figure 2). Further workup was pursued including complete blood cell count, comprehensive metabolic profile, liver function panel, Sjögren syndrome antigen A/Sjögren syndrome antigen B test, antinuclear antibody test, human immunodeficiency virus 1/2 antigen/antibody test, hepatitis panel, and mycobacterium tuberculosis test, which were all within reference range. Photodermatosis was suspected and she underwent phototesting including UVA, NB-UVB, and visible light. Phototesting confirmed she had a UVB photosensitivity with a markedly decreased minimal erythema dose (MED) to NB-UVB. The MED to NB-UVB was positive at 24 hours to all tested sites, the lowest of which was 0.135 J/cm². Eczematous changes began to develop at day 6 at doses of 0.945 and 1.080 J/cm². The patient also underwent visible light testing, which was negative. The patient was patch tested for multiple standardized agents as well as personal products, all of which were negative. Subsequent photopatch testing revealed a slightly positive reaction to benzophenone 4, a common ingredient in sunscreens.

The patient was then started on mycophenolate mofetil and prednisone. Repeat MED testing to NB-UVB was performed. Her repeat MED to NB-UVB was determined to be 0.405 J/cm², and hardening commenced at 3 times per week at 70% of the MED (0.2835 J/cm²). She began to flare and develop an eczematous reaction, thus the dose was decreased to 50% of the MED (0.2025 J/cm²), which she tolerated.

Comment

Classification and Clinical Presentation
The literature on photosensitive AD is scant, and this disease entity is rare. Alternative names include photoaggravated AD, photosensitive eczema, and light-exacerbated eczema.⁵ Two main studies have been conducted in recent years that were intended to characterize photosensitive AD. ten Berge et al⁵ conducted a retrospective study of 145 patients with AD that were phototested in 2009. They found that 3% of their total AD patient population had photosensitive AD.⁵ In 2016, Ellenbogen et al² performed a similar single-center retrospective analysis of 17 patients with long-standing AD who suddenly developed photosensitivity.

Patients with photosensitive AD typically present with lesions on sun-exposed skin with coexisting eczematous lesions in sites with a predilection for AD.² In the study conducted by ten Berge et al,⁵ 2 main reaction patterns were observed: erythematous papules with pruritus and an eczematous reaction. The authors suggested one subset of patients demonstrated polymorphous light eruption (PMLE), a common photoinduced eruption thought to represent a delayed-type hypersensitivity, coexisting with AD while the other subset had true photosensitive AD.^5,6 Ellenbogen et al² also found 2 reaction patterns, which they labeled papular (PMLE type) and eczematous (photosensitive AD type). The authors contested the theory of coexisting PMLE in AD because PMLE gets better in the summer with UV radiation hardening.² On the contrary, photosensitive AD worsens with uncontrolled exposure to sunlight. Only with controlled exposure to small doses of UV radiation at a time does this condition improve. Ellenbogen et al² believe both reaction patterns are consistent with photosensitive AD and the PMLE type should be termed papular photosensitive AD type.

Histopathology
The histopathologic findings of photosensitive AD are nonspecific but are characterized by spongiotic dermatitis with a perivascular lymphohistiocytic infiltrate.²

Diagnosis With Phototesting
Phototesting of patients with AD should be considered if there is a suspicion for photosensitivity based on persistent disease despite use of photoprotection and local treatment.^5-7 Patients may not notice a correlation of skin exacerbations with UV exposure, especially if they are only sensitive to UVA, as it is still present on cloudy days and can penetrate glass windows.⁸ Phototesting evaluates the degree of sensitivity to UV light and the specific wavelength eliciting the cutaneous response. Phototesting consists of determining the MED to UVA and UVB, the minimal phototoxic dose for PUVA, and visible light exposure. Further evaluation may include photoprovocation testing or photopatch testing, as these patients can have coexisting photocontact allergies.

The MED is defined as the minimal dose of UV light needed to induce perceptible erythema in exposed skin.⁵ It is dependent on the light source and patient’s skin type, and individual units may vary. To determine the MED to UVA or UVB, 2×2-cm skin fields are irradiated with increasing cumulative UVA/UVB. The dose varies by skin type and it is then read at 24 hours. The majority of patients with photosensitive AD are reported to have a normal MED; however, some studies have reported the MED to be decreased.^5,7-9 ten Berge et al⁵ found 7% of their study participants exhibited a lower MED, as seen in our patient.

The minimal phototoxic dose for PUVA is defined as the least exposure dose of UVA 1 hour after ingestion of 0.4 mg/kg of methoxsalen that produces pink erythema with 4 distinct borders at 48, 72, or 96 hours after ingestion.¹⁰ Visible light exposure is tested using a slide projector as the light source to an approximately 10×5-cm area of skin for 45 minutes. Any immediate or delayed reaction is abnormal and considered positive.¹⁰

Photoprovocation testing has been performed in several studies.^2,5 It consists of exposing an 8-cm area of skin to 80 J/cm² UVA and 10 mJ/cm² UVB, which is read at 24, 48, or 72 hours. A papular or eczematous reaction is considered positive.^2,11

The results of phototesting have varied between studies. ten Berge et al⁵ phototested 107 patients with AD and photosensitivity and 17% were found to be solely sensitive to UVA whereas 67% were found to be sensitive to UVA and UVB. In contrast, Ellenbogen et al² only tested 17 patients with AD and photosensitivity and they found that 56% (9/16) were sensitive to UVA alone while only 44% (7/16) were sensitive to UVA and UVB.

Photopatch testing can help to rule out photosensitivity due to a substance in the presence of UV light. In studies of patients with photosensitive AD (N=125), photocontact reactions occurred in 23% and were predominantly associated with sunscreens, skin care products, and fragrances.^5,12 Photopatch testing is done by placing duplicate sets of patches on nonlesional skin using the Finn Chamber technique. A published list of allergens, which were agreed upon by the European Society of Contact Dermatitis and the European Society for Photodermatology in 2000 are seen in Table 1.¹³ The list contains mainly UV filters and drugs. The patients’ own products also should be tested in addition to the published list of allergens, but a maximum of 30 patches should be placed at one time. The patches are removed at either 24 or 48 hours; some researchers have found greater sensitivity with the 48-hour time period, while others have not found a significant difference.¹⁰ One set of skin fields then is covered with an impermeable occlusive dressing as a control while the other is irradiated with 5 J/cm² of a broad-spectrum UVA light source. UVA fluorescent lamps are the light source of choice because of their widespread availability, reproducible broad spectrum, and beam uniformity.¹⁰ In the study conducted by ten Berge et al,⁵ photopatch testing was performed on 125 patients, and 29 patients were found to be positive to one or more substances. Ellenbogen et al² photopatch tested 5 patients with photosensitive AD and a clinical suspicion of photoallergy; however, all 5 were negative. Our patient underwent traditional patch testing due to clinical suspicion of a coexisting contact allergy, which was negative.

Conclusion

Photosensitive AD is a rare entity characterized by a photodistributed rash and involvement of non–sun-exposed skin. Patients will either have a history of AD or fulfill the criteria of AD. They have positive photoprovocation testing and generally have a normal MED. They may have positive photopatch testing with coexisting photoallergies. Histopathology is nonspecific but shows spongiotic dermatitis with perivascular lymphohistiocytic infiltrate. Diagnosis is essential, as this disease can be life altering and affect quality of life. Effective treatment options are available, and the therapeutic ladder is based on severity of disease.^2,5

Instability of formulary coverage for drug and insulin can make it tough to treat patients with diabetes, and the problem is getting worse.

Just one example: CVS Caremark removed 22 insulin products and drugs to treat diabetes in its July 2017 formulary update.

“This is a real problem,” Philip Levy, MD, an endocrinologist at Banner University Medical Group in Phoenix, said in an interview. “We have people that are doing well on one medication and then all of a sudden, their insurance carrier says you have to use a different medication and they don’t tolerate it. It’s a real problem.”

Claresa Levetan, MD, with Chestnut Hill Endocrinology, Diabetes & Metabolic Associates of Philadelphia, agreed. “It’s a very big problem. ... In my practice, it’s a nightmare because I cannot choose to put them on the insulin or the medications that would be best for them.”

[email protected]

Instability of formulary coverage for drug and insulin can make it tough to treat patients with diabetes, and the problem is getting worse.

Just one example: CVS Caremark removed 22 insulin products and drugs to treat diabetes in its July 2017 formulary update.

“This is a real problem,” Philip Levy, MD, an endocrinologist at Banner University Medical Group in Phoenix, said in an interview. “We have people that are doing well on one medication and then all of a sudden, their insurance carrier says you have to use a different medication and they don’t tolerate it. It’s a real problem.”

Claresa Levetan, MD, with Chestnut Hill Endocrinology, Diabetes & Metabolic Associates of Philadelphia, agreed. “It’s a very big problem. ... In my practice, it’s a nightmare because I cannot choose to put them on the insulin or the medications that would be best for them.”

[email protected]

Instability of formulary coverage for drug and insulin can make it tough to treat patients with diabetes, and the problem is getting worse.

Just one example: CVS Caremark removed 22 insulin products and drugs to treat diabetes in its July 2017 formulary update.

“This is a real problem,” Philip Levy, MD, an endocrinologist at Banner University Medical Group in Phoenix, said in an interview. “We have people that are doing well on one medication and then all of a sudden, their insurance carrier says you have to use a different medication and they don’t tolerate it. It’s a real problem.”

Claresa Levetan, MD, with Chestnut Hill Endocrinology, Diabetes & Metabolic Associates of Philadelphia, agreed. “It’s a very big problem. ... In my practice, it’s a nightmare because I cannot choose to put them on the insulin or the medications that would be best for them.”

[email protected]

“Encouraging” results from a study with an experimental drug offer hope to patients with Niemann-Pick disease type C1 (NPC1), a fatal neurologic disease that affects children and adolescents.

Symptoms of NPC1 result from cholesterol building in brain cells. The drug VTS-270 showed signs of improving cholesterol metabolism in neurons. After treatment, a molecule derived from cholesterol metabolism in neurons had increased, and 2 proteins indicative of brain injury had decreased.

In a phase 1/2a clinical trial, 14 participants received the experimental drug once a month for 12 to 18 months. Another 3 participants received the drug every 2 weeks for 18 months. After observing that the drug was safe and well tolerated, the researchers increased dosing for all participants. Their progress was compared with that of 21 participants in a previous study of NPC1.

The researchers also evaluated the drug’s effectiveness using a neurologic severity score (higher scores indicated more severe disease effects). Participants treated with VTS-270 had lower scores in cognition, speech, and mobility, indicating that the drug can stabilize or slow disease progression.

No one was observed to have serious adverse outcomes, but earlier studies had shown that the treatment carries the risk for hearing loss. After treatment in this study, participants, most of whom had already lost some hearing due to the disease, had further loss, for which they compensated with hearing aids.

“Encouraging” results from a study with an experimental drug offer hope to patients with Niemann-Pick disease type C1 (NPC1), a fatal neurologic disease that affects children and adolescents.

Symptoms of NPC1 result from cholesterol building in brain cells. The drug VTS-270 showed signs of improving cholesterol metabolism in neurons. After treatment, a molecule derived from cholesterol metabolism in neurons had increased, and 2 proteins indicative of brain injury had decreased.

In a phase 1/2a clinical trial, 14 participants received the experimental drug once a month for 12 to 18 months. Another 3 participants received the drug every 2 weeks for 18 months. After observing that the drug was safe and well tolerated, the researchers increased dosing for all participants. Their progress was compared with that of 21 participants in a previous study of NPC1.

The researchers also evaluated the drug’s effectiveness using a neurologic severity score (higher scores indicated more severe disease effects). Participants treated with VTS-270 had lower scores in cognition, speech, and mobility, indicating that the drug can stabilize or slow disease progression.

No one was observed to have serious adverse outcomes, but earlier studies had shown that the treatment carries the risk for hearing loss. After treatment in this study, participants, most of whom had already lost some hearing due to the disease, had further loss, for which they compensated with hearing aids.

“Encouraging” results from a study with an experimental drug offer hope to patients with Niemann-Pick disease type C1 (NPC1), a fatal neurologic disease that affects children and adolescents.

Symptoms of NPC1 result from cholesterol building in brain cells. The drug VTS-270 showed signs of improving cholesterol metabolism in neurons. After treatment, a molecule derived from cholesterol metabolism in neurons had increased, and 2 proteins indicative of brain injury had decreased.

In a phase 1/2a clinical trial, 14 participants received the experimental drug once a month for 12 to 18 months. Another 3 participants received the drug every 2 weeks for 18 months. After observing that the drug was safe and well tolerated, the researchers increased dosing for all participants. Their progress was compared with that of 21 participants in a previous study of NPC1.

The researchers also evaluated the drug’s effectiveness using a neurologic severity score (higher scores indicated more severe disease effects). Participants treated with VTS-270 had lower scores in cognition, speech, and mobility, indicating that the drug can stabilize or slow disease progression.

No one was observed to have serious adverse outcomes, but earlier studies had shown that the treatment carries the risk for hearing loss. After treatment in this study, participants, most of whom had already lost some hearing due to the disease, had further loss, for which they compensated with hearing aids.

Photo by Whaldener Endo

Molecular analysis has confirmed zoonotic transmission of malaria in southern Brazil, according to an article published in The Lancet Global Health.

Researchers identified 28 humans infected with Plasmodium simium, a malaria parasite usually only found in monkeys.

The researchers said screening of local monkeys and mosquitoes will be required to evaluate the extent of the emerging zoonotic threat to public health.

Malaria was thought to have been eliminated from southern Brazil over 50 years ago. However, between 2006 and 2014, 43 cases of malaria were reported in the Atlantic Forest area in southern Brazil. An additional 49 cases were reported from 2015 through 2016.

This prompted researchers to investigate the possibility of zoonotic transmission. The team looked at the 49 cases reported in 2015 and 2016, and they were able to sequence DNA samples from 28 of the 49 patients.

In all 28 cases, the parasite was confirmed to be P simium—not the human parasite Plasmodium vivax, as previously thought.

P simium is transmitted via the Anopheles mosquito and is known to infect some species of howler and capuchin monkeys in the Atlantic Forest region.

All 28 humans infected with P simium had entered the forest or visited the surrounding area. The patients’ main symptom was fever, none of them were admitted to the hospital, and all made full recoveries following treatment.

“There is no evidence that zoonotic malaria can be transmitted from human to human via mosquitoes,” said study author Patrícia Brasil, MD, of Instituto Nacional de Infectologia Evandro Chagas in Rio de Janeiro, Brazil.

“In addition, there is no current threat to people in the city of Rio de Janeiro or in other non-forest areas of the Rio de Janeiro state where transmission of the disease does not exist. However, its unique mode of transmission via monkeys and the fact that it occurs in areas of high forest coverage mean that zoonotic malaria poses a unique problem for malaria control efforts and may complicate the drive towards eventual elimination of the disease. Although [this type of malaria is] benign and treatable, visitors should follow measures to avoid insect bites when going into the forest.”

Dr Brasil and her colleagues noted that samples from previous malaria cases reported in the Atlantic Forest area have not yet been tested. Therefore, it is not possible to establish whether P simium has only recently acquired the ability to infect human beings or if zoonotic malaria has previously infected humans in this region.

“In the 1960s, there was a probable case of zoonotic malaria described in a forest guard in the Atlantic Forest of São Paulo, but, until now, there has been no molecular evidence of the parasite being present in humans,” said study author Cláudio Tadeu Daniel-Ribeiro, MD, of Instituto Oswaldo Cruz in Rio de Janeiro, Brazil.

“This is the first demonstration of P simium naturally infecting human beings in forest locations in a region considered to have eliminated transmission of malaria at least 50 years ago.”

Photo by Whaldener Endo

Molecular analysis has confirmed zoonotic transmission of malaria in southern Brazil, according to an article published in The Lancet Global Health.

Researchers identified 28 humans infected with Plasmodium simium, a malaria parasite usually only found in monkeys.

The researchers said screening of local monkeys and mosquitoes will be required to evaluate the extent of the emerging zoonotic threat to public health.

Malaria was thought to have been eliminated from southern Brazil over 50 years ago. However, between 2006 and 2014, 43 cases of malaria were reported in the Atlantic Forest area in southern Brazil. An additional 49 cases were reported from 2015 through 2016.

This prompted researchers to investigate the possibility of zoonotic transmission. The team looked at the 49 cases reported in 2015 and 2016, and they were able to sequence DNA samples from 28 of the 49 patients.

In all 28 cases, the parasite was confirmed to be P simium—not the human parasite Plasmodium vivax, as previously thought.

P simium is transmitted via the Anopheles mosquito and is known to infect some species of howler and capuchin monkeys in the Atlantic Forest region.

All 28 humans infected with P simium had entered the forest or visited the surrounding area. The patients’ main symptom was fever, none of them were admitted to the hospital, and all made full recoveries following treatment.

“There is no evidence that zoonotic malaria can be transmitted from human to human via mosquitoes,” said study author Patrícia Brasil, MD, of Instituto Nacional de Infectologia Evandro Chagas in Rio de Janeiro, Brazil.

“In addition, there is no current threat to people in the city of Rio de Janeiro or in other non-forest areas of the Rio de Janeiro state where transmission of the disease does not exist. However, its unique mode of transmission via monkeys and the fact that it occurs in areas of high forest coverage mean that zoonotic malaria poses a unique problem for malaria control efforts and may complicate the drive towards eventual elimination of the disease. Although [this type of malaria is] benign and treatable, visitors should follow measures to avoid insect bites when going into the forest.”

Dr Brasil and her colleagues noted that samples from previous malaria cases reported in the Atlantic Forest area have not yet been tested. Therefore, it is not possible to establish whether P simium has only recently acquired the ability to infect human beings or if zoonotic malaria has previously infected humans in this region.

“In the 1960s, there was a probable case of zoonotic malaria described in a forest guard in the Atlantic Forest of São Paulo, but, until now, there has been no molecular evidence of the parasite being present in humans,” said study author Cláudio Tadeu Daniel-Ribeiro, MD, of Instituto Oswaldo Cruz in Rio de Janeiro, Brazil.

“This is the first demonstration of P simium naturally infecting human beings in forest locations in a region considered to have eliminated transmission of malaria at least 50 years ago.”

Photo by Whaldener Endo

Molecular analysis has confirmed zoonotic transmission of malaria in southern Brazil, according to an article published in The Lancet Global Health.

Researchers identified 28 humans infected with Plasmodium simium, a malaria parasite usually only found in monkeys.

The researchers said screening of local monkeys and mosquitoes will be required to evaluate the extent of the emerging zoonotic threat to public health.

Malaria was thought to have been eliminated from southern Brazil over 50 years ago. However, between 2006 and 2014, 43 cases of malaria were reported in the Atlantic Forest area in southern Brazil. An additional 49 cases were reported from 2015 through 2016.

This prompted researchers to investigate the possibility of zoonotic transmission. The team looked at the 49 cases reported in 2015 and 2016, and they were able to sequence DNA samples from 28 of the 49 patients.

In all 28 cases, the parasite was confirmed to be P simium—not the human parasite Plasmodium vivax, as previously thought.

P simium is transmitted via the Anopheles mosquito and is known to infect some species of howler and capuchin monkeys in the Atlantic Forest region.

All 28 humans infected with P simium had entered the forest or visited the surrounding area. The patients’ main symptom was fever, none of them were admitted to the hospital, and all made full recoveries following treatment.

“There is no evidence that zoonotic malaria can be transmitted from human to human via mosquitoes,” said study author Patrícia Brasil, MD, of Instituto Nacional de Infectologia Evandro Chagas in Rio de Janeiro, Brazil.

“In addition, there is no current threat to people in the city of Rio de Janeiro or in other non-forest areas of the Rio de Janeiro state where transmission of the disease does not exist. However, its unique mode of transmission via monkeys and the fact that it occurs in areas of high forest coverage mean that zoonotic malaria poses a unique problem for malaria control efforts and may complicate the drive towards eventual elimination of the disease. Although [this type of malaria is] benign and treatable, visitors should follow measures to avoid insect bites when going into the forest.”

Dr Brasil and her colleagues noted that samples from previous malaria cases reported in the Atlantic Forest area have not yet been tested. Therefore, it is not possible to establish whether P simium has only recently acquired the ability to infect human beings or if zoonotic malaria has previously infected humans in this region.

“In the 1960s, there was a probable case of zoonotic malaria described in a forest guard in the Atlantic Forest of São Paulo, but, until now, there has been no molecular evidence of the parasite being present in humans,” said study author Cláudio Tadeu Daniel-Ribeiro, MD, of Instituto Oswaldo Cruz in Rio de Janeiro, Brazil.

“This is the first demonstration of P simium naturally infecting human beings in forest locations in a region considered to have eliminated transmission of malaria at least 50 years ago.”

IN THIS ARTICLE

• Lab values for case patient
• Differential diagnoses
• Case outcome

A 32-year-old man presents to the urgent care center at a community hospital with severe scrotal pain and swelling of five days’ duration. What began as mild left scrotal discomfort is now causing increasing pain, swelling, hematuria, dysuria, low-grade fever, and nausea, prompting him to seek medical attention.

The patient, who is a pipefitter in a hospital, was at work when his symptoms began. He denies any history of scrotal trauma, and his review of systems is otherwise unremarkable. His medical history is significant for mild hypertension and morbid obesity, but he is not immunocompromised. Two months ago, he had an excision and repair of a left ureterocele, for which he was treated prophylactically with ciprofloxacin for one week. He has a 3–pack-year history of smoking and consumes three alcoholic beverages per week. He denies illicit drug use and has no report of sexually transmitted infection.

Upon arrival to urgent care, the patient appears to be in moderate distress, with a blood pressure (BP) of 111/79 mm Hg; pulse, 104 beats/min; respiratory rate, 18 breaths/min^-1; temperature, 100.1°F; and SpO₂, 94%. Physical exam reveals left scrotal erythema, severe tenderness upon palpation, marked scrotal edema, and a slight amount of foul-smelling discharge seeping from a pinpoint opening in the left perineum (see Figure 1a). Given his scrotal presentation, he is quickly transferred to a regional emergency department (ED) for a urology consult.

In the ED, lab testing yields significant findings (see Table 1). His ECG demonstrates sinus tachycardia at 126 beats/min without rhythm or ST changes. His urinalysis reveals a cloudy appearance, a protein level of 100 mg/dL, and trace leukocyte esterase.

Urgent CT with contrast is obtained; it shows significant soft-tissue inflammatory changes in the left groin and scrotum that extend into the left thigh. In addition, a collection of fluid is seen in the inferior aspect of the left scrotal wall, indicating a probable abscess. There is no free air or lymphadenopathy.

Given the patient’s worsening condition and his apparent advancement to a systemic inflammatory response syndrome, surgical consult is obtained. He is diagnosed with a scrotal abscess and cellulitis; two blood and two scrotal cultures are obtained, and the patient is empirically started on IV ampicillin and gentamicin.

Two hours later, he has a BP of 122/74 mm Hg; pulse, 112 beats/min; respiratory rate, 20 breaths/min^-1; and temperature, 103.1°F. His genital inflammation has advanced to the perineum and the left lower abdomen. The purulent, bloody, foul-smelling drainage from the opening in the left perineum is increasingly apparent. The patient is taken emergently to surgery for an incision and drainage, along with exploration of the scrotal abscess. During surgery, the patient is discovered to have Fournier’s gangrene.

DISCUSSION

Fournier’s gangrene (FG) is a necrotizing fasciitis of the perineal, perianal, and/or genital areas involving the superficial and deep fascial planes while sparing the deep muscular structures and overlying skin.¹ A rare but potentially fatal disease, FG spreads at a rate of up to 3 cm/h.^2,3

Mortality rates range from 7.5% to 88%, with the highest mortality occurring within the first 96 hours of hospitalization.^1,4-7 Mortality is often related to the onset of sepsis.^4,5 Survival requires early recognition; immediate, aggressive surgical debridement of all necrotic tissue; and concomitant, early administration of appropriate antibiotics.^1,4,5,8 Mortality risk and prognosis are improved in patients younger than 60 with localized disease and no toxicity, along with sterile blood cultures.¹

Risk Factors

FG is most commonly seen in males between the ages of 50 and 70, with a 10:1 male-to-female ratio.^3,9 Impaired immunity typically increases a patient’s susceptibility to FG, with type 2 diabetes having the highest incidence (85% of patients).^1,4,6,8,10 Other conditions that can increase the risk for FG include obesity, alcoholism, cirrhosis, cardiac disease, tobacco use, peripheral vascular disease, malignancy, chronic steroid use, renal insufficiency, IV drug abuse, and HIV.^1,4,6,8,9,11

Trauma frequently initiates the infectious process,with urogenital trauma (eg, placement of urethral instrumentation, surgery, and urinary tract infection) being the main cause of bacterial introduction.^1,3 Localized infection causes the development of an obliterative endarteritis, resulting in subcutaneous vascular ischemia, necrosis, and bacterial proliferation.^3,7,9

Presentation and Diagnosis

Presenting symptoms of FG include intense, abrupt genital pain that is disproportionate to the physical exam findings.⁹ This rapidly escalates to include extreme swelling, erythema, bullae, discolored skin, and tissue crepitus with eventual necrosis.^2,10 Lab results typically show leukocytosis > 18.0 × 10⁹/L.⁴ The testicle and spermatic cord are generally unaffected (as in this patient), due to the anatomic relationship between the various layers of fascia within the scrotum and the anterior abdominal wall, as well as the independent blood supply of the compartmentalized testicular tissue.^1-3

During an exam of the acute scrotum, the differential diagnosis includes cellulitis, scrotal abscess, acute epididymitis, and testicular torsion, with scrotal abscess being most frequently diagnosed (57% of patients).^9,11,12 The distinguishing features of these diagnoses can be found in Table 2. Necrotizing fasciitis in the form of FG tends to be an unexpected, rare finding usually only diagnosed during the surgical draining of an abscess.¹²

CT is the test of choice to detect FG and determine the extent of its spread by identifying subcutaneous air/gas within the involved fascial planes.^10,13 However, an incisional biopsy with culture is needed to confirm the diagnosis.^3,9 Most patients with FG require an average of four surgeries (eg, reconstruction, skin grafting, and possibly colostomy if the infection has entered the peritoneal cavity) in order to eradicate the disease and achieve the best functional and cosmetic outcome.⁴

Etiology

About 83% of FG cases are polymicrobial infections comprised of enterobacter, enterococci, Escherichia coli, group A streptococci, pseudomonas, and clostridium, with symptoms evolving two to four days following the initial insult.^4,7,11,14,15 Monomicrobial infections are much less common, but the symptoms progress even more rapidly.¹⁵ Methicillin-resistant Staphylococcus aureus (MRSA) necrotizing fasciitis infections occur in about 3% of monomicrobial cases.¹² MRSA emerged in the early 2000s as an additional causative pathogen for polymicrobial necrotizing fasciitis infections.^12,14,15 Prior to that time, S aureus strains were almost uniformly susceptible to penicillinase-resistant ß lactams.¹²

A distinction should be made between health care-associated (HA) MRSA and community-acquired (CA) MRSA due to treatment considerations. HA-MRSA infections are contracted through previous health care exposure (within the past year) and are less resistant to treatment.^16,17 In contrast, CA-MRSA, which comprises 29% of MRSA cases, causes infections in previously healthy young patients without prior health care contact within the past year.¹⁶ CA-MRSA strains are more robust than HA-MRSA strains and can cause sepsis and other invasive, rapidly progressive, and possibly life-threatening infections due to the amount of tissue destruction and necrosis.^16,18 Transmission of CA-MRSA is often associated with crowded environments, frequent skin-to-skin contact, compromised skin integrity, contaminated items or surfaces, and lack of cleanliness.¹⁶ Over the years, CA-MRSA has developed resistance to multiple antimicrobials; providers should therefore consider CA-MRSA on initial evaluation of necrotizing infections, to ensure appropriate initiation of treatment.^12,16

CASE CONTINUED

Extensive debridement was completed down to healthy tissue in all affected areas (see Figure 1b). The necrotizing fasciitis had spared the left testicle and spermatic cord, and a colostomy was not required.

The patient’s initial postoperative vital signs were unremarkable, except for his BP (86/54 mm Hg). The patient was taken postoperatively to the surgical intensive care unit (SICU) with the diagnosis of FG. Aggressive IV fluids were administered for resuscitation, and he was closely monitored for increasing sepsis. Metronidazole was added for anaerobic and gram-positive coverage. His postoperative lab results can also be found in Table 1.

His ECG showed a normal sinus rhythm without ST changes, and he denied any cardiac symptoms. His physical exam was significant for mild pallor, dry mucus membranes, and a left scrotal and pelvic packed dressing. He was given two units of packed red blood cells for acute postoperative blood-loss anemia. The preliminary tissue culture results showed gram-positive cocci consistent with a staphylococcal infection; his antibiotics were then changed to IV ampicillin/sulbactam and clindamycin.

Approximately five hours postoperatively, an ECG suddenly showed acute ST elevation in leads II, II, and aVF, with reciprocal changes. The patient was diagnosed with an acute myocardial infarction (AMI). He denied any chest pain, shortness of breath, or diaphoresis. The SICU team initiated aspirin therapy and immediately contacted cardiology for an emergent coronary angiogram.

The angiogram and cardiac catheterization revealed an elevated left ventricular end diastolic (LVED) volume, inferior wall hypokinesis, a low-normal ejection fraction, and a 30% lesion in the first diagonal of his left anterior descending artery. A postprocedure echocardiogram demonstrated left ventricular (LV) ejection fraction of 50%, with LV hypokinesis in the inferior base and mild left atrial enlargement. The patient was started on metoprolol for myocardial protection and recovery.

Complications

Perioperative complications of FG, including AMI, must be considered due to the physiologic stress on the body.¹⁹ Most patients with perioperative AMI after noncardiac surgery do not experience ischemic symptoms.²⁰

Growing evidence suggests the pivotal role of acute inflammation (postoperatively or from infection) as a precipitating event in AMI.^20,21 Chemical mediators, such as inflammatory cytokines, endotoxins, and nitric oxide, may play a role in the development of an AMI.²²

If cardiovascular disease and/or significant cardiovascular risk factors (ie, older age, male, cigarette smoking, cardiac family history, acute kidney injury) are present, the risk for AMI increases in the first two days following surgery.^21,23 Acute infections and sepsis also initiate or increase systemic inflammatory activity via these same chemical mediators.²¹

Most suspected infectious agents also produce coronary artery sheer stress and destabilization of vulnerable plaques, leading to plaque rupture and thrombosis.^19,24 Proinflammatory cytokines promote enhanced platelet activation and contribute to this thrombotic environment.^21,23 Thrombus leads to obstructed coronary blood flow, myocardial ischemia, and finally, infarction.²¹

A reversible myocardial depression, cardiomyopathy, or myocardial ischemia may occur in patients with acute systemic infection or sepsis when the myocardium is functionally and structurally injured by these inflammatory chemical mediators.^19,22-24 Characteristics of such a cardiomyopathy include left ventricle dilation with a low filling pressure, an abnormal increase in LVED volume, and a depressed ejection fraction.²²

An acute infectious or septic process can raise troponin levels in 43% to 85% of patients.^22,24 Troponin biomarkers can assist in predicting myocardial injury and events after surgery with nearly absolute myocardial tissue specificity.²⁰ Cardiovascular involvement caused by myocardial injury–related sepsis is observed in up to 70% of patients in the ICU for these reasons.²³ Therefore, providers should consider measuring troponin biomarkers during such infectious and septic processes, as this team did for the case patient. The providers were able to diagnose his AMI early and institute appropriate treatment measures to avoid extensive myocardial tissue damage.

Several studies have already demonstrated a correlation between pneumococcal pneumonia and an increased risk for AMI, and the same mechanisms are presumed responsible for any severe acute infectious state.²¹ More research is needed to understand the pathophysiology of AMI in sepsis and acute systemic infections.²³

OUTCOME FOR THE CASE PATIENT

On postoperative day 2, the patient’s vital signs and lab results were normal. Additional lab results included an A1C of 5.2%. His ECG showed a resolving ST-elevation myocardial infarction (STEMI). The surgical wound had initiation of early granulation tissue without any further signs of necrosis.

A postoperative acute STEMI was unexpected in this patient, as his only risk factors included being male, mild hypertension, obesity, and tobacco use. At the time of his initial elevated troponin level, he had no cardiac symptoms or ECG changes. This initial high troponin level may have been stress-induced from the acute infectious process, and his acute inferior wall STEMI may have been secondary to a transient thrombotic event. The STEMI may then have resolved on its own during the cardiac catheterization with the administration of heparin, IV fluids, blood products, aspirin, or dye infiltration, thus enhancing reperfusion of the coronary artery system.

The final tissue culture showed MRSA. Given his job and his history of a genitourinary procedure, as well as the less fulminant form of disease and relatively quick recovery, it was likely HA-MRSA (rather than CA-MRSA). Only clindamycin was used for treatment.

The wound continued to have decreasing erythema, a reduction in tenderness, and evidence of viable, pink granulation tissue. HIV testing was not completed during his admission. The remainder of the patient’s hospital course was unremarkable, and he was discharged home with wound care, urology, and cardiology follow-up services.

CONCLUSION

Multiple factors contribute to a delayed or mistaken diagnosis of FG; it may be overlooked in the initial working diagnoses because of its low incidence and manifestations similar to those of other soft-tissue infections (eg, cellulitis, scrotal abscess). The cutaneous signs of FG often lag behind the disease manifestation, with minimal or no external presence while extensive internal tissue destruction is occurring. Constant review of symptoms is required when treating patients with soft-tissue infections, and early signs—such as pain out of proportion to physical findings—should prompt a clinician to include FG in the differential.

Early diagnosis with prompt debridement and antibiotic therapy are crucial to patient survival. Detecting FG within the first 24 hours is critical. Further differentiation between CA-MRSA and HA-MRSA can assist in patient recovery and survival by guiding appropriate antibiotic therapy. Perioperative risk assessment and serial troponin biomarkers may identify patients in need of intensive monitoring and management postoperatively to avoid an AMI, since patients may not experience ischemic symptoms.

IN THIS ARTICLE

• Lab values for case patient
• Differential diagnoses
• Case outcome

A 32-year-old man presents to the urgent care center at a community hospital with severe scrotal pain and swelling of five days’ duration. What began as mild left scrotal discomfort is now causing increasing pain, swelling, hematuria, dysuria, low-grade fever, and nausea, prompting him to seek medical attention.

The patient, who is a pipefitter in a hospital, was at work when his symptoms began. He denies any history of scrotal trauma, and his review of systems is otherwise unremarkable. His medical history is significant for mild hypertension and morbid obesity, but he is not immunocompromised. Two months ago, he had an excision and repair of a left ureterocele, for which he was treated prophylactically with ciprofloxacin for one week. He has a 3–pack-year history of smoking and consumes three alcoholic beverages per week. He denies illicit drug use and has no report of sexually transmitted infection.

Upon arrival to urgent care, the patient appears to be in moderate distress, with a blood pressure (BP) of 111/79 mm Hg; pulse, 104 beats/min; respiratory rate, 18 breaths/min^-1; temperature, 100.1°F; and SpO₂, 94%. Physical exam reveals left scrotal erythema, severe tenderness upon palpation, marked scrotal edema, and a slight amount of foul-smelling discharge seeping from a pinpoint opening in the left perineum (see Figure 1a). Given his scrotal presentation, he is quickly transferred to a regional emergency department (ED) for a urology consult.

In the ED, lab testing yields significant findings (see Table 1). His ECG demonstrates sinus tachycardia at 126 beats/min without rhythm or ST changes. His urinalysis reveals a cloudy appearance, a protein level of 100 mg/dL, and trace leukocyte esterase.

Urgent CT with contrast is obtained; it shows significant soft-tissue inflammatory changes in the left groin and scrotum that extend into the left thigh. In addition, a collection of fluid is seen in the inferior aspect of the left scrotal wall, indicating a probable abscess. There is no free air or lymphadenopathy.

Given the patient’s worsening condition and his apparent advancement to a systemic inflammatory response syndrome, surgical consult is obtained. He is diagnosed with a scrotal abscess and cellulitis; two blood and two scrotal cultures are obtained, and the patient is empirically started on IV ampicillin and gentamicin.

Two hours later, he has a BP of 122/74 mm Hg; pulse, 112 beats/min; respiratory rate, 20 breaths/min^-1; and temperature, 103.1°F. His genital inflammation has advanced to the perineum and the left lower abdomen. The purulent, bloody, foul-smelling drainage from the opening in the left perineum is increasingly apparent. The patient is taken emergently to surgery for an incision and drainage, along with exploration of the scrotal abscess. During surgery, the patient is discovered to have Fournier’s gangrene.

DISCUSSION

Fournier’s gangrene (FG) is a necrotizing fasciitis of the perineal, perianal, and/or genital areas involving the superficial and deep fascial planes while sparing the deep muscular structures and overlying skin.¹ A rare but potentially fatal disease, FG spreads at a rate of up to 3 cm/h.^2,3

Mortality rates range from 7.5% to 88%, with the highest mortality occurring within the first 96 hours of hospitalization.^1,4-7 Mortality is often related to the onset of sepsis.^4,5 Survival requires early recognition; immediate, aggressive surgical debridement of all necrotic tissue; and concomitant, early administration of appropriate antibiotics.^1,4,5,8 Mortality risk and prognosis are improved in patients younger than 60 with localized disease and no toxicity, along with sterile blood cultures.¹

Risk Factors

FG is most commonly seen in males between the ages of 50 and 70, with a 10:1 male-to-female ratio.^3,9 Impaired immunity typically increases a patient’s susceptibility to FG, with type 2 diabetes having the highest incidence (85% of patients).^1,4,6,8,10 Other conditions that can increase the risk for FG include obesity, alcoholism, cirrhosis, cardiac disease, tobacco use, peripheral vascular disease, malignancy, chronic steroid use, renal insufficiency, IV drug abuse, and HIV.^1,4,6,8,9,11

Trauma frequently initiates the infectious process,with urogenital trauma (eg, placement of urethral instrumentation, surgery, and urinary tract infection) being the main cause of bacterial introduction.^1,3 Localized infection causes the development of an obliterative endarteritis, resulting in subcutaneous vascular ischemia, necrosis, and bacterial proliferation.^3,7,9

Presentation and Diagnosis

Presenting symptoms of FG include intense, abrupt genital pain that is disproportionate to the physical exam findings.⁹ This rapidly escalates to include extreme swelling, erythema, bullae, discolored skin, and tissue crepitus with eventual necrosis.^2,10 Lab results typically show leukocytosis > 18.0 × 10⁹/L.⁴ The testicle and spermatic cord are generally unaffected (as in this patient), due to the anatomic relationship between the various layers of fascia within the scrotum and the anterior abdominal wall, as well as the independent blood supply of the compartmentalized testicular tissue.^1-3

During an exam of the acute scrotum, the differential diagnosis includes cellulitis, scrotal abscess, acute epididymitis, and testicular torsion, with scrotal abscess being most frequently diagnosed (57% of patients).^9,11,12 The distinguishing features of these diagnoses can be found in Table 2. Necrotizing fasciitis in the form of FG tends to be an unexpected, rare finding usually only diagnosed during the surgical draining of an abscess.¹²

CT is the test of choice to detect FG and determine the extent of its spread by identifying subcutaneous air/gas within the involved fascial planes.^10,13 However, an incisional biopsy with culture is needed to confirm the diagnosis.^3,9 Most patients with FG require an average of four surgeries (eg, reconstruction, skin grafting, and possibly colostomy if the infection has entered the peritoneal cavity) in order to eradicate the disease and achieve the best functional and cosmetic outcome.⁴

Etiology

About 83% of FG cases are polymicrobial infections comprised of enterobacter, enterococci, Escherichia coli, group A streptococci, pseudomonas, and clostridium, with symptoms evolving two to four days following the initial insult.^4,7,11,14,15 Monomicrobial infections are much less common, but the symptoms progress even more rapidly.¹⁵ Methicillin-resistant Staphylococcus aureus (MRSA) necrotizing fasciitis infections occur in about 3% of monomicrobial cases.¹² MRSA emerged in the early 2000s as an additional causative pathogen for polymicrobial necrotizing fasciitis infections.^12,14,15 Prior to that time, S aureus strains were almost uniformly susceptible to penicillinase-resistant ß lactams.¹²

A distinction should be made between health care-associated (HA) MRSA and community-acquired (CA) MRSA due to treatment considerations. HA-MRSA infections are contracted through previous health care exposure (within the past year) and are less resistant to treatment.^16,17 In contrast, CA-MRSA, which comprises 29% of MRSA cases, causes infections in previously healthy young patients without prior health care contact within the past year.¹⁶ CA-MRSA strains are more robust than HA-MRSA strains and can cause sepsis and other invasive, rapidly progressive, and possibly life-threatening infections due to the amount of tissue destruction and necrosis.^16,18 Transmission of CA-MRSA is often associated with crowded environments, frequent skin-to-skin contact, compromised skin integrity, contaminated items or surfaces, and lack of cleanliness.¹⁶ Over the years, CA-MRSA has developed resistance to multiple antimicrobials; providers should therefore consider CA-MRSA on initial evaluation of necrotizing infections, to ensure appropriate initiation of treatment.^12,16

CASE CONTINUED

Extensive debridement was completed down to healthy tissue in all affected areas (see Figure 1b). The necrotizing fasciitis had spared the left testicle and spermatic cord, and a colostomy was not required.

The patient’s initial postoperative vital signs were unremarkable, except for his BP (86/54 mm Hg). The patient was taken postoperatively to the surgical intensive care unit (SICU) with the diagnosis of FG. Aggressive IV fluids were administered for resuscitation, and he was closely monitored for increasing sepsis. Metronidazole was added for anaerobic and gram-positive coverage. His postoperative lab results can also be found in Table 1.

His ECG showed a normal sinus rhythm without ST changes, and he denied any cardiac symptoms. His physical exam was significant for mild pallor, dry mucus membranes, and a left scrotal and pelvic packed dressing. He was given two units of packed red blood cells for acute postoperative blood-loss anemia. The preliminary tissue culture results showed gram-positive cocci consistent with a staphylococcal infection; his antibiotics were then changed to IV ampicillin/sulbactam and clindamycin.

Approximately five hours postoperatively, an ECG suddenly showed acute ST elevation in leads II, II, and aVF, with reciprocal changes. The patient was diagnosed with an acute myocardial infarction (AMI). He denied any chest pain, shortness of breath, or diaphoresis. The SICU team initiated aspirin therapy and immediately contacted cardiology for an emergent coronary angiogram.

The angiogram and cardiac catheterization revealed an elevated left ventricular end diastolic (LVED) volume, inferior wall hypokinesis, a low-normal ejection fraction, and a 30% lesion in the first diagonal of his left anterior descending artery. A postprocedure echocardiogram demonstrated left ventricular (LV) ejection fraction of 50%, with LV hypokinesis in the inferior base and mild left atrial enlargement. The patient was started on metoprolol for myocardial protection and recovery.

Complications

Perioperative complications of FG, including AMI, must be considered due to the physiologic stress on the body.¹⁹ Most patients with perioperative AMI after noncardiac surgery do not experience ischemic symptoms.²⁰

Growing evidence suggests the pivotal role of acute inflammation (postoperatively or from infection) as a precipitating event in AMI.^20,21 Chemical mediators, such as inflammatory cytokines, endotoxins, and nitric oxide, may play a role in the development of an AMI.²²

If cardiovascular disease and/or significant cardiovascular risk factors (ie, older age, male, cigarette smoking, cardiac family history, acute kidney injury) are present, the risk for AMI increases in the first two days following surgery.^21,23 Acute infections and sepsis also initiate or increase systemic inflammatory activity via these same chemical mediators.²¹

Most suspected infectious agents also produce coronary artery sheer stress and destabilization of vulnerable plaques, leading to plaque rupture and thrombosis.^19,24 Proinflammatory cytokines promote enhanced platelet activation and contribute to this thrombotic environment.^21,23 Thrombus leads to obstructed coronary blood flow, myocardial ischemia, and finally, infarction.²¹

A reversible myocardial depression, cardiomyopathy, or myocardial ischemia may occur in patients with acute systemic infection or sepsis when the myocardium is functionally and structurally injured by these inflammatory chemical mediators.^19,22-24 Characteristics of such a cardiomyopathy include left ventricle dilation with a low filling pressure, an abnormal increase in LVED volume, and a depressed ejection fraction.²²

An acute infectious or septic process can raise troponin levels in 43% to 85% of patients.^22,24 Troponin biomarkers can assist in predicting myocardial injury and events after surgery with nearly absolute myocardial tissue specificity.²⁰ Cardiovascular involvement caused by myocardial injury–related sepsis is observed in up to 70% of patients in the ICU for these reasons.²³ Therefore, providers should consider measuring troponin biomarkers during such infectious and septic processes, as this team did for the case patient. The providers were able to diagnose his AMI early and institute appropriate treatment measures to avoid extensive myocardial tissue damage.

Several studies have already demonstrated a correlation between pneumococcal pneumonia and an increased risk for AMI, and the same mechanisms are presumed responsible for any severe acute infectious state.²¹ More research is needed to understand the pathophysiology of AMI in sepsis and acute systemic infections.²³

OUTCOME FOR THE CASE PATIENT

On postoperative day 2, the patient’s vital signs and lab results were normal. Additional lab results included an A1C of 5.2%. His ECG showed a resolving ST-elevation myocardial infarction (STEMI). The surgical wound had initiation of early granulation tissue without any further signs of necrosis.

A postoperative acute STEMI was unexpected in this patient, as his only risk factors included being male, mild hypertension, obesity, and tobacco use. At the time of his initial elevated troponin level, he had no cardiac symptoms or ECG changes. This initial high troponin level may have been stress-induced from the acute infectious process, and his acute inferior wall STEMI may have been secondary to a transient thrombotic event. The STEMI may then have resolved on its own during the cardiac catheterization with the administration of heparin, IV fluids, blood products, aspirin, or dye infiltration, thus enhancing reperfusion of the coronary artery system.

The final tissue culture showed MRSA. Given his job and his history of a genitourinary procedure, as well as the less fulminant form of disease and relatively quick recovery, it was likely HA-MRSA (rather than CA-MRSA). Only clindamycin was used for treatment.

The wound continued to have decreasing erythema, a reduction in tenderness, and evidence of viable, pink granulation tissue. HIV testing was not completed during his admission. The remainder of the patient’s hospital course was unremarkable, and he was discharged home with wound care, urology, and cardiology follow-up services.

CONCLUSION

Multiple factors contribute to a delayed or mistaken diagnosis of FG; it may be overlooked in the initial working diagnoses because of its low incidence and manifestations similar to those of other soft-tissue infections (eg, cellulitis, scrotal abscess). The cutaneous signs of FG often lag behind the disease manifestation, with minimal or no external presence while extensive internal tissue destruction is occurring. Constant review of symptoms is required when treating patients with soft-tissue infections, and early signs—such as pain out of proportion to physical findings—should prompt a clinician to include FG in the differential.

Early diagnosis with prompt debridement and antibiotic therapy are crucial to patient survival. Detecting FG within the first 24 hours is critical. Further differentiation between CA-MRSA and HA-MRSA can assist in patient recovery and survival by guiding appropriate antibiotic therapy. Perioperative risk assessment and serial troponin biomarkers may identify patients in need of intensive monitoring and management postoperatively to avoid an AMI, since patients may not experience ischemic symptoms.

IN THIS ARTICLE

• Lab values for case patient
• Differential diagnoses
• Case outcome

A 32-year-old man presents to the urgent care center at a community hospital with severe scrotal pain and swelling of five days’ duration. What began as mild left scrotal discomfort is now causing increasing pain, swelling, hematuria, dysuria, low-grade fever, and nausea, prompting him to seek medical attention.

The patient, who is a pipefitter in a hospital, was at work when his symptoms began. He denies any history of scrotal trauma, and his review of systems is otherwise unremarkable. His medical history is significant for mild hypertension and morbid obesity, but he is not immunocompromised. Two months ago, he had an excision and repair of a left ureterocele, for which he was treated prophylactically with ciprofloxacin for one week. He has a 3–pack-year history of smoking and consumes three alcoholic beverages per week. He denies illicit drug use and has no report of sexually transmitted infection.

Upon arrival to urgent care, the patient appears to be in moderate distress, with a blood pressure (BP) of 111/79 mm Hg; pulse, 104 beats/min; respiratory rate, 18 breaths/min^-1; temperature, 100.1°F; and SpO₂, 94%. Physical exam reveals left scrotal erythema, severe tenderness upon palpation, marked scrotal edema, and a slight amount of foul-smelling discharge seeping from a pinpoint opening in the left perineum (see Figure 1a). Given his scrotal presentation, he is quickly transferred to a regional emergency department (ED) for a urology consult.

In the ED, lab testing yields significant findings (see Table 1). His ECG demonstrates sinus tachycardia at 126 beats/min without rhythm or ST changes. His urinalysis reveals a cloudy appearance, a protein level of 100 mg/dL, and trace leukocyte esterase.

Urgent CT with contrast is obtained; it shows significant soft-tissue inflammatory changes in the left groin and scrotum that extend into the left thigh. In addition, a collection of fluid is seen in the inferior aspect of the left scrotal wall, indicating a probable abscess. There is no free air or lymphadenopathy.

Given the patient’s worsening condition and his apparent advancement to a systemic inflammatory response syndrome, surgical consult is obtained. He is diagnosed with a scrotal abscess and cellulitis; two blood and two scrotal cultures are obtained, and the patient is empirically started on IV ampicillin and gentamicin.

Two hours later, he has a BP of 122/74 mm Hg; pulse, 112 beats/min; respiratory rate, 20 breaths/min^-1; and temperature, 103.1°F. His genital inflammation has advanced to the perineum and the left lower abdomen. The purulent, bloody, foul-smelling drainage from the opening in the left perineum is increasingly apparent. The patient is taken emergently to surgery for an incision and drainage, along with exploration of the scrotal abscess. During surgery, the patient is discovered to have Fournier’s gangrene.

DISCUSSION

Fournier’s gangrene (FG) is a necrotizing fasciitis of the perineal, perianal, and/or genital areas involving the superficial and deep fascial planes while sparing the deep muscular structures and overlying skin.¹ A rare but potentially fatal disease, FG spreads at a rate of up to 3 cm/h.^2,3

Mortality rates range from 7.5% to 88%, with the highest mortality occurring within the first 96 hours of hospitalization.^1,4-7 Mortality is often related to the onset of sepsis.^4,5 Survival requires early recognition; immediate, aggressive surgical debridement of all necrotic tissue; and concomitant, early administration of appropriate antibiotics.^1,4,5,8 Mortality risk and prognosis are improved in patients younger than 60 with localized disease and no toxicity, along with sterile blood cultures.¹

Risk Factors

FG is most commonly seen in males between the ages of 50 and 70, with a 10:1 male-to-female ratio.^3,9 Impaired immunity typically increases a patient’s susceptibility to FG, with type 2 diabetes having the highest incidence (85% of patients).^1,4,6,8,10 Other conditions that can increase the risk for FG include obesity, alcoholism, cirrhosis, cardiac disease, tobacco use, peripheral vascular disease, malignancy, chronic steroid use, renal insufficiency, IV drug abuse, and HIV.^1,4,6,8,9,11

Trauma frequently initiates the infectious process,with urogenital trauma (eg, placement of urethral instrumentation, surgery, and urinary tract infection) being the main cause of bacterial introduction.^1,3 Localized infection causes the development of an obliterative endarteritis, resulting in subcutaneous vascular ischemia, necrosis, and bacterial proliferation.^3,7,9

Presentation and Diagnosis

Presenting symptoms of FG include intense, abrupt genital pain that is disproportionate to the physical exam findings.⁹ This rapidly escalates to include extreme swelling, erythema, bullae, discolored skin, and tissue crepitus with eventual necrosis.^2,10 Lab results typically show leukocytosis > 18.0 × 10⁹/L.⁴ The testicle and spermatic cord are generally unaffected (as in this patient), due to the anatomic relationship between the various layers of fascia within the scrotum and the anterior abdominal wall, as well as the independent blood supply of the compartmentalized testicular tissue.^1-3

During an exam of the acute scrotum, the differential diagnosis includes cellulitis, scrotal abscess, acute epididymitis, and testicular torsion, with scrotal abscess being most frequently diagnosed (57% of patients).^9,11,12 The distinguishing features of these diagnoses can be found in Table 2. Necrotizing fasciitis in the form of FG tends to be an unexpected, rare finding usually only diagnosed during the surgical draining of an abscess.¹²

CT is the test of choice to detect FG and determine the extent of its spread by identifying subcutaneous air/gas within the involved fascial planes.^10,13 However, an incisional biopsy with culture is needed to confirm the diagnosis.^3,9 Most patients with FG require an average of four surgeries (eg, reconstruction, skin grafting, and possibly colostomy if the infection has entered the peritoneal cavity) in order to eradicate the disease and achieve the best functional and cosmetic outcome.⁴

Etiology

About 83% of FG cases are polymicrobial infections comprised of enterobacter, enterococci, Escherichia coli, group A streptococci, pseudomonas, and clostridium, with symptoms evolving two to four days following the initial insult.^4,7,11,14,15 Monomicrobial infections are much less common, but the symptoms progress even more rapidly.¹⁵ Methicillin-resistant Staphylococcus aureus (MRSA) necrotizing fasciitis infections occur in about 3% of monomicrobial cases.¹² MRSA emerged in the early 2000s as an additional causative pathogen for polymicrobial necrotizing fasciitis infections.^12,14,15 Prior to that time, S aureus strains were almost uniformly susceptible to penicillinase-resistant ß lactams.¹²

A distinction should be made between health care-associated (HA) MRSA and community-acquired (CA) MRSA due to treatment considerations. HA-MRSA infections are contracted through previous health care exposure (within the past year) and are less resistant to treatment.^16,17 In contrast, CA-MRSA, which comprises 29% of MRSA cases, causes infections in previously healthy young patients without prior health care contact within the past year.¹⁶ CA-MRSA strains are more robust than HA-MRSA strains and can cause sepsis and other invasive, rapidly progressive, and possibly life-threatening infections due to the amount of tissue destruction and necrosis.^16,18 Transmission of CA-MRSA is often associated with crowded environments, frequent skin-to-skin contact, compromised skin integrity, contaminated items or surfaces, and lack of cleanliness.¹⁶ Over the years, CA-MRSA has developed resistance to multiple antimicrobials; providers should therefore consider CA-MRSA on initial evaluation of necrotizing infections, to ensure appropriate initiation of treatment.^12,16

CASE CONTINUED

Extensive debridement was completed down to healthy tissue in all affected areas (see Figure 1b). The necrotizing fasciitis had spared the left testicle and spermatic cord, and a colostomy was not required.

The patient’s initial postoperative vital signs were unremarkable, except for his BP (86/54 mm Hg). The patient was taken postoperatively to the surgical intensive care unit (SICU) with the diagnosis of FG. Aggressive IV fluids were administered for resuscitation, and he was closely monitored for increasing sepsis. Metronidazole was added for anaerobic and gram-positive coverage. His postoperative lab results can also be found in Table 1.

His ECG showed a normal sinus rhythm without ST changes, and he denied any cardiac symptoms. His physical exam was significant for mild pallor, dry mucus membranes, and a left scrotal and pelvic packed dressing. He was given two units of packed red blood cells for acute postoperative blood-loss anemia. The preliminary tissue culture results showed gram-positive cocci consistent with a staphylococcal infection; his antibiotics were then changed to IV ampicillin/sulbactam and clindamycin.

Approximately five hours postoperatively, an ECG suddenly showed acute ST elevation in leads II, II, and aVF, with reciprocal changes. The patient was diagnosed with an acute myocardial infarction (AMI). He denied any chest pain, shortness of breath, or diaphoresis. The SICU team initiated aspirin therapy and immediately contacted cardiology for an emergent coronary angiogram.

The angiogram and cardiac catheterization revealed an elevated left ventricular end diastolic (LVED) volume, inferior wall hypokinesis, a low-normal ejection fraction, and a 30% lesion in the first diagonal of his left anterior descending artery. A postprocedure echocardiogram demonstrated left ventricular (LV) ejection fraction of 50%, with LV hypokinesis in the inferior base and mild left atrial enlargement. The patient was started on metoprolol for myocardial protection and recovery.

Complications

Perioperative complications of FG, including AMI, must be considered due to the physiologic stress on the body.¹⁹ Most patients with perioperative AMI after noncardiac surgery do not experience ischemic symptoms.²⁰

Growing evidence suggests the pivotal role of acute inflammation (postoperatively or from infection) as a precipitating event in AMI.^20,21 Chemical mediators, such as inflammatory cytokines, endotoxins, and nitric oxide, may play a role in the development of an AMI.²²

If cardiovascular disease and/or significant cardiovascular risk factors (ie, older age, male, cigarette smoking, cardiac family history, acute kidney injury) are present, the risk for AMI increases in the first two days following surgery.^21,23 Acute infections and sepsis also initiate or increase systemic inflammatory activity via these same chemical mediators.²¹

Most suspected infectious agents also produce coronary artery sheer stress and destabilization of vulnerable plaques, leading to plaque rupture and thrombosis.^19,24 Proinflammatory cytokines promote enhanced platelet activation and contribute to this thrombotic environment.^21,23 Thrombus leads to obstructed coronary blood flow, myocardial ischemia, and finally, infarction.²¹

A reversible myocardial depression, cardiomyopathy, or myocardial ischemia may occur in patients with acute systemic infection or sepsis when the myocardium is functionally and structurally injured by these inflammatory chemical mediators.^19,22-24 Characteristics of such a cardiomyopathy include left ventricle dilation with a low filling pressure, an abnormal increase in LVED volume, and a depressed ejection fraction.²²

An acute infectious or septic process can raise troponin levels in 43% to 85% of patients.^22,24 Troponin biomarkers can assist in predicting myocardial injury and events after surgery with nearly absolute myocardial tissue specificity.²⁰ Cardiovascular involvement caused by myocardial injury–related sepsis is observed in up to 70% of patients in the ICU for these reasons.²³ Therefore, providers should consider measuring troponin biomarkers during such infectious and septic processes, as this team did for the case patient. The providers were able to diagnose his AMI early and institute appropriate treatment measures to avoid extensive myocardial tissue damage.

Several studies have already demonstrated a correlation between pneumococcal pneumonia and an increased risk for AMI, and the same mechanisms are presumed responsible for any severe acute infectious state.²¹ More research is needed to understand the pathophysiology of AMI in sepsis and acute systemic infections.²³

OUTCOME FOR THE CASE PATIENT

On postoperative day 2, the patient’s vital signs and lab results were normal. Additional lab results included an A1C of 5.2%. His ECG showed a resolving ST-elevation myocardial infarction (STEMI). The surgical wound had initiation of early granulation tissue without any further signs of necrosis.

A postoperative acute STEMI was unexpected in this patient, as his only risk factors included being male, mild hypertension, obesity, and tobacco use. At the time of his initial elevated troponin level, he had no cardiac symptoms or ECG changes. This initial high troponin level may have been stress-induced from the acute infectious process, and his acute inferior wall STEMI may have been secondary to a transient thrombotic event. The STEMI may then have resolved on its own during the cardiac catheterization with the administration of heparin, IV fluids, blood products, aspirin, or dye infiltration, thus enhancing reperfusion of the coronary artery system.

The final tissue culture showed MRSA. Given his job and his history of a genitourinary procedure, as well as the less fulminant form of disease and relatively quick recovery, it was likely HA-MRSA (rather than CA-MRSA). Only clindamycin was used for treatment.

The wound continued to have decreasing erythema, a reduction in tenderness, and evidence of viable, pink granulation tissue. HIV testing was not completed during his admission. The remainder of the patient’s hospital course was unremarkable, and he was discharged home with wound care, urology, and cardiology follow-up services.

CONCLUSION

Multiple factors contribute to a delayed or mistaken diagnosis of FG; it may be overlooked in the initial working diagnoses because of its low incidence and manifestations similar to those of other soft-tissue infections (eg, cellulitis, scrotal abscess). The cutaneous signs of FG often lag behind the disease manifestation, with minimal or no external presence while extensive internal tissue destruction is occurring. Constant review of symptoms is required when treating patients with soft-tissue infections, and early signs—such as pain out of proportion to physical findings—should prompt a clinician to include FG in the differential.

Early diagnosis with prompt debridement and antibiotic therapy are crucial to patient survival. Detecting FG within the first 24 hours is critical. Further differentiation between CA-MRSA and HA-MRSA can assist in patient recovery and survival by guiding appropriate antibiotic therapy. Perioperative risk assessment and serial troponin biomarkers may identify patients in need of intensive monitoring and management postoperatively to avoid an AMI, since patients may not experience ischemic symptoms.

Clinical Question: Does triple therapy (long-acting beta₂-agonist, long-acting muscarinic antagonist, and inhaled corticosteroid) reduce exacerbations in patients with symptomatic chronic obstructive pulmonary disease (COPD)?

Background: Guidelines from GOLD and NICE recommend considering a step-up to triple therapy for patients with refractory COPD symptoms or exacerbations. However, it is unknown if this reduces the long term risk of exacerbations.

Study Design: A randomized controlled trial.

Dr. Troy is assistant professor in the University of Kentucky division of hospital medicine.

Clinical Question: Does triple therapy (long-acting beta₂-agonist, long-acting muscarinic antagonist, and inhaled corticosteroid) reduce exacerbations in patients with symptomatic chronic obstructive pulmonary disease (COPD)?

Background: Guidelines from GOLD and NICE recommend considering a step-up to triple therapy for patients with refractory COPD symptoms or exacerbations. However, it is unknown if this reduces the long term risk of exacerbations.

Study Design: A randomized controlled trial.

Dr. Troy is assistant professor in the University of Kentucky division of hospital medicine.

Clinical Question: Does triple therapy (long-acting beta₂-agonist, long-acting muscarinic antagonist, and inhaled corticosteroid) reduce exacerbations in patients with symptomatic chronic obstructive pulmonary disease (COPD)?

Background: Guidelines from GOLD and NICE recommend considering a step-up to triple therapy for patients with refractory COPD symptoms or exacerbations. However, it is unknown if this reduces the long term risk of exacerbations.

Study Design: A randomized controlled trial.

Dr. Troy is assistant professor in the University of Kentucky division of hospital medicine.

The FDA has approved Besponsa (inotuzumab ozogamicin) for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), a rapidly progressing cancer affecting about 6,000 people each year. About 1 in 4 patients affected will die of the disease. 

Inotuzumab ozogamicin is a targeted therapy “thought to work” by binding to B-cell ALL cancer cells that express the CD22 antigen, blocking the growth of cancerous cells. In a study of 326 patients with relapsed or refractory B-cell ALL who had received 1 or 2 prior treatments, 36% of 218 evaluated patients experienced complete remission for a median 8 months. Of the patients who received alternative chemotherapy, 17% experienced complete remission for a median 5 months.

A second drug, Vyxeos ( daunorubicin and cytarabine) liposome injection, is approved for adults with 2 types of acute myeloid leukemia (AML): newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

An estimated 8% to 10% of patients with AML develop t-AML as a complication of chemotherapy or radiation. AML-MRC is characterized by a history of certain blood disorders and other significant mutations within cancer cells. Patients with either disease have a low life expectancy. Vyxeos is a fixed-combination of daunorubicin and cytarabine. It’s the first approved treatment specifically for these patients, says Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.

In a study of 309 patients with newly diagnosed t-AML or AML-MRC, those in the Vyxeos group lived longer: median survival, 9.56 months vs. 5.95 months in the patients who received separate treatments with daunorubicin and cytarabine.The third drug, Idhifa (enasidenib), is approved for adults with relapsed or refractory AML who have a mutation in the IDH2 gene. Idhifa is an isocitrate dehydrogenase-2 inhibitor that blocks several enzymes that promote cell growth.

The drug was studied in a single-arm trial of 199 patients. With a minimum of 6 months of treatment, 19% of patients experienced complete remission for a median of 8.2 months; 4% experienced complete remission with partial hematologic recovery for a median 9.6 months. Of the 157 patients who required blood or platelet transfusions due to AML at the start of the study, 34% no longer did after treatment with Idhifa.

Idhifa is approved for use with a companion diagnostic, the RealTime IDH2 Assay, which is used to detect mutations in the IDH2 gene in blood or bone marrow.

Source:

FDA approves new treatment for adults with relapsed or refractory acute lymphoblastic leukemia [news release]. Silver Spring, MD: U.S. Food & Drug Administration; August 17,2017. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm572131.htm. Accessed August 31, 2017.

FDA approves new targeted treatment for relapsed or refractory acute myeloid leukemia [news release]. Silver Spring, MD: U.S. Food & Drug Administration; August 1, 2017. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm569421.htm. Accessed August 31, 2017.

FDA approves first treatment for certain types of poor-prognosis acute myeloid leukemia [news release]. Silver Spring, MD: U.S. Food & Drug Administration; August 3, 2017. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm569883.htm. Accessed August 31, 2017.

The FDA has approved Besponsa (inotuzumab ozogamicin) for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), a rapidly progressing cancer affecting about 6,000 people each year. About 1 in 4 patients affected will die of the disease. 

Inotuzumab ozogamicin is a targeted therapy “thought to work” by binding to B-cell ALL cancer cells that express the CD22 antigen, blocking the growth of cancerous cells. In a study of 326 patients with relapsed or refractory B-cell ALL who had received 1 or 2 prior treatments, 36% of 218 evaluated patients experienced complete remission for a median 8 months. Of the patients who received alternative chemotherapy, 17% experienced complete remission for a median 5 months.

A second drug, Vyxeos ( daunorubicin and cytarabine) liposome injection, is approved for adults with 2 types of acute myeloid leukemia (AML): newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

An estimated 8% to 10% of patients with AML develop t-AML as a complication of chemotherapy or radiation. AML-MRC is characterized by a history of certain blood disorders and other significant mutations within cancer cells. Patients with either disease have a low life expectancy. Vyxeos is a fixed-combination of daunorubicin and cytarabine. It’s the first approved treatment specifically for these patients, says Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.

In a study of 309 patients with newly diagnosed t-AML or AML-MRC, those in the Vyxeos group lived longer: median survival, 9.56 months vs. 5.95 months in the patients who received separate treatments with daunorubicin and cytarabine.The third drug, Idhifa (enasidenib), is approved for adults with relapsed or refractory AML who have a mutation in the IDH2 gene. Idhifa is an isocitrate dehydrogenase-2 inhibitor that blocks several enzymes that promote cell growth.

The drug was studied in a single-arm trial of 199 patients. With a minimum of 6 months of treatment, 19% of patients experienced complete remission for a median of 8.2 months; 4% experienced complete remission with partial hematologic recovery for a median 9.6 months. Of the 157 patients who required blood or platelet transfusions due to AML at the start of the study, 34% no longer did after treatment with Idhifa.

Idhifa is approved for use with a companion diagnostic, the RealTime IDH2 Assay, which is used to detect mutations in the IDH2 gene in blood or bone marrow.

Source:

FDA approves new treatment for adults with relapsed or refractory acute lymphoblastic leukemia [news release]. Silver Spring, MD: U.S. Food & Drug Administration; August 17,2017. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm572131.htm. Accessed August 31, 2017.

FDA approves new targeted treatment for relapsed or refractory acute myeloid leukemia [news release]. Silver Spring, MD: U.S. Food & Drug Administration; August 1, 2017. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm569421.htm. Accessed August 31, 2017.

FDA approves first treatment for certain types of poor-prognosis acute myeloid leukemia [news release]. Silver Spring, MD: U.S. Food & Drug Administration; August 3, 2017. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm569883.htm. Accessed August 31, 2017.

The FDA has approved Besponsa (inotuzumab ozogamicin) for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), a rapidly progressing cancer affecting about 6,000 people each year. About 1 in 4 patients affected will die of the disease. 

Inotuzumab ozogamicin is a targeted therapy “thought to work” by binding to B-cell ALL cancer cells that express the CD22 antigen, blocking the growth of cancerous cells. In a study of 326 patients with relapsed or refractory B-cell ALL who had received 1 or 2 prior treatments, 36% of 218 evaluated patients experienced complete remission for a median 8 months. Of the patients who received alternative chemotherapy, 17% experienced complete remission for a median 5 months.

A second drug, Vyxeos ( daunorubicin and cytarabine) liposome injection, is approved for adults with 2 types of acute myeloid leukemia (AML): newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

An estimated 8% to 10% of patients with AML develop t-AML as a complication of chemotherapy or radiation. AML-MRC is characterized by a history of certain blood disorders and other significant mutations within cancer cells. Patients with either disease have a low life expectancy. Vyxeos is a fixed-combination of daunorubicin and cytarabine. It’s the first approved treatment specifically for these patients, says Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence.

In a study of 309 patients with newly diagnosed t-AML or AML-MRC, those in the Vyxeos group lived longer: median survival, 9.56 months vs. 5.95 months in the patients who received separate treatments with daunorubicin and cytarabine.The third drug, Idhifa (enasidenib), is approved for adults with relapsed or refractory AML who have a mutation in the IDH2 gene. Idhifa is an isocitrate dehydrogenase-2 inhibitor that blocks several enzymes that promote cell growth.

The drug was studied in a single-arm trial of 199 patients. With a minimum of 6 months of treatment, 19% of patients experienced complete remission for a median of 8.2 months; 4% experienced complete remission with partial hematologic recovery for a median 9.6 months. Of the 157 patients who required blood or platelet transfusions due to AML at the start of the study, 34% no longer did after treatment with Idhifa.

Idhifa is approved for use with a companion diagnostic, the RealTime IDH2 Assay, which is used to detect mutations in the IDH2 gene in blood or bone marrow.

Source:

FDA approves new treatment for adults with relapsed or refractory acute lymphoblastic leukemia [news release]. Silver Spring, MD: U.S. Food & Drug Administration; August 17,2017. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm572131.htm. Accessed August 31, 2017.

FDA approves new targeted treatment for relapsed or refractory acute myeloid leukemia [news release]. Silver Spring, MD: U.S. Food & Drug Administration; August 1, 2017. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm569421.htm. Accessed August 31, 2017.

FDA approves first treatment for certain types of poor-prognosis acute myeloid leukemia [news release]. Silver Spring, MD: U.S. Food & Drug Administration; August 3, 2017. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm569883.htm. Accessed August 31, 2017.

Cardiovascular risk factors, such as diabetes and high blood pressure, increase the risk of dementia. That is not new information, but a long-term funded study by the National Institutes of Health found that not only is diabetes almost as strong a predictor of dementia as the APOE4 gene, but also prehypertension.

The researchers analyzed data on 15,744 participants aged 45 to 64 years in the Atherosclerosis Risk in Communities (ARIC) study. Over 25 years, the participants were examined 4 times, including being given cognitive tests during all but the first and third exams.

Over an average of 23 follow-up years, 1,516 people were diagnosed with dementia. During the time of the first exams, the risk of dementia increased most strongly with age, followed by the presence of APOE4. But as time went on, the link between cardiovascular risk factors and dementia became clearer. A separate study of an ARIC subgroup found that the presence of ≥ 1 vascular risk factor during midlife was associated with higher levels of beta amyloid, a protein that often accumulates in the brains of Alzheimer patients. The relationship was not affected by the presence of the APOE4 gene.

When the researchers reanalyzed the data according to who had a stroke, they found similar results: Diabetes, hypertension, prehypertension, and smoking raised the risk of dementia for people who had a stroke and those who had not.

“Our results contribute to a growing body of evidence linking midlife vascular health to dementia,” said study leader Rebecca Gottesman, MD, PhD, professor of neurology at Johns Hopkins University in Maryland. “These are modifiable risk factors. Our hope is that by addressing these types of factors early, people can reduce the chances that they will suffer from dementia later in life.”

Cardiovascular risk factors, such as diabetes and high blood pressure, increase the risk of dementia. That is not new information, but a long-term funded study by the National Institutes of Health found that not only is diabetes almost as strong a predictor of dementia as the APOE4 gene, but also prehypertension.

The researchers analyzed data on 15,744 participants aged 45 to 64 years in the Atherosclerosis Risk in Communities (ARIC) study. Over 25 years, the participants were examined 4 times, including being given cognitive tests during all but the first and third exams.

Over an average of 23 follow-up years, 1,516 people were diagnosed with dementia. During the time of the first exams, the risk of dementia increased most strongly with age, followed by the presence of APOE4. But as time went on, the link between cardiovascular risk factors and dementia became clearer. A separate study of an ARIC subgroup found that the presence of ≥ 1 vascular risk factor during midlife was associated with higher levels of beta amyloid, a protein that often accumulates in the brains of Alzheimer patients. The relationship was not affected by the presence of the APOE4 gene.

When the researchers reanalyzed the data according to who had a stroke, they found similar results: Diabetes, hypertension, prehypertension, and smoking raised the risk of dementia for people who had a stroke and those who had not.

“Our results contribute to a growing body of evidence linking midlife vascular health to dementia,” said study leader Rebecca Gottesman, MD, PhD, professor of neurology at Johns Hopkins University in Maryland. “These are modifiable risk factors. Our hope is that by addressing these types of factors early, people can reduce the chances that they will suffer from dementia later in life.”

Cardiovascular risk factors, such as diabetes and high blood pressure, increase the risk of dementia. That is not new information, but a long-term funded study by the National Institutes of Health found that not only is diabetes almost as strong a predictor of dementia as the APOE4 gene, but also prehypertension.

The researchers analyzed data on 15,744 participants aged 45 to 64 years in the Atherosclerosis Risk in Communities (ARIC) study. Over 25 years, the participants were examined 4 times, including being given cognitive tests during all but the first and third exams.

Over an average of 23 follow-up years, 1,516 people were diagnosed with dementia. During the time of the first exams, the risk of dementia increased most strongly with age, followed by the presence of APOE4. But as time went on, the link between cardiovascular risk factors and dementia became clearer. A separate study of an ARIC subgroup found that the presence of ≥ 1 vascular risk factor during midlife was associated with higher levels of beta amyloid, a protein that often accumulates in the brains of Alzheimer patients. The relationship was not affected by the presence of the APOE4 gene.

When the researchers reanalyzed the data according to who had a stroke, they found similar results: Diabetes, hypertension, prehypertension, and smoking raised the risk of dementia for people who had a stroke and those who had not.

“Our results contribute to a growing body of evidence linking midlife vascular health to dementia,” said study leader Rebecca Gottesman, MD, PhD, professor of neurology at Johns Hopkins University in Maryland. “These are modifiable risk factors. Our hope is that by addressing these types of factors early, people can reduce the chances that they will suffer from dementia later in life.”

Images courtesy of Jonathan B. Grimm

Chemists have reported the creation of new fluorescent dyes that can be used in cells, tissues, and animals.

The scientists found that swapping out specific chemical building blocks in fluorescent molecules called rhodamines can generate dyes of nearly every color.

Such an expanded palette of dyes could help researchers better illuminate the inner workings of cells, said Luke Lavis, PhD, of the Howard Hughes Medical Institute’s Janelia Research Campus in Ashburn, Virginia.

Dr Lavis and his colleagues used their new dyes to light up cell nuclei, label living brain tissue from fruit fly larvae, and highlight visual cortex neurons in mice that had tiny glass windows fitted into their skulls.

The team detailed their work in Nature Methods.

Dr Lavis noted that scientists used to concoct different dyes mostly by trial and error.

“Now, we’ve figured out the rules, and we can make almost any color,” he said.

Dr Lavis’s team focused their research on rhodamines because they’re especially bright and cell-permeable.

Chemists had been working with rhodamines for more than 100 years but created only a few dozen colors. Most were similar shades ranging from green to orange.

That’s because, until recently, making new rhodamines wasn’t easy. Scientists still used techniques from the earliest days of chemistry, boiling chemical ingredients in sulfuric acid. This forces the molecules to link together in a condensation reaction.

Mixing in different building blocks could yield new and unusual dyes, but ingredients had to be tough enough to survive the boiling acid bath. This didn’t leave a lot of options.

In 2011, Dr Lavis’s team developed a new way to tinker with rhodamines’ structure, under milder conditions. Using a reaction sparked by the metal palladium, the scientists could skip the acid step and construct dyes with more complicated building blocks than had been used before.

Four years later, the team revealed the Janelia Fluor dyes. The secret behind these dyes is a tiny, square-shaped appendage called an azetidine ring.

The scientists found that incorporating 4-membered azetidine rings into classic fluorophore structures elicited “substantial increases in brightness and photostability.” In fact, the Janelia Fluor dyes are up to 50 times brighter than other dyes.

Now, Dr Lavis’s group has figured out how to fine-tune their fluorescent dyes by tweaking rhodamines’ structure even further. The team showed that incorporating 3-substituted azetidine groups allowed them to tune spectral and chemical properties with “unprecedented precision.”

The dyes can be synthesized in a single step with inexpensive ingredients. The low cost has allowed Dr Lavis and his colleagues to share their work, shipping thousands of vials to hundreds of labs around the world.

Images courtesy of Jonathan B. Grimm

Chemists have reported the creation of new fluorescent dyes that can be used in cells, tissues, and animals.

The scientists found that swapping out specific chemical building blocks in fluorescent molecules called rhodamines can generate dyes of nearly every color.

Such an expanded palette of dyes could help researchers better illuminate the inner workings of cells, said Luke Lavis, PhD, of the Howard Hughes Medical Institute’s Janelia Research Campus in Ashburn, Virginia.

Dr Lavis and his colleagues used their new dyes to light up cell nuclei, label living brain tissue from fruit fly larvae, and highlight visual cortex neurons in mice that had tiny glass windows fitted into their skulls.

The team detailed their work in Nature Methods.

Dr Lavis noted that scientists used to concoct different dyes mostly by trial and error.

“Now, we’ve figured out the rules, and we can make almost any color,” he said.

Dr Lavis’s team focused their research on rhodamines because they’re especially bright and cell-permeable.

Chemists had been working with rhodamines for more than 100 years but created only a few dozen colors. Most were similar shades ranging from green to orange.

That’s because, until recently, making new rhodamines wasn’t easy. Scientists still used techniques from the earliest days of chemistry, boiling chemical ingredients in sulfuric acid. This forces the molecules to link together in a condensation reaction.

Mixing in different building blocks could yield new and unusual dyes, but ingredients had to be tough enough to survive the boiling acid bath. This didn’t leave a lot of options.

In 2011, Dr Lavis’s team developed a new way to tinker with rhodamines’ structure, under milder conditions. Using a reaction sparked by the metal palladium, the scientists could skip the acid step and construct dyes with more complicated building blocks than had been used before.

Four years later, the team revealed the Janelia Fluor dyes. The secret behind these dyes is a tiny, square-shaped appendage called an azetidine ring.

The scientists found that incorporating 4-membered azetidine rings into classic fluorophore structures elicited “substantial increases in brightness and photostability.” In fact, the Janelia Fluor dyes are up to 50 times brighter than other dyes.

Now, Dr Lavis’s group has figured out how to fine-tune their fluorescent dyes by tweaking rhodamines’ structure even further. The team showed that incorporating 3-substituted azetidine groups allowed them to tune spectral and chemical properties with “unprecedented precision.”

The dyes can be synthesized in a single step with inexpensive ingredients. The low cost has allowed Dr Lavis and his colleagues to share their work, shipping thousands of vials to hundreds of labs around the world.

Images courtesy of Jonathan B. Grimm

Chemists have reported the creation of new fluorescent dyes that can be used in cells, tissues, and animals.

The scientists found that swapping out specific chemical building blocks in fluorescent molecules called rhodamines can generate dyes of nearly every color.

Such an expanded palette of dyes could help researchers better illuminate the inner workings of cells, said Luke Lavis, PhD, of the Howard Hughes Medical Institute’s Janelia Research Campus in Ashburn, Virginia.

Dr Lavis and his colleagues used their new dyes to light up cell nuclei, label living brain tissue from fruit fly larvae, and highlight visual cortex neurons in mice that had tiny glass windows fitted into their skulls.

The team detailed their work in Nature Methods.

Dr Lavis noted that scientists used to concoct different dyes mostly by trial and error.

“Now, we’ve figured out the rules, and we can make almost any color,” he said.

Dr Lavis’s team focused their research on rhodamines because they’re especially bright and cell-permeable.

Chemists had been working with rhodamines for more than 100 years but created only a few dozen colors. Most were similar shades ranging from green to orange.

That’s because, until recently, making new rhodamines wasn’t easy. Scientists still used techniques from the earliest days of chemistry, boiling chemical ingredients in sulfuric acid. This forces the molecules to link together in a condensation reaction.

Mixing in different building blocks could yield new and unusual dyes, but ingredients had to be tough enough to survive the boiling acid bath. This didn’t leave a lot of options.

In 2011, Dr Lavis’s team developed a new way to tinker with rhodamines’ structure, under milder conditions. Using a reaction sparked by the metal palladium, the scientists could skip the acid step and construct dyes with more complicated building blocks than had been used before.

Four years later, the team revealed the Janelia Fluor dyes. The secret behind these dyes is a tiny, square-shaped appendage called an azetidine ring.

The scientists found that incorporating 4-membered azetidine rings into classic fluorophore structures elicited “substantial increases in brightness and photostability.” In fact, the Janelia Fluor dyes are up to 50 times brighter than other dyes.

Now, Dr Lavis’s group has figured out how to fine-tune their fluorescent dyes by tweaking rhodamines’ structure even further. The team showed that incorporating 3-substituted azetidine groups allowed them to tune spectral and chemical properties with “unprecedented precision.”

The dyes can be synthesized in a single step with inexpensive ingredients. The low cost has allowed Dr Lavis and his colleagues to share their work, shipping thousands of vials to hundreds of labs around the world.