Cutis

To the Editor:

A 56-year-old man with a history of opioid abuse and splenectomy decades prior due to a motor vehicle accident was brought to an outside emergency department with confusion, slurred speech, and difficulty breathing. Over the next few days, he became febrile and hypotensive, requiring vasopressors. Clinical laboratory testing revealed a urine drug screen positive for opioids and a low platelet count in the setting of a rapidly evolving retiform purpuric rash.

The patient was transferred to our institution 6 days after initial presentation with primary diagnoses of septic shock with multiorgan failure and disseminated intravascular coagulation (DIC). Blood cultures were positive for gram-negative rods. After several days of broad-spectrum antibiotics and supportive care, cultures were reported as positive for Capnocytophaga canimorsus. Upon further questioning, the patient’s wife reported that the couple had a new puppy and that the patient often allowed the dog to bite him playfully and lick abrasions on his hands and legs. He had not received medical treatment for any of the dog’s bites.

On initial examination at the time of transfer, the patient’s skin was remarkable for diffuse areas of stellate and retiform purpura with dusky centers and necrosis of the nasal tip and earlobes. Both hands were purpuric, with necrosis of the fingertips (Figure 1A). The flank was marked by large areas of full-thickness sloughing of the skin (Figure 1B). The lower extremities were edematous, with some areas of stellate purpura and numerous large bullae that drained straw-colored fluid (Figure 1C). Lower extremity pulses were found with Doppler ultrasonography.

Given the presence of rapidly developing retiform purpura in the clinical context of severe sepsis, purpura fulminans (PF) was the primary consideration in the differential diagnosis. Levamisole-induced necrosis syndrome also was considered because of necrosis of the ears and nose as well as the history of substance use; however, the patient was not known to have a history of cocaine abuse, and a test of antineutrophil cytoplasmic antibody was negative.

A punch biopsy of the abdomen revealed intravascular thrombi with epidermal and sweat gland necrosis, consistent with PF (Figure 2). Gram, Giemsa, and Gomori methenamine-silver stains were negative for organisms. Tissue culture remained negative. Repeat blood cultures demonstrated Candida parapsilosis fungemia. Respiratory culture was positive for budding yeast.

The patient was treated with antimicrobials, intravenous argatroban, and subcutaneous heparin. Purpura and bullae on the trunk slowly resolved with systemic therapy and wound care with petrolatum and nonadherent dressings. However, lesions on the nasal tip, all fingers of both hands, and several toes evolved into dry gangrene. The hospital course was complicated by renal failure requiring continuous renal replacement therapy; respiratory failure requiring ventilator support; and elevated levels of liver enzymes, consistent with involvement of the hepatic microvasculature.

The patient was in the medical intensive care unit at our institution for 2 weeks and was transferred to a burn center for specialized wound care. At transfer, he was still on a ventilator and receiving continuous renal replacement therapy. Subsequently, the patient required a left above-the-knee amputation, right below-the-knee amputation, and amputation of several digits of the upper extremities. In the months after the amputations, he required multiple stump revisions and experienced surgical site infections that complicated healing.

Purpura fulminans is an uncommon syndrome characterized by intravascular thrombosis and hemorrhagic infarction of the skin. The condition commonly is associated with septic shock, causing vascular collapse and DIC. It often develops rapidly.

Because of associated high mortality, it is important to differentiate PF from other causes of cutaneous retiform purpura, including other causes of thrombosis and large vessel vasculitis. Leading causes of PF include infection and hereditary or acquired deficiency of protein C, protein S, or antithrombin III. Regardless of cause, biopsy results demonstrate vascular thrombosis out of proportion to vasculitis. The mortality rate is 42% to 50%. The incidence of postinfectious sepsis sequelae in PF is higher than in survivors of sepsis only, especially amputation.^1-3 Most patients do not die from complications of sepsis but from sequelae of the hypercoagulable and prothrombotic state associated with PF.⁴ Hemorrhagic infarction can affect the kidneys, brain, lungs, heart, eyes, and adrenal glands (ie, necrosis, namely Waterhouse-Friderichsen syndrome).⁵

The most common infectious cause of PF is sepsis secondary to Neisseria meningitidis, with as many as 25% of infected patients developing PF.⁶Streptococcus pneumoniae is another common cause. Other important causative organisms include Streptococcus pyogenes; Staphylococcus aureus (in the setting of intravenous substance use); Klebsiella oxytoca; Klebsiella aerogenes; rickettsial organisms; and viruses, including cytomegalovirus and varicella-zoster virus.^2,7-13 Two earlier cases associated with Capnocytophaga were characterized by concomitant renal failure, metabolic acidosis, hemolytic anemia, and DIC.¹⁴

It is estimated that Capnocytophaga causes 11% to 46% of all cases of sepsis¹⁵; sepsis resulting from Capnocytophaga has extremely poor outcomes, with mortality reaching as high as 60%. The organism is part of the normal oral flora of cats and dogs, and a bite (less often, a scratch) is the cause of most Capnocytophaga infections. The clinical spectrum of C canimorsus infection associated with dog saliva exposure more commonly includes cellulitis at or around the site of inoculation, meningitis, and endocarditis.¹⁶

Although patients affected by PF can be young and healthy, several risk factors for PF have been identified^2,6,16: asplenia, an immunocompromised state, systemic corticosteroid use, cirrhosis, and alcoholism. Asplenic patients have been shown to be particularly susceptible to systemic Capnocytophaga infection; when bitten by a dog, they should be treated with prophylactic antibiotics to cover Capnocytophaga.¹⁷ Immunocompetent patients rarely develop severe infection with Capnocytophaga.^16,18,19 The complement system in particular is critically important in defending against C canimorsus.²⁰

The underlying pathophysiology of acute infectious PF is multifactorial, encompassing increased expression of procoagulant tissue factor by monocytes and endothelial cells in the presence of bacterial pathogens. Dysfunction of protein C, an anticoagulant component of the coagulation cascade, often is cited as a crucial derangement leading to the development of a prothrombotic state in acute infectious PF.²¹ Serum protein S and antithrombin deficiency also can play a role.²² Specific in vitro examination of C canimorsus has revealed a protease that catalyzes N-terminal cleavage of procoagulant factor X, resulting in loss of function.¹⁵

Retiform purpura is a hallmark feature of PF, often beginning as nonblanching erythema with localized edema and petechiae before evolving into the characteristic stellate lesions with hemorrhagic bullae and subsequent necrosis.²³ Pathologic examination reveals microthrombi involving arterioles and smaller vessels.²⁴ There typically is laboratory evidence of DIC in PF, including elevated prothrombin time and partial thromboplastin time, thrombocytopenia, elevated D-dimer, and a decreased fibrinogen level.^6,23

Capnocytophaga bacteria are challenging to grow on standard culture media. Optimal media for growth include 5% sheep’s blood and chocolate agar.¹⁶ Polymerase chain reaction can identify Capnocytophaga; in cases in which blood culture does not produce growth, 16S ribosomal RNA gene sequencing of tissue from skin biopsy has identified the pathogen.²⁵

Some Capnocytophaga isolates have been shown to produce beta-lactamase; individual strains can be resistant to penicillins, cephalosporins, and imipenem.²⁶ Factors associated with an increased risk for death include decreased leukocyte and platelet counts and an increased level of arterial lactate.²⁷

Empiric antibiotic therapy for Capnocytophaga sepsis should include a beta-lactam and beta-lactamase inhibitor, such as piperacillin-tazobactam. Management of DIC can include therapeutic heparin or low-molecular-weight heparin and prophylactic platelet transfusion to maintain a pre-established value.^28-30 Debridement should be conservative; it is important to wait for definite delineation between viable and necrotic tissue,³¹ which might take several months.³² Human skin allografts, in addition to artificial skin, are utilized as supplemental therapy for more rapid wound closure after removal of necrotic tissue.^33,34 Hyperoxygenated fatty acids have been noted to aid in more rapid wound healing in infants with PF.³⁵

Fresh frozen plasma is one method to replace missing factors, but it contains little protein C.³⁶ Outcomes with recombinant human activated protein C (drotrecogin alfa) are mixed, and studies have shown no benefit in reducing the risk for death.^37,38 Protein C concentrate has shown therapeutic benefit in some case reports and small retrospective studies.⁴ In one case report, protein C concentrate and heparin were utilized in combination with antithrombin III.²¹

Hyperbaric O₂ might be of benefit when initiated within 5 days after onset of PF. However, hyperbaric O₂ does carry risk; O₂ toxicity, barotrauma, and barriers to timely resuscitation when the patient is inside the pressurized chamber can occur.²

There is a single report of successful use of the vasodilator iloprost for meningococcal PF without need for surgical intervention; the team also utilized topical nitroglycerin patches on the fingers to avoid digital amputation.³⁹ Epoprostenol, tissue plasminogen activator, and antithrombin have been utilized in cases of extensive PF. Fibrinolytic therapy might have some utility, but only in a setting of malignancy-associated DIC.⁴⁰

Treatment of acute infectious PF lacks a high level of evidence. Options include replacement of anticoagulant factors, anticoagulant therapy, hyperbaric O₂, topical and systemic vasodilators, and, in the setting of underlying cancer, fibrinolytics. Even with therapy, prognosis is guarded.

To the Editor:

A 56-year-old man with a history of opioid abuse and splenectomy decades prior due to a motor vehicle accident was brought to an outside emergency department with confusion, slurred speech, and difficulty breathing. Over the next few days, he became febrile and hypotensive, requiring vasopressors. Clinical laboratory testing revealed a urine drug screen positive for opioids and a low platelet count in the setting of a rapidly evolving retiform purpuric rash.

The patient was transferred to our institution 6 days after initial presentation with primary diagnoses of septic shock with multiorgan failure and disseminated intravascular coagulation (DIC). Blood cultures were positive for gram-negative rods. After several days of broad-spectrum antibiotics and supportive care, cultures were reported as positive for Capnocytophaga canimorsus. Upon further questioning, the patient’s wife reported that the couple had a new puppy and that the patient often allowed the dog to bite him playfully and lick abrasions on his hands and legs. He had not received medical treatment for any of the dog’s bites.

On initial examination at the time of transfer, the patient’s skin was remarkable for diffuse areas of stellate and retiform purpura with dusky centers and necrosis of the nasal tip and earlobes. Both hands were purpuric, with necrosis of the fingertips (Figure 1A). The flank was marked by large areas of full-thickness sloughing of the skin (Figure 1B). The lower extremities were edematous, with some areas of stellate purpura and numerous large bullae that drained straw-colored fluid (Figure 1C). Lower extremity pulses were found with Doppler ultrasonography.

Given the presence of rapidly developing retiform purpura in the clinical context of severe sepsis, purpura fulminans (PF) was the primary consideration in the differential diagnosis. Levamisole-induced necrosis syndrome also was considered because of necrosis of the ears and nose as well as the history of substance use; however, the patient was not known to have a history of cocaine abuse, and a test of antineutrophil cytoplasmic antibody was negative.

A punch biopsy of the abdomen revealed intravascular thrombi with epidermal and sweat gland necrosis, consistent with PF (Figure 2). Gram, Giemsa, and Gomori methenamine-silver stains were negative for organisms. Tissue culture remained negative. Repeat blood cultures demonstrated Candida parapsilosis fungemia. Respiratory culture was positive for budding yeast.

The patient was treated with antimicrobials, intravenous argatroban, and subcutaneous heparin. Purpura and bullae on the trunk slowly resolved with systemic therapy and wound care with petrolatum and nonadherent dressings. However, lesions on the nasal tip, all fingers of both hands, and several toes evolved into dry gangrene. The hospital course was complicated by renal failure requiring continuous renal replacement therapy; respiratory failure requiring ventilator support; and elevated levels of liver enzymes, consistent with involvement of the hepatic microvasculature.

The patient was in the medical intensive care unit at our institution for 2 weeks and was transferred to a burn center for specialized wound care. At transfer, he was still on a ventilator and receiving continuous renal replacement therapy. Subsequently, the patient required a left above-the-knee amputation, right below-the-knee amputation, and amputation of several digits of the upper extremities. In the months after the amputations, he required multiple stump revisions and experienced surgical site infections that complicated healing.

Purpura fulminans is an uncommon syndrome characterized by intravascular thrombosis and hemorrhagic infarction of the skin. The condition commonly is associated with septic shock, causing vascular collapse and DIC. It often develops rapidly.

Because of associated high mortality, it is important to differentiate PF from other causes of cutaneous retiform purpura, including other causes of thrombosis and large vessel vasculitis. Leading causes of PF include infection and hereditary or acquired deficiency of protein C, protein S, or antithrombin III. Regardless of cause, biopsy results demonstrate vascular thrombosis out of proportion to vasculitis. The mortality rate is 42% to 50%. The incidence of postinfectious sepsis sequelae in PF is higher than in survivors of sepsis only, especially amputation.^1-3 Most patients do not die from complications of sepsis but from sequelae of the hypercoagulable and prothrombotic state associated with PF.⁴ Hemorrhagic infarction can affect the kidneys, brain, lungs, heart, eyes, and adrenal glands (ie, necrosis, namely Waterhouse-Friderichsen syndrome).⁵

The most common infectious cause of PF is sepsis secondary to Neisseria meningitidis, with as many as 25% of infected patients developing PF.⁶Streptococcus pneumoniae is another common cause. Other important causative organisms include Streptococcus pyogenes; Staphylococcus aureus (in the setting of intravenous substance use); Klebsiella oxytoca; Klebsiella aerogenes; rickettsial organisms; and viruses, including cytomegalovirus and varicella-zoster virus.^2,7-13 Two earlier cases associated with Capnocytophaga were characterized by concomitant renal failure, metabolic acidosis, hemolytic anemia, and DIC.¹⁴

It is estimated that Capnocytophaga causes 11% to 46% of all cases of sepsis¹⁵; sepsis resulting from Capnocytophaga has extremely poor outcomes, with mortality reaching as high as 60%. The organism is part of the normal oral flora of cats and dogs, and a bite (less often, a scratch) is the cause of most Capnocytophaga infections. The clinical spectrum of C canimorsus infection associated with dog saliva exposure more commonly includes cellulitis at or around the site of inoculation, meningitis, and endocarditis.¹⁶

Although patients affected by PF can be young and healthy, several risk factors for PF have been identified^2,6,16: asplenia, an immunocompromised state, systemic corticosteroid use, cirrhosis, and alcoholism. Asplenic patients have been shown to be particularly susceptible to systemic Capnocytophaga infection; when bitten by a dog, they should be treated with prophylactic antibiotics to cover Capnocytophaga.¹⁷ Immunocompetent patients rarely develop severe infection with Capnocytophaga.^16,18,19 The complement system in particular is critically important in defending against C canimorsus.²⁰

The underlying pathophysiology of acute infectious PF is multifactorial, encompassing increased expression of procoagulant tissue factor by monocytes and endothelial cells in the presence of bacterial pathogens. Dysfunction of protein C, an anticoagulant component of the coagulation cascade, often is cited as a crucial derangement leading to the development of a prothrombotic state in acute infectious PF.²¹ Serum protein S and antithrombin deficiency also can play a role.²² Specific in vitro examination of C canimorsus has revealed a protease that catalyzes N-terminal cleavage of procoagulant factor X, resulting in loss of function.¹⁵

Retiform purpura is a hallmark feature of PF, often beginning as nonblanching erythema with localized edema and petechiae before evolving into the characteristic stellate lesions with hemorrhagic bullae and subsequent necrosis.²³ Pathologic examination reveals microthrombi involving arterioles and smaller vessels.²⁴ There typically is laboratory evidence of DIC in PF, including elevated prothrombin time and partial thromboplastin time, thrombocytopenia, elevated D-dimer, and a decreased fibrinogen level.^6,23

Capnocytophaga bacteria are challenging to grow on standard culture media. Optimal media for growth include 5% sheep’s blood and chocolate agar.¹⁶ Polymerase chain reaction can identify Capnocytophaga; in cases in which blood culture does not produce growth, 16S ribosomal RNA gene sequencing of tissue from skin biopsy has identified the pathogen.²⁵

Some Capnocytophaga isolates have been shown to produce beta-lactamase; individual strains can be resistant to penicillins, cephalosporins, and imipenem.²⁶ Factors associated with an increased risk for death include decreased leukocyte and platelet counts and an increased level of arterial lactate.²⁷

Empiric antibiotic therapy for Capnocytophaga sepsis should include a beta-lactam and beta-lactamase inhibitor, such as piperacillin-tazobactam. Management of DIC can include therapeutic heparin or low-molecular-weight heparin and prophylactic platelet transfusion to maintain a pre-established value.^28-30 Debridement should be conservative; it is important to wait for definite delineation between viable and necrotic tissue,³¹ which might take several months.³² Human skin allografts, in addition to artificial skin, are utilized as supplemental therapy for more rapid wound closure after removal of necrotic tissue.^33,34 Hyperoxygenated fatty acids have been noted to aid in more rapid wound healing in infants with PF.³⁵

Fresh frozen plasma is one method to replace missing factors, but it contains little protein C.³⁶ Outcomes with recombinant human activated protein C (drotrecogin alfa) are mixed, and studies have shown no benefit in reducing the risk for death.^37,38 Protein C concentrate has shown therapeutic benefit in some case reports and small retrospective studies.⁴ In one case report, protein C concentrate and heparin were utilized in combination with antithrombin III.²¹

Hyperbaric O₂ might be of benefit when initiated within 5 days after onset of PF. However, hyperbaric O₂ does carry risk; O₂ toxicity, barotrauma, and barriers to timely resuscitation when the patient is inside the pressurized chamber can occur.²

There is a single report of successful use of the vasodilator iloprost for meningococcal PF without need for surgical intervention; the team also utilized topical nitroglycerin patches on the fingers to avoid digital amputation.³⁹ Epoprostenol, tissue plasminogen activator, and antithrombin have been utilized in cases of extensive PF. Fibrinolytic therapy might have some utility, but only in a setting of malignancy-associated DIC.⁴⁰

Treatment of acute infectious PF lacks a high level of evidence. Options include replacement of anticoagulant factors, anticoagulant therapy, hyperbaric O₂, topical and systemic vasodilators, and, in the setting of underlying cancer, fibrinolytics. Even with therapy, prognosis is guarded.

To the Editor:

A 56-year-old man with a history of opioid abuse and splenectomy decades prior due to a motor vehicle accident was brought to an outside emergency department with confusion, slurred speech, and difficulty breathing. Over the next few days, he became febrile and hypotensive, requiring vasopressors. Clinical laboratory testing revealed a urine drug screen positive for opioids and a low platelet count in the setting of a rapidly evolving retiform purpuric rash.

The patient was transferred to our institution 6 days after initial presentation with primary diagnoses of septic shock with multiorgan failure and disseminated intravascular coagulation (DIC). Blood cultures were positive for gram-negative rods. After several days of broad-spectrum antibiotics and supportive care, cultures were reported as positive for Capnocytophaga canimorsus. Upon further questioning, the patient’s wife reported that the couple had a new puppy and that the patient often allowed the dog to bite him playfully and lick abrasions on his hands and legs. He had not received medical treatment for any of the dog’s bites.

On initial examination at the time of transfer, the patient’s skin was remarkable for diffuse areas of stellate and retiform purpura with dusky centers and necrosis of the nasal tip and earlobes. Both hands were purpuric, with necrosis of the fingertips (Figure 1A). The flank was marked by large areas of full-thickness sloughing of the skin (Figure 1B). The lower extremities were edematous, with some areas of stellate purpura and numerous large bullae that drained straw-colored fluid (Figure 1C). Lower extremity pulses were found with Doppler ultrasonography.

Given the presence of rapidly developing retiform purpura in the clinical context of severe sepsis, purpura fulminans (PF) was the primary consideration in the differential diagnosis. Levamisole-induced necrosis syndrome also was considered because of necrosis of the ears and nose as well as the history of substance use; however, the patient was not known to have a history of cocaine abuse, and a test of antineutrophil cytoplasmic antibody was negative.

A punch biopsy of the abdomen revealed intravascular thrombi with epidermal and sweat gland necrosis, consistent with PF (Figure 2). Gram, Giemsa, and Gomori methenamine-silver stains were negative for organisms. Tissue culture remained negative. Repeat blood cultures demonstrated Candida parapsilosis fungemia. Respiratory culture was positive for budding yeast.

The patient was treated with antimicrobials, intravenous argatroban, and subcutaneous heparin. Purpura and bullae on the trunk slowly resolved with systemic therapy and wound care with petrolatum and nonadherent dressings. However, lesions on the nasal tip, all fingers of both hands, and several toes evolved into dry gangrene. The hospital course was complicated by renal failure requiring continuous renal replacement therapy; respiratory failure requiring ventilator support; and elevated levels of liver enzymes, consistent with involvement of the hepatic microvasculature.

The patient was in the medical intensive care unit at our institution for 2 weeks and was transferred to a burn center for specialized wound care. At transfer, he was still on a ventilator and receiving continuous renal replacement therapy. Subsequently, the patient required a left above-the-knee amputation, right below-the-knee amputation, and amputation of several digits of the upper extremities. In the months after the amputations, he required multiple stump revisions and experienced surgical site infections that complicated healing.

Purpura fulminans is an uncommon syndrome characterized by intravascular thrombosis and hemorrhagic infarction of the skin. The condition commonly is associated with septic shock, causing vascular collapse and DIC. It often develops rapidly.

Because of associated high mortality, it is important to differentiate PF from other causes of cutaneous retiform purpura, including other causes of thrombosis and large vessel vasculitis. Leading causes of PF include infection and hereditary or acquired deficiency of protein C, protein S, or antithrombin III. Regardless of cause, biopsy results demonstrate vascular thrombosis out of proportion to vasculitis. The mortality rate is 42% to 50%. The incidence of postinfectious sepsis sequelae in PF is higher than in survivors of sepsis only, especially amputation.^1-3 Most patients do not die from complications of sepsis but from sequelae of the hypercoagulable and prothrombotic state associated with PF.⁴ Hemorrhagic infarction can affect the kidneys, brain, lungs, heart, eyes, and adrenal glands (ie, necrosis, namely Waterhouse-Friderichsen syndrome).⁵

The most common infectious cause of PF is sepsis secondary to Neisseria meningitidis, with as many as 25% of infected patients developing PF.⁶Streptococcus pneumoniae is another common cause. Other important causative organisms include Streptococcus pyogenes; Staphylococcus aureus (in the setting of intravenous substance use); Klebsiella oxytoca; Klebsiella aerogenes; rickettsial organisms; and viruses, including cytomegalovirus and varicella-zoster virus.^2,7-13 Two earlier cases associated with Capnocytophaga were characterized by concomitant renal failure, metabolic acidosis, hemolytic anemia, and DIC.¹⁴

It is estimated that Capnocytophaga causes 11% to 46% of all cases of sepsis¹⁵; sepsis resulting from Capnocytophaga has extremely poor outcomes, with mortality reaching as high as 60%. The organism is part of the normal oral flora of cats and dogs, and a bite (less often, a scratch) is the cause of most Capnocytophaga infections. The clinical spectrum of C canimorsus infection associated with dog saliva exposure more commonly includes cellulitis at or around the site of inoculation, meningitis, and endocarditis.¹⁶

Although patients affected by PF can be young and healthy, several risk factors for PF have been identified^2,6,16: asplenia, an immunocompromised state, systemic corticosteroid use, cirrhosis, and alcoholism. Asplenic patients have been shown to be particularly susceptible to systemic Capnocytophaga infection; when bitten by a dog, they should be treated with prophylactic antibiotics to cover Capnocytophaga.¹⁷ Immunocompetent patients rarely develop severe infection with Capnocytophaga.^16,18,19 The complement system in particular is critically important in defending against C canimorsus.²⁰

The underlying pathophysiology of acute infectious PF is multifactorial, encompassing increased expression of procoagulant tissue factor by monocytes and endothelial cells in the presence of bacterial pathogens. Dysfunction of protein C, an anticoagulant component of the coagulation cascade, often is cited as a crucial derangement leading to the development of a prothrombotic state in acute infectious PF.²¹ Serum protein S and antithrombin deficiency also can play a role.²² Specific in vitro examination of C canimorsus has revealed a protease that catalyzes N-terminal cleavage of procoagulant factor X, resulting in loss of function.¹⁵

Retiform purpura is a hallmark feature of PF, often beginning as nonblanching erythema with localized edema and petechiae before evolving into the characteristic stellate lesions with hemorrhagic bullae and subsequent necrosis.²³ Pathologic examination reveals microthrombi involving arterioles and smaller vessels.²⁴ There typically is laboratory evidence of DIC in PF, including elevated prothrombin time and partial thromboplastin time, thrombocytopenia, elevated D-dimer, and a decreased fibrinogen level.^6,23

Capnocytophaga bacteria are challenging to grow on standard culture media. Optimal media for growth include 5% sheep’s blood and chocolate agar.¹⁶ Polymerase chain reaction can identify Capnocytophaga; in cases in which blood culture does not produce growth, 16S ribosomal RNA gene sequencing of tissue from skin biopsy has identified the pathogen.²⁵

Some Capnocytophaga isolates have been shown to produce beta-lactamase; individual strains can be resistant to penicillins, cephalosporins, and imipenem.²⁶ Factors associated with an increased risk for death include decreased leukocyte and platelet counts and an increased level of arterial lactate.²⁷

Empiric antibiotic therapy for Capnocytophaga sepsis should include a beta-lactam and beta-lactamase inhibitor, such as piperacillin-tazobactam. Management of DIC can include therapeutic heparin or low-molecular-weight heparin and prophylactic platelet transfusion to maintain a pre-established value.^28-30 Debridement should be conservative; it is important to wait for definite delineation between viable and necrotic tissue,³¹ which might take several months.³² Human skin allografts, in addition to artificial skin, are utilized as supplemental therapy for more rapid wound closure after removal of necrotic tissue.^33,34 Hyperoxygenated fatty acids have been noted to aid in more rapid wound healing in infants with PF.³⁵

Fresh frozen plasma is one method to replace missing factors, but it contains little protein C.³⁶ Outcomes with recombinant human activated protein C (drotrecogin alfa) are mixed, and studies have shown no benefit in reducing the risk for death.^37,38 Protein C concentrate has shown therapeutic benefit in some case reports and small retrospective studies.⁴ In one case report, protein C concentrate and heparin were utilized in combination with antithrombin III.²¹

Hyperbaric O₂ might be of benefit when initiated within 5 days after onset of PF. However, hyperbaric O₂ does carry risk; O₂ toxicity, barotrauma, and barriers to timely resuscitation when the patient is inside the pressurized chamber can occur.²

There is a single report of successful use of the vasodilator iloprost for meningococcal PF without need for surgical intervention; the team also utilized topical nitroglycerin patches on the fingers to avoid digital amputation.³⁹ Epoprostenol, tissue plasminogen activator, and antithrombin have been utilized in cases of extensive PF. Fibrinolytic therapy might have some utility, but only in a setting of malignancy-associated DIC.⁴⁰

Treatment of acute infectious PF lacks a high level of evidence. Options include replacement of anticoagulant factors, anticoagulant therapy, hyperbaric O₂, topical and systemic vasodilators, and, in the setting of underlying cancer, fibrinolytics. Even with therapy, prognosis is guarded.

To the Editor:

Purpura fulminans (PF) is an acute, life-threatening condition characterized by intravascular thrombosis and hemorrhagic necrosis of the skin. It classically presents as retiform purpura with branched or angular purpuric lesions. Purpura fulminans often occurs in the setting of disseminated intravascular coagulation, secondary to sepsis, trauma, malignancy, autoimmune disease, and congenital or acquired protein C or S deficiency, among other abnormalities.¹ Rapid identification and treatment of the underlying cause are mainstays of management. We report a case of PF secondary to Vibrio vulnificus infection and highlight the importance of timely consideration of this etiologic agent due to the high mortality rate and specific treatment required.

A 58-year-old man with liver cirrhosis and hepatitis B virus presented with pain, swelling, and localized erythema affecting both legs as well as a fever. He reported vomiting blood and an episode of bloody diarrhea over the preceding 24 hours. He denied exposure to sick contacts or a history of autoimmune disease. At initial presentation to the emergency department, physical examination revealed few scattered, sharply demarcated, erythematous to violaceous patches that rapidly progressed overnight to hemorrhagic bullae and widespread retiform purpuric patches on both legs (Figure 1). As the patient’s skin condition worsened, he had a blood pressure of 80/50 mm Hg and a pulse rate of 110/min. Serum analysis was notable for mild leukocytosis (10.74×10⁹/L [reference range, 4.8–10.8×10⁹/L), thrombocytopenia (39×10⁹/L [reference range, 150–450×10⁹/L]), and decreased C3 (25 mg/dL [reference range, 81–157 mg/dL]) and C4 (8 mg/dL [reference range, 13–39 mg/dL]). Laboratory findings also were remarkable for prothrombin time (23.3 seconds [reference range, 8.8–12.3 seconds]), partial thromboplastin time (52.5 seconds [reference range, 23.6–35.8 seconds]), and international normalized ratio (2.01 [reference range, 0.8–1.13]). Aspartate transaminase (237 U/L [reference range, 11–39 U/L]) and alanine transaminase (80 U/L [reference range, 11–35 U/L]) were elevated, while antineutrophil cytoplasmic antibodies, serum immunoglobulin, and cryoglobulins were unremarkable. Punch biopsies of the left thigh were performed, and histopathology revealed small vessel thrombosis and ischemic changes consistent with PF (Figure 2). Vancomycin, clindamycin, cefepime injection, and piperacillin-tazobactam were administered intravenously for empiric broad-spectrum sepsis coverage. Within hours, the patient experienced refractory septic shock with disseminated intravascular coagulation and died from pulmonary embolism and subsequent cardiac arrest. Tissue and blood cultures grew V vulnificus.

Vibrio vulnificus is a gram-negative bacillus and a rare cause of primary septicemia following consumption of shellfish, especially oysters. Wounds exposed to saltwater or brackish water contaminated with the microorganism can produce soft-tissue infections. Individuals with chronic liver disease are at greater risk for V vulnificus infection.² The clinical presentation of V vulnificus includes early cellulitislike patches, late purpura with hemorrhagic bullae, and rapidly progressing shock.³

Mortality rates from V vulnificus infection are high.⁴ Therefore, it is recommended to presumptively diagnose V vulnificus septicemia in any individual at risk for infection who presents with the characteristic history in the setting of hypotension, fever, or septic shock. It is crucial for providers to be aware that broad-spectrum antibiotics commonly used for sepsis are inadequate for the treatment of V vulnificus. Immediate treatment with tetracycline (minocycline or doxycycline) and a third-generation cephalosporin (cefotaxime or ceftriaxone injection) or in combination with ciprofloxacin has been proven effective.^4,5

Vibrio vulnificus rarely is described in the literature as inducing PF. In one previously reported case, the patient was otherwise healthy and managed to recover following antibiotic therapy and wound debridement,⁶ whereas in another case the patient had undiagnosed liver cirrhosis and died from the infection.^6,7 In the latter case, the patient presented to the emergency department in a coma. Our patient did not have the clinical signs of sepsis upon initial presentation to the emergency department. It is possible the infection rapidly progressed because of his underlying liver disease. Genotyping analysis of V vulnificus has shown that strains with low pathogenicity can cause primary septicemia in humans.⁷

Our case reinforces the need to quickly recognize V vulnificus as a rare underlying cause of PF and administer the appropriate treatment.

To the Editor:

Purpura fulminans (PF) is an acute, life-threatening condition characterized by intravascular thrombosis and hemorrhagic necrosis of the skin. It classically presents as retiform purpura with branched or angular purpuric lesions. Purpura fulminans often occurs in the setting of disseminated intravascular coagulation, secondary to sepsis, trauma, malignancy, autoimmune disease, and congenital or acquired protein C or S deficiency, among other abnormalities.¹ Rapid identification and treatment of the underlying cause are mainstays of management. We report a case of PF secondary to Vibrio vulnificus infection and highlight the importance of timely consideration of this etiologic agent due to the high mortality rate and specific treatment required.

A 58-year-old man with liver cirrhosis and hepatitis B virus presented with pain, swelling, and localized erythema affecting both legs as well as a fever. He reported vomiting blood and an episode of bloody diarrhea over the preceding 24 hours. He denied exposure to sick contacts or a history of autoimmune disease. At initial presentation to the emergency department, physical examination revealed few scattered, sharply demarcated, erythematous to violaceous patches that rapidly progressed overnight to hemorrhagic bullae and widespread retiform purpuric patches on both legs (Figure 1). As the patient’s skin condition worsened, he had a blood pressure of 80/50 mm Hg and a pulse rate of 110/min. Serum analysis was notable for mild leukocytosis (10.74×10⁹/L [reference range, 4.8–10.8×10⁹/L), thrombocytopenia (39×10⁹/L [reference range, 150–450×10⁹/L]), and decreased C3 (25 mg/dL [reference range, 81–157 mg/dL]) and C4 (8 mg/dL [reference range, 13–39 mg/dL]). Laboratory findings also were remarkable for prothrombin time (23.3 seconds [reference range, 8.8–12.3 seconds]), partial thromboplastin time (52.5 seconds [reference range, 23.6–35.8 seconds]), and international normalized ratio (2.01 [reference range, 0.8–1.13]). Aspartate transaminase (237 U/L [reference range, 11–39 U/L]) and alanine transaminase (80 U/L [reference range, 11–35 U/L]) were elevated, while antineutrophil cytoplasmic antibodies, serum immunoglobulin, and cryoglobulins were unremarkable. Punch biopsies of the left thigh were performed, and histopathology revealed small vessel thrombosis and ischemic changes consistent with PF (Figure 2). Vancomycin, clindamycin, cefepime injection, and piperacillin-tazobactam were administered intravenously for empiric broad-spectrum sepsis coverage. Within hours, the patient experienced refractory septic shock with disseminated intravascular coagulation and died from pulmonary embolism and subsequent cardiac arrest. Tissue and blood cultures grew V vulnificus.

Vibrio vulnificus is a gram-negative bacillus and a rare cause of primary septicemia following consumption of shellfish, especially oysters. Wounds exposed to saltwater or brackish water contaminated with the microorganism can produce soft-tissue infections. Individuals with chronic liver disease are at greater risk for V vulnificus infection.² The clinical presentation of V vulnificus includes early cellulitislike patches, late purpura with hemorrhagic bullae, and rapidly progressing shock.³

Mortality rates from V vulnificus infection are high.⁴ Therefore, it is recommended to presumptively diagnose V vulnificus septicemia in any individual at risk for infection who presents with the characteristic history in the setting of hypotension, fever, or septic shock. It is crucial for providers to be aware that broad-spectrum antibiotics commonly used for sepsis are inadequate for the treatment of V vulnificus. Immediate treatment with tetracycline (minocycline or doxycycline) and a third-generation cephalosporin (cefotaxime or ceftriaxone injection) or in combination with ciprofloxacin has been proven effective.^4,5

Vibrio vulnificus rarely is described in the literature as inducing PF. In one previously reported case, the patient was otherwise healthy and managed to recover following antibiotic therapy and wound debridement,⁶ whereas in another case the patient had undiagnosed liver cirrhosis and died from the infection.^6,7 In the latter case, the patient presented to the emergency department in a coma. Our patient did not have the clinical signs of sepsis upon initial presentation to the emergency department. It is possible the infection rapidly progressed because of his underlying liver disease. Genotyping analysis of V vulnificus has shown that strains with low pathogenicity can cause primary septicemia in humans.⁷

Our case reinforces the need to quickly recognize V vulnificus as a rare underlying cause of PF and administer the appropriate treatment.

To the Editor:

Purpura fulminans (PF) is an acute, life-threatening condition characterized by intravascular thrombosis and hemorrhagic necrosis of the skin. It classically presents as retiform purpura with branched or angular purpuric lesions. Purpura fulminans often occurs in the setting of disseminated intravascular coagulation, secondary to sepsis, trauma, malignancy, autoimmune disease, and congenital or acquired protein C or S deficiency, among other abnormalities.¹ Rapid identification and treatment of the underlying cause are mainstays of management. We report a case of PF secondary to Vibrio vulnificus infection and highlight the importance of timely consideration of this etiologic agent due to the high mortality rate and specific treatment required.

A 58-year-old man with liver cirrhosis and hepatitis B virus presented with pain, swelling, and localized erythema affecting both legs as well as a fever. He reported vomiting blood and an episode of bloody diarrhea over the preceding 24 hours. He denied exposure to sick contacts or a history of autoimmune disease. At initial presentation to the emergency department, physical examination revealed few scattered, sharply demarcated, erythematous to violaceous patches that rapidly progressed overnight to hemorrhagic bullae and widespread retiform purpuric patches on both legs (Figure 1). As the patient’s skin condition worsened, he had a blood pressure of 80/50 mm Hg and a pulse rate of 110/min. Serum analysis was notable for mild leukocytosis (10.74×10⁹/L [reference range, 4.8–10.8×10⁹/L), thrombocytopenia (39×10⁹/L [reference range, 150–450×10⁹/L]), and decreased C3 (25 mg/dL [reference range, 81–157 mg/dL]) and C4 (8 mg/dL [reference range, 13–39 mg/dL]). Laboratory findings also were remarkable for prothrombin time (23.3 seconds [reference range, 8.8–12.3 seconds]), partial thromboplastin time (52.5 seconds [reference range, 23.6–35.8 seconds]), and international normalized ratio (2.01 [reference range, 0.8–1.13]). Aspartate transaminase (237 U/L [reference range, 11–39 U/L]) and alanine transaminase (80 U/L [reference range, 11–35 U/L]) were elevated, while antineutrophil cytoplasmic antibodies, serum immunoglobulin, and cryoglobulins were unremarkable. Punch biopsies of the left thigh were performed, and histopathology revealed small vessel thrombosis and ischemic changes consistent with PF (Figure 2). Vancomycin, clindamycin, cefepime injection, and piperacillin-tazobactam were administered intravenously for empiric broad-spectrum sepsis coverage. Within hours, the patient experienced refractory septic shock with disseminated intravascular coagulation and died from pulmonary embolism and subsequent cardiac arrest. Tissue and blood cultures grew V vulnificus.

Vibrio vulnificus is a gram-negative bacillus and a rare cause of primary septicemia following consumption of shellfish, especially oysters. Wounds exposed to saltwater or brackish water contaminated with the microorganism can produce soft-tissue infections. Individuals with chronic liver disease are at greater risk for V vulnificus infection.² The clinical presentation of V vulnificus includes early cellulitislike patches, late purpura with hemorrhagic bullae, and rapidly progressing shock.³

Mortality rates from V vulnificus infection are high.⁴ Therefore, it is recommended to presumptively diagnose V vulnificus septicemia in any individual at risk for infection who presents with the characteristic history in the setting of hypotension, fever, or septic shock. It is crucial for providers to be aware that broad-spectrum antibiotics commonly used for sepsis are inadequate for the treatment of V vulnificus. Immediate treatment with tetracycline (minocycline or doxycycline) and a third-generation cephalosporin (cefotaxime or ceftriaxone injection) or in combination with ciprofloxacin has been proven effective.^4,5

Vibrio vulnificus rarely is described in the literature as inducing PF. In one previously reported case, the patient was otherwise healthy and managed to recover following antibiotic therapy and wound debridement,⁶ whereas in another case the patient had undiagnosed liver cirrhosis and died from the infection.^6,7 In the latter case, the patient presented to the emergency department in a coma. Our patient did not have the clinical signs of sepsis upon initial presentation to the emergency department. It is possible the infection rapidly progressed because of his underlying liver disease. Genotyping analysis of V vulnificus has shown that strains with low pathogenicity can cause primary septicemia in humans.⁷

Our case reinforces the need to quickly recognize V vulnificus as a rare underlying cause of PF and administer the appropriate treatment.

Read More

Read More

Read More

The Diagnosis: Osteoma Cutis

Osteoma cutis is the heterotopic development of cutaneous ossifications in the dermis or subcutaneous fat and presents as plaquelike, stony, hard nodules. It can manifest as either a primary or secondary condition based on the presence or absence of a prior skin insult at the lesion site. Primary osteoma cutis occurs in 15% of patients and arises either de novo or in association with any of several inflammatory, neoplastic, and metabolic diseases that provide a favorable environment for abnormal mesenchymal stem cell commitment to osteoid,¹ including Albright hereditary osteodystrophy, myositis ossificans progressiva, and progressive osseous heteroplasia, which are all associated with mutations in the heterotrimeric G-protein alpha subunit encoding gene, GNAS. ^1,2 It is suggested that an insufficiency of Gsα leads to uncontrolled negative regulation of nonosseous connective tissue differentiation, forming osteoid.³ Additionally, diseases involving gain-of-function mutations in the activin A receptor type 1 encoding gene, ACVR1, such as fibrodysplasia ossificans progressiva, have been associated with osteoma cutis.⁴ These mutations lead to decreased receptor affinity to molecular safeguards of bone morphogenetic protein signaling, ultimately contributing to progressive ectopic bone formation.⁵ Secondary osteoma cutis occurs in 85% of patients and develops at the site of prior skin damage due to inflammation, neoplasm, or trauma.⁶ It is believed that tissue damage and degeneration lead to mesenchymal stem cell proliferation and skeletogenicinducing factor recruitment forming cartilaginous tissue, later replaced by bone through endochondral ossification.⁷

Although osteoma cutis previously was believed to be rare, more recent radiologic studies suggest otherwise, detecting cutaneous osteomas in up to 42.1% of patients.⁸ Consequently, it is likely that osteoma cutis is underdiagnosed due to its subclinical nature. Our patient, however, presented with a solitary osteoma cutis with perforation of the epidermis, a rare phenomenon.^9-12

A shave biopsy in our patient revealed moderate to focally marked, irregular epidermal hyperplasia with a large focus of moderate, compact, parakeratotic crust overlying the epidermis in the center of the specimen. The papillary dermis in the center of the specimen revealed large foci of dark pink to purple bone fragments surrounded by moderate lymphocytic infiltrate with few foci perforating through the overlying epidermis (Figure, A). These findings were characteristic of osteoma cutis with perforation through the overlying epidermis.

The diagnosis of osteoma cutis at the age of 62 years suggested that the lesion was not primary in association with previously described diseases. Furthermore, the lack of phenotypic features of these diseases including obesity, developmental disability, and high parathyroid hormone levels essentially excluded this possibility. The presence of the lesion on the lower extremities initially may have suggested osteoma cutis secondary to chronic venous insufficiency¹³; however, the absence of visible varicose veins or obvious signs of stasis disease made this unlikely. No further cutaneous disorders at or around the lesion site clinically and histologically suggested that our patient’s lesion was primary and of idiopathic nature. Dermatofibroma can present similarly in appearance but would characteristically dimple centrally when pinched. Keratoacanthoma presents with central ulceration and keratin plugging. Pilomatricoma more commonly presents on the head and neck and less frequently as a firm nodule. Lastly, prurigo nodularis more commonly presents as a symmetrically diffuse rash compared to an isolated nodule.

Osteoma cutis is a cutaneous ossification that may be primary or secondary in nature and less rare than originally thought. Workup for potentially associated inflammatory, neoplastic, and metabolic diseases should be considered in patients with this condition. Perforating osteoma cutis is a rare variant that presents as solitary or multiple nodules with central erosion and crust. The mechanism of transepidermal elimination leading to skin perforation is hypothesized to involve epidermal hyperproliferation leading to upward movement.¹⁴ Shave biopsy establishes a definitive histopathologic diagnosis and often is curative. Given that lesions of osteoma cutis themselves are benign, removal may not be necessary.

The Diagnosis: Osteoma Cutis

Osteoma cutis is the heterotopic development of cutaneous ossifications in the dermis or subcutaneous fat and presents as plaquelike, stony, hard nodules. It can manifest as either a primary or secondary condition based on the presence or absence of a prior skin insult at the lesion site. Primary osteoma cutis occurs in 15% of patients and arises either de novo or in association with any of several inflammatory, neoplastic, and metabolic diseases that provide a favorable environment for abnormal mesenchymal stem cell commitment to osteoid,¹ including Albright hereditary osteodystrophy, myositis ossificans progressiva, and progressive osseous heteroplasia, which are all associated with mutations in the heterotrimeric G-protein alpha subunit encoding gene, GNAS. ^1,2 It is suggested that an insufficiency of Gsα leads to uncontrolled negative regulation of nonosseous connective tissue differentiation, forming osteoid.³ Additionally, diseases involving gain-of-function mutations in the activin A receptor type 1 encoding gene, ACVR1, such as fibrodysplasia ossificans progressiva, have been associated with osteoma cutis.⁴ These mutations lead to decreased receptor affinity to molecular safeguards of bone morphogenetic protein signaling, ultimately contributing to progressive ectopic bone formation.⁵ Secondary osteoma cutis occurs in 85% of patients and develops at the site of prior skin damage due to inflammation, neoplasm, or trauma.⁶ It is believed that tissue damage and degeneration lead to mesenchymal stem cell proliferation and skeletogenicinducing factor recruitment forming cartilaginous tissue, later replaced by bone through endochondral ossification.⁷

Although osteoma cutis previously was believed to be rare, more recent radiologic studies suggest otherwise, detecting cutaneous osteomas in up to 42.1% of patients.⁸ Consequently, it is likely that osteoma cutis is underdiagnosed due to its subclinical nature. Our patient, however, presented with a solitary osteoma cutis with perforation of the epidermis, a rare phenomenon.^9-12

A shave biopsy in our patient revealed moderate to focally marked, irregular epidermal hyperplasia with a large focus of moderate, compact, parakeratotic crust overlying the epidermis in the center of the specimen. The papillary dermis in the center of the specimen revealed large foci of dark pink to purple bone fragments surrounded by moderate lymphocytic infiltrate with few foci perforating through the overlying epidermis (Figure, A). These findings were characteristic of osteoma cutis with perforation through the overlying epidermis.

The diagnosis of osteoma cutis at the age of 62 years suggested that the lesion was not primary in association with previously described diseases. Furthermore, the lack of phenotypic features of these diseases including obesity, developmental disability, and high parathyroid hormone levels essentially excluded this possibility. The presence of the lesion on the lower extremities initially may have suggested osteoma cutis secondary to chronic venous insufficiency¹³; however, the absence of visible varicose veins or obvious signs of stasis disease made this unlikely. No further cutaneous disorders at or around the lesion site clinically and histologically suggested that our patient’s lesion was primary and of idiopathic nature. Dermatofibroma can present similarly in appearance but would characteristically dimple centrally when pinched. Keratoacanthoma presents with central ulceration and keratin plugging. Pilomatricoma more commonly presents on the head and neck and less frequently as a firm nodule. Lastly, prurigo nodularis more commonly presents as a symmetrically diffuse rash compared to an isolated nodule.

Osteoma cutis is a cutaneous ossification that may be primary or secondary in nature and less rare than originally thought. Workup for potentially associated inflammatory, neoplastic, and metabolic diseases should be considered in patients with this condition. Perforating osteoma cutis is a rare variant that presents as solitary or multiple nodules with central erosion and crust. The mechanism of transepidermal elimination leading to skin perforation is hypothesized to involve epidermal hyperproliferation leading to upward movement.¹⁴ Shave biopsy establishes a definitive histopathologic diagnosis and often is curative. Given that lesions of osteoma cutis themselves are benign, removal may not be necessary.

The Diagnosis: Osteoma Cutis

Osteoma cutis is the heterotopic development of cutaneous ossifications in the dermis or subcutaneous fat and presents as plaquelike, stony, hard nodules. It can manifest as either a primary or secondary condition based on the presence or absence of a prior skin insult at the lesion site. Primary osteoma cutis occurs in 15% of patients and arises either de novo or in association with any of several inflammatory, neoplastic, and metabolic diseases that provide a favorable environment for abnormal mesenchymal stem cell commitment to osteoid,¹ including Albright hereditary osteodystrophy, myositis ossificans progressiva, and progressive osseous heteroplasia, which are all associated with mutations in the heterotrimeric G-protein alpha subunit encoding gene, GNAS. ^1,2 It is suggested that an insufficiency of Gsα leads to uncontrolled negative regulation of nonosseous connective tissue differentiation, forming osteoid.³ Additionally, diseases involving gain-of-function mutations in the activin A receptor type 1 encoding gene, ACVR1, such as fibrodysplasia ossificans progressiva, have been associated with osteoma cutis.⁴ These mutations lead to decreased receptor affinity to molecular safeguards of bone morphogenetic protein signaling, ultimately contributing to progressive ectopic bone formation.⁵ Secondary osteoma cutis occurs in 85% of patients and develops at the site of prior skin damage due to inflammation, neoplasm, or trauma.⁶ It is believed that tissue damage and degeneration lead to mesenchymal stem cell proliferation and skeletogenicinducing factor recruitment forming cartilaginous tissue, later replaced by bone through endochondral ossification.⁷

Although osteoma cutis previously was believed to be rare, more recent radiologic studies suggest otherwise, detecting cutaneous osteomas in up to 42.1% of patients.⁸ Consequently, it is likely that osteoma cutis is underdiagnosed due to its subclinical nature. Our patient, however, presented with a solitary osteoma cutis with perforation of the epidermis, a rare phenomenon.^9-12

A shave biopsy in our patient revealed moderate to focally marked, irregular epidermal hyperplasia with a large focus of moderate, compact, parakeratotic crust overlying the epidermis in the center of the specimen. The papillary dermis in the center of the specimen revealed large foci of dark pink to purple bone fragments surrounded by moderate lymphocytic infiltrate with few foci perforating through the overlying epidermis (Figure, A). These findings were characteristic of osteoma cutis with perforation through the overlying epidermis.

The diagnosis of osteoma cutis at the age of 62 years suggested that the lesion was not primary in association with previously described diseases. Furthermore, the lack of phenotypic features of these diseases including obesity, developmental disability, and high parathyroid hormone levels essentially excluded this possibility. The presence of the lesion on the lower extremities initially may have suggested osteoma cutis secondary to chronic venous insufficiency¹³; however, the absence of visible varicose veins or obvious signs of stasis disease made this unlikely. No further cutaneous disorders at or around the lesion site clinically and histologically suggested that our patient’s lesion was primary and of idiopathic nature. Dermatofibroma can present similarly in appearance but would characteristically dimple centrally when pinched. Keratoacanthoma presents with central ulceration and keratin plugging. Pilomatricoma more commonly presents on the head and neck and less frequently as a firm nodule. Lastly, prurigo nodularis more commonly presents as a symmetrically diffuse rash compared to an isolated nodule.

Osteoma cutis is a cutaneous ossification that may be primary or secondary in nature and less rare than originally thought. Workup for potentially associated inflammatory, neoplastic, and metabolic diseases should be considered in patients with this condition. Perforating osteoma cutis is a rare variant that presents as solitary or multiple nodules with central erosion and crust. The mechanism of transepidermal elimination leading to skin perforation is hypothesized to involve epidermal hyperproliferation leading to upward movement.¹⁴ Shave biopsy establishes a definitive histopathologic diagnosis and often is curative. Given that lesions of osteoma cutis themselves are benign, removal may not be necessary.

Kowtoniuk RA, Liu YE, Jeter JP. Cutaneous cold weather injuries in the US Military. Cutis. 2021;108:181-184, 202. doi:10.12788/cutis.0363

In the article above from the October 2021 issue, an author’s name was spelled incorrectly. The correct byline appears below. The article has been corrected online at www.mdedge.com/dermatology. We apologize for the error.

Robert A. Kowtoniuk, DO; Yizhen E. Liu, MD; Jonathan P. Jeter, MD

Kowtoniuk RA, Liu YE, Jeter JP. Cutaneous cold weather injuries in the US Military. Cutis. 2021;108:181-184, 202. doi:10.12788/cutis.0363

In the article above from the October 2021 issue, an author’s name was spelled incorrectly. The correct byline appears below. The article has been corrected online at www.mdedge.com/dermatology. We apologize for the error.

Robert A. Kowtoniuk, DO; Yizhen E. Liu, MD; Jonathan P. Jeter, MD

Kowtoniuk RA, Liu YE, Jeter JP. Cutaneous cold weather injuries in the US Military. Cutis. 2021;108:181-184, 202. doi:10.12788/cutis.0363

In the article above from the October 2021 issue, an author’s name was spelled incorrectly. The correct byline appears below. The article has been corrected online at www.mdedge.com/dermatology. We apologize for the error.

Robert A. Kowtoniuk, DO; Yizhen E. Liu, MD; Jonathan P. Jeter, MD

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Seborrheic dermatitis in a woman with brown-gray greasy scale as well as petaloid papules and plaques that are especially prominent in the nasolabial folds.

B Seborrheic dermatitis in a man with erythema, scale, and mild postinflammatory hypopigmentation that are especially prominent in the nasolabial folds.

C Seborrheic dermatitis in a man with erythema, faint scale, and postinflammatory hypopigmentation that are especially prominent in the nasolabial folds.

D Seborrheic dermatitis in a man with erythema and scale of the eyebrows and glabellar region.

Seborrheic dermatitis (SD) is an inflammatory condition that is thought to be part of a response to Malassezia yeast. The scalp and face are most commonly affected, particularly the nasolabial folds, eyebrows, ears, postauricular areas, and beard area. Men also may have SD on the mid upper chest in association with chest hair. In infants, the scalp and body skin folds often are affected.

Epidemiology

Seborrheic dermatitis affects patients of all ages: infants, adolescents, and adults. It is among the most common dermatologic diagnoses reported in Black patients in the United States.¹

Key clinical features in darker skin tones

• In those with darker skin tones, arcuate, polycyclic, or petaloid (flower petal–like) plaques may be present (Figure A). Also, hypopigmented patches and plaques may be prominent (Figures B and C). The classic description includes thin pink patches and plaques with white greasy scale on the face (Figure D).
• The scalp may have diffuse scale or isolated scaly plaques.

Worth noting

• In those with tightly coiled hair, there is a predisposition for dry hair and increased risk for breakage.
• Treatment plans for patients with SD often include frequent hair washing. However, in those with tightly coiled hair, the treatment plan may need to be modified due to hair texture, tendency for dryness, and washing frequency preferences. Washing the scalp at least every 1 to 2 weeks may be a preferred approach for those with tightly coiled hair at increased risk for dryness/breakage vs washing daily.² In a sample of 201 caregivers of Black girls, Rucker Wright et al3 found that washing the hair more than once per week was not correlated with a lower prevalence of SD.
• If tightly coiled hair is temporarily straightened with heat (eg, blow-dryer, flat iron), adding a liquid-based treatment such as clobetasol solution or fluocinonide solution will cause the hair to revert to its normal curl pattern.
• It is appropriate to ask patients for their vehicle preference for medications.² For example, if clobetasol is the treatment selected for the patient, the vehicle can reflect patient preference for a liquid, foam, cream, or ointment.
• Some antifungal/antiyeast shampoos may cause further hair dryness and breakage.
• Treatment may be delayed because patients often use various topical pomades and ointments to cover up the scale and help with pruritus.
• Diffuse scale of tinea capitis in school-aged children can be mistaken for SD, which leads to delayed diagnosis and treatment.
• Clinicians should become comfortable with scalp examinations in patients with tightly coiled hair. Patients with chief concerns related to their hair and scalp expect their clinicians to touch these areas. Avoid leaning in to examine the patient without touching the patient’s hair and scalp.^2,4

Health disparity highlight

Seborrheic dermatitis is among the most common cutaneous disorders diagnosed in patients with skin of color.^1,5 Delay in recognition of SD in those with darker skin tones leads to delayed treatment. Seborrheic dermatitis of the face can cause notable postinflammatory pigmentation alteration. Pigmentation changes in the skin further impact quality of life.

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Seborrheic dermatitis in a woman with brown-gray greasy scale as well as petaloid papules and plaques that are especially prominent in the nasolabial folds.

B Seborrheic dermatitis in a man with erythema, scale, and mild postinflammatory hypopigmentation that are especially prominent in the nasolabial folds.

C Seborrheic dermatitis in a man with erythema, faint scale, and postinflammatory hypopigmentation that are especially prominent in the nasolabial folds.

D Seborrheic dermatitis in a man with erythema and scale of the eyebrows and glabellar region.

Seborrheic dermatitis (SD) is an inflammatory condition that is thought to be part of a response to Malassezia yeast. The scalp and face are most commonly affected, particularly the nasolabial folds, eyebrows, ears, postauricular areas, and beard area. Men also may have SD on the mid upper chest in association with chest hair. In infants, the scalp and body skin folds often are affected.

Epidemiology

Seborrheic dermatitis affects patients of all ages: infants, adolescents, and adults. It is among the most common dermatologic diagnoses reported in Black patients in the United States.¹

Key clinical features in darker skin tones

• In those with darker skin tones, arcuate, polycyclic, or petaloid (flower petal–like) plaques may be present (Figure A). Also, hypopigmented patches and plaques may be prominent (Figures B and C). The classic description includes thin pink patches and plaques with white greasy scale on the face (Figure D).
• The scalp may have diffuse scale or isolated scaly plaques.

Worth noting

• In those with tightly coiled hair, there is a predisposition for dry hair and increased risk for breakage.
• Treatment plans for patients with SD often include frequent hair washing. However, in those with tightly coiled hair, the treatment plan may need to be modified due to hair texture, tendency for dryness, and washing frequency preferences. Washing the scalp at least every 1 to 2 weeks may be a preferred approach for those with tightly coiled hair at increased risk for dryness/breakage vs washing daily.² In a sample of 201 caregivers of Black girls, Rucker Wright et al3 found that washing the hair more than once per week was not correlated with a lower prevalence of SD.
• If tightly coiled hair is temporarily straightened with heat (eg, blow-dryer, flat iron), adding a liquid-based treatment such as clobetasol solution or fluocinonide solution will cause the hair to revert to its normal curl pattern.
• It is appropriate to ask patients for their vehicle preference for medications.² For example, if clobetasol is the treatment selected for the patient, the vehicle can reflect patient preference for a liquid, foam, cream, or ointment.
• Some antifungal/antiyeast shampoos may cause further hair dryness and breakage.
• Treatment may be delayed because patients often use various topical pomades and ointments to cover up the scale and help with pruritus.
• Diffuse scale of tinea capitis in school-aged children can be mistaken for SD, which leads to delayed diagnosis and treatment.
• Clinicians should become comfortable with scalp examinations in patients with tightly coiled hair. Patients with chief concerns related to their hair and scalp expect their clinicians to touch these areas. Avoid leaning in to examine the patient without touching the patient’s hair and scalp.^2,4

Health disparity highlight

Seborrheic dermatitis is among the most common cutaneous disorders diagnosed in patients with skin of color.^1,5 Delay in recognition of SD in those with darker skin tones leads to delayed treatment. Seborrheic dermatitis of the face can cause notable postinflammatory pigmentation alteration. Pigmentation changes in the skin further impact quality of life.

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Seborrheic dermatitis in a woman with brown-gray greasy scale as well as petaloid papules and plaques that are especially prominent in the nasolabial folds.

B Seborrheic dermatitis in a man with erythema, scale, and mild postinflammatory hypopigmentation that are especially prominent in the nasolabial folds.

C Seborrheic dermatitis in a man with erythema, faint scale, and postinflammatory hypopigmentation that are especially prominent in the nasolabial folds.

D Seborrheic dermatitis in a man with erythema and scale of the eyebrows and glabellar region.

Seborrheic dermatitis (SD) is an inflammatory condition that is thought to be part of a response to Malassezia yeast. The scalp and face are most commonly affected, particularly the nasolabial folds, eyebrows, ears, postauricular areas, and beard area. Men also may have SD on the mid upper chest in association with chest hair. In infants, the scalp and body skin folds often are affected.

Epidemiology

Seborrheic dermatitis affects patients of all ages: infants, adolescents, and adults. It is among the most common dermatologic diagnoses reported in Black patients in the United States.¹

Key clinical features in darker skin tones

• In those with darker skin tones, arcuate, polycyclic, or petaloid (flower petal–like) plaques may be present (Figure A). Also, hypopigmented patches and plaques may be prominent (Figures B and C). The classic description includes thin pink patches and plaques with white greasy scale on the face (Figure D).
• The scalp may have diffuse scale or isolated scaly plaques.

Worth noting

• In those with tightly coiled hair, there is a predisposition for dry hair and increased risk for breakage.
• Treatment plans for patients with SD often include frequent hair washing. However, in those with tightly coiled hair, the treatment plan may need to be modified due to hair texture, tendency for dryness, and washing frequency preferences. Washing the scalp at least every 1 to 2 weeks may be a preferred approach for those with tightly coiled hair at increased risk for dryness/breakage vs washing daily.² In a sample of 201 caregivers of Black girls, Rucker Wright et al3 found that washing the hair more than once per week was not correlated with a lower prevalence of SD.
• If tightly coiled hair is temporarily straightened with heat (eg, blow-dryer, flat iron), adding a liquid-based treatment such as clobetasol solution or fluocinonide solution will cause the hair to revert to its normal curl pattern.
• It is appropriate to ask patients for their vehicle preference for medications.² For example, if clobetasol is the treatment selected for the patient, the vehicle can reflect patient preference for a liquid, foam, cream, or ointment.
• Some antifungal/antiyeast shampoos may cause further hair dryness and breakage.
• Treatment may be delayed because patients often use various topical pomades and ointments to cover up the scale and help with pruritus.
• Diffuse scale of tinea capitis in school-aged children can be mistaken for SD, which leads to delayed diagnosis and treatment.
• Clinicians should become comfortable with scalp examinations in patients with tightly coiled hair. Patients with chief concerns related to their hair and scalp expect their clinicians to touch these areas. Avoid leaning in to examine the patient without touching the patient’s hair and scalp.^2,4

Health disparity highlight

Seborrheic dermatitis is among the most common cutaneous disorders diagnosed in patients with skin of color.^1,5 Delay in recognition of SD in those with darker skin tones leads to delayed treatment. Seborrheic dermatitis of the face can cause notable postinflammatory pigmentation alteration. Pigmentation changes in the skin further impact quality of life.

The Diagnosis: Infantile Digital Fibromatosis

Infantile digital fibromatosis (IDF) is a rare benign neoplasm of infancy prone to recurrence after resection but not to metastasis. It usually is limited to the fingers and toes.¹ One-third of cases occur at birth. Most patients develop clinical symptoms within the first year of life, but presentation can occur in adolescents and adults. The exact etiology and pathogenesis of IDF remain unclear, but trauma is thought to be a trigger.

Physical examination reveals single or multiple smooth, round, pink papules or nodules confined to the sides and backs of the fingers, sparing the thumb and first toe.^2,3 The nodules typically are firm, less than 2 cm in diameter, and often painless. Infantile digital fibromatosis exhibits an indolent progression followed by a rapid growth phase during several months, which may lead to functional impairment and joint deformities.^4,5 Histopathology displays spindle cells with eosinophilic cytoplasmic inclusions that range from round to oval with uneven distribution, lack of refraction, and a large size difference (3–15 μm).6 The inclusions are deep red with Masson trichrome staining and can express smooth muscle actin and calponin. Tumor cells usually express vimentin, smooth muscle actin, calponin, and desmin but fail to express S-100 protein. The Ki67 proliferation index is 2% to 15%.^6,7

Nonsurgical treatments for IDF include topical imiquimod, topical or intradermal injection of glucocorticoids, and intradermal injection of 5-fluorouracil. Complete resection should be reserved for cases with invasive growth that may lead to joint deformities, tendon or ligament involvement, digit or contracture deformity, and complications such as decreased joint mobility. Although there is a recurrence rate of up to 50% after excision, most lesions eventually will spontaneously regress and will leave no scar.^8-10

The clinical and histopathologic differential diagnoses of IDF include other cutaneous diseases that occur in the digits. A dermatofibroma is a round, firm, fibrohistiocytic nodule that mainly occurs on the extensor limbs. Histopathology includes both fibrous and cellular types.¹¹ Histologic analysis shows an ill-defined dermal proliferation of spindled fibroblasts with pale eosinophilic cytoplasm and bland fusiform nuclei growing in bands or fascicles that trap collagen fibers at the periphery (Figure 1). Generally, dermatofibromas have marked epidermal hyperplasia, which differs from IDF.

A digital myxoid cyst is characterized by a fleshcolored, hemispherical, and translucent cystic nodule that arises from the dorsum of the distal interphalangeal joint.¹² It commonly is associated with injury and chronic pressure. Translucent viscous liquid may flow out when the cyst is punctured, a hallmark feature of this entity. Clinical variants of myxoid cyst include myxomatous and ganglion types. Histopathology reveals excessive mucin deposited in the dermis, and the surrounding collagen is compressed to form the pseudocyst (Figure 2).

A giant cell tumor of the tendon sheath presents with asymptomatic nodules or lumps. Lesions frequently are localized to the tendon sheath, especially on the fingers and wrists, with no malignant tendency or propensity for spontaneous regression.¹³ The local recurrence rate is as high as 45%, which is related to surgical resection insufficiency.¹⁴ Histopathologic examination shows lobulated tumor tissue surrounded by dense fibrosis. The tumor cells are histiocytic with scattered giant cells (Figure 3). The characteristic osteoclastlike giant cells have eosinophilic cytoplasm and irregularly arranged nuclei in varying numbers.

Keloids are connective tissue hyperplasias caused by skin injury. Histopathologically, keloids are characterized by nodules of thick hyalinized collagen bundles and whorled fibroblasts (Figure 4). No inclusions in the fibroblasts and a history of trauma can differentiate keloids from IDF.

The Diagnosis: Infantile Digital Fibromatosis

Infantile digital fibromatosis (IDF) is a rare benign neoplasm of infancy prone to recurrence after resection but not to metastasis. It usually is limited to the fingers and toes.¹ One-third of cases occur at birth. Most patients develop clinical symptoms within the first year of life, but presentation can occur in adolescents and adults. The exact etiology and pathogenesis of IDF remain unclear, but trauma is thought to be a trigger.

Physical examination reveals single or multiple smooth, round, pink papules or nodules confined to the sides and backs of the fingers, sparing the thumb and first toe.^2,3 The nodules typically are firm, less than 2 cm in diameter, and often painless. Infantile digital fibromatosis exhibits an indolent progression followed by a rapid growth phase during several months, which may lead to functional impairment and joint deformities.^4,5 Histopathology displays spindle cells with eosinophilic cytoplasmic inclusions that range from round to oval with uneven distribution, lack of refraction, and a large size difference (3–15 μm).6 The inclusions are deep red with Masson trichrome staining and can express smooth muscle actin and calponin. Tumor cells usually express vimentin, smooth muscle actin, calponin, and desmin but fail to express S-100 protein. The Ki67 proliferation index is 2% to 15%.^6,7

Nonsurgical treatments for IDF include topical imiquimod, topical or intradermal injection of glucocorticoids, and intradermal injection of 5-fluorouracil. Complete resection should be reserved for cases with invasive growth that may lead to joint deformities, tendon or ligament involvement, digit or contracture deformity, and complications such as decreased joint mobility. Although there is a recurrence rate of up to 50% after excision, most lesions eventually will spontaneously regress and will leave no scar.^8-10

The clinical and histopathologic differential diagnoses of IDF include other cutaneous diseases that occur in the digits. A dermatofibroma is a round, firm, fibrohistiocytic nodule that mainly occurs on the extensor limbs. Histopathology includes both fibrous and cellular types.¹¹ Histologic analysis shows an ill-defined dermal proliferation of spindled fibroblasts with pale eosinophilic cytoplasm and bland fusiform nuclei growing in bands or fascicles that trap collagen fibers at the periphery (Figure 1). Generally, dermatofibromas have marked epidermal hyperplasia, which differs from IDF.

A digital myxoid cyst is characterized by a fleshcolored, hemispherical, and translucent cystic nodule that arises from the dorsum of the distal interphalangeal joint.¹² It commonly is associated with injury and chronic pressure. Translucent viscous liquid may flow out when the cyst is punctured, a hallmark feature of this entity. Clinical variants of myxoid cyst include myxomatous and ganglion types. Histopathology reveals excessive mucin deposited in the dermis, and the surrounding collagen is compressed to form the pseudocyst (Figure 2).

A giant cell tumor of the tendon sheath presents with asymptomatic nodules or lumps. Lesions frequently are localized to the tendon sheath, especially on the fingers and wrists, with no malignant tendency or propensity for spontaneous regression.¹³ The local recurrence rate is as high as 45%, which is related to surgical resection insufficiency.¹⁴ Histopathologic examination shows lobulated tumor tissue surrounded by dense fibrosis. The tumor cells are histiocytic with scattered giant cells (Figure 3). The characteristic osteoclastlike giant cells have eosinophilic cytoplasm and irregularly arranged nuclei in varying numbers.

Keloids are connective tissue hyperplasias caused by skin injury. Histopathologically, keloids are characterized by nodules of thick hyalinized collagen bundles and whorled fibroblasts (Figure 4). No inclusions in the fibroblasts and a history of trauma can differentiate keloids from IDF.

The Diagnosis: Infantile Digital Fibromatosis

Infantile digital fibromatosis (IDF) is a rare benign neoplasm of infancy prone to recurrence after resection but not to metastasis. It usually is limited to the fingers and toes.¹ One-third of cases occur at birth. Most patients develop clinical symptoms within the first year of life, but presentation can occur in adolescents and adults. The exact etiology and pathogenesis of IDF remain unclear, but trauma is thought to be a trigger.

Physical examination reveals single or multiple smooth, round, pink papules or nodules confined to the sides and backs of the fingers, sparing the thumb and first toe.^2,3 The nodules typically are firm, less than 2 cm in diameter, and often painless. Infantile digital fibromatosis exhibits an indolent progression followed by a rapid growth phase during several months, which may lead to functional impairment and joint deformities.^4,5 Histopathology displays spindle cells with eosinophilic cytoplasmic inclusions that range from round to oval with uneven distribution, lack of refraction, and a large size difference (3–15 μm).6 The inclusions are deep red with Masson trichrome staining and can express smooth muscle actin and calponin. Tumor cells usually express vimentin, smooth muscle actin, calponin, and desmin but fail to express S-100 protein. The Ki67 proliferation index is 2% to 15%.^6,7

Nonsurgical treatments for IDF include topical imiquimod, topical or intradermal injection of glucocorticoids, and intradermal injection of 5-fluorouracil. Complete resection should be reserved for cases with invasive growth that may lead to joint deformities, tendon or ligament involvement, digit or contracture deformity, and complications such as decreased joint mobility. Although there is a recurrence rate of up to 50% after excision, most lesions eventually will spontaneously regress and will leave no scar.^8-10

The clinical and histopathologic differential diagnoses of IDF include other cutaneous diseases that occur in the digits. A dermatofibroma is a round, firm, fibrohistiocytic nodule that mainly occurs on the extensor limbs. Histopathology includes both fibrous and cellular types.¹¹ Histologic analysis shows an ill-defined dermal proliferation of spindled fibroblasts with pale eosinophilic cytoplasm and bland fusiform nuclei growing in bands or fascicles that trap collagen fibers at the periphery (Figure 1). Generally, dermatofibromas have marked epidermal hyperplasia, which differs from IDF.

A digital myxoid cyst is characterized by a fleshcolored, hemispherical, and translucent cystic nodule that arises from the dorsum of the distal interphalangeal joint.¹² It commonly is associated with injury and chronic pressure. Translucent viscous liquid may flow out when the cyst is punctured, a hallmark feature of this entity. Clinical variants of myxoid cyst include myxomatous and ganglion types. Histopathology reveals excessive mucin deposited in the dermis, and the surrounding collagen is compressed to form the pseudocyst (Figure 2).

A giant cell tumor of the tendon sheath presents with asymptomatic nodules or lumps. Lesions frequently are localized to the tendon sheath, especially on the fingers and wrists, with no malignant tendency or propensity for spontaneous regression.¹³ The local recurrence rate is as high as 45%, which is related to surgical resection insufficiency.¹⁴ Histopathologic examination shows lobulated tumor tissue surrounded by dense fibrosis. The tumor cells are histiocytic with scattered giant cells (Figure 3). The characteristic osteoclastlike giant cells have eosinophilic cytoplasm and irregularly arranged nuclei in varying numbers.

Keloids are connective tissue hyperplasias caused by skin injury. Histopathologically, keloids are characterized by nodules of thick hyalinized collagen bundles and whorled fibroblasts (Figure 4). No inclusions in the fibroblasts and a history of trauma can differentiate keloids from IDF.

Topical medications frequently are prescribed in dermatology and provide the advantages of direct skin penetration and targeted application while typically sparing patients from systemic effects. Adverse cutaneous effects include allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), photosensitivity, urticaria, hyperpigmentation or hypopigmentation, atrophy, periorificial dermatitis, and acneform eruptions. Allergic contact dermatitis can develop from the active drug or vehicle components.

Patients with medicament ACD often present with symptoms of pruritus and dermatitis at the site of topical application. They may express concern that the medication is no longer working or seems to be making things worse. Certain sites are more prone to developing medicament dermatitis, including the face, groin, and lower legs. Older adults may be more at risk. Other risk factors include pre-existing skin diseases such as stasis dermatitis, acne, psoriasis, atopic dermatitis, and genital dermatoses.¹ A review of 14,911 patch-tested patients from a single referral clinic revealed that 17.4% had iatrogenic contact dermatitis, with the most common culprits being topical antibiotics, antiseptics, and steroids.²

In this 2-part series, we will focus on the active drug as a source of ACD. Part 1 explores ACD associated with acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations.

Acne and Rosacea Medications

Retinoids—Topical retinoids are first-line acne treatments that help normalize skin keratinization. Irritant contact dermatitis from retinoids is a well-known and common side effect. Although far less common than ICD, ACD from topical retinoid use has been reported.^3,4 Reactions to tretinoin are most frequently reported in the literature compared to adapalene gel⁵ and tazarotene foam, which have lower potential for sensitization.⁶ Allergic contact dermatitis also has been reported from retinyl palmitate^7,8 in cosmetic creams and from occupational exposure in settings of industrial vitamin A production.⁹ Both ICD and ACD from topical retinoids can present with pruritus, erythema, and scaling. Given this clinical overlap between ACD and ICD, patch testing is crucial in differentiating the underlying etiology of the dermatitis.

Benzoyl Peroxide—Benzoyl peroxide (BP) is another popular topical acne treatment that targets Cutibacterium acnes, a bacterium often implicated in the pathogenesis of acne vulgaris. Similar to retinoids, ICD is more common than ACD. Several cases of ACD to BP have been reported.^10-14 Occasionally, honey-colored crusting associated with ACD to BP can mimic impetigo.¹⁰ Aside from use of BP as an acne treatment, other potential exposures to BP include bleached flour¹³ and orthopedic bone cement. Occupations at risk for potential BP exposure include dental technicians¹⁵ and those working in plastic manufacturing.

Brimonidine—Brimonidine tartrate is a selective α₂-adrenergic agonist initially used to treat open-angle glaucoma and also is used as a topical treatment for rosacea. Allergic reactions to brimonidine eye drops may present with periorbital hyperpigmentation and pruritic bullous lesions.¹⁶ Case reports of topical brimonidine ACD have demonstrated mixed patch test results, with positive patch tests to Mirvaso (Galderma) as is but negative patch tests to pure brimonidine tartrate 0.33%.^17,18 Ringuet and Houle¹⁹ reported the first known positive patch test reaction to pure topical brimonidine, testing with brimonidine tartrate 1% in petrolatum.^20,21 Clinicians should be attuned to ACD to topical brimonidine in patients previously treated for glaucoma, as prior use of ophthalmic preparations may result in sensitization.^18,20

Antimicrobials

Clindamycin—Clindamycin targets bacterial protein synthesis and is an effective adjunct in the treatment of acne. Despite its widespread and often long-term use, topical clindamycin is a weak sensitizer.²² To date, limited case reports on ACD to topical clindamycin exist.^23-28 Rare clinical patterns of ACD to clindamycin include mimickers of irritant retinoid dermatitis, erythema multiforme, or pustular rosacea.^25,26,29

Metronidazole—Metronidazole is a bactericidal agent that disrupts nucleic acid synthesis with additional anti-inflammatory properties used in the treatment of rosacea. Allergic contact dermatitis to topical metronidazole has been reported.^30-34 In 2006, Beutner at al³⁵ patch tested 215 patients using metronidazole gel 1%, which revealed no positive reactions to indicate contact sensitization. Similarly, Jappe et al³⁶ found no positive reactions to metronidazole 2% in petrolatum in their prospective analysis of 78 rosacea patients, further highlighting the exceptionally low incidence of ACD. Cross-reaction with isothiazolinone, which shares structurally similar properties to metronidazole, has been speculated.^31,34 One patient developed an acute reaction to metronidazole gel 0.75% within 24 hours of application, suggesting that isothiazolinone may act as a sensitizer, though this relationship has not been proven.³¹

Neomycin—Neomycin blocks bacterial protein synthesis and is available in both prescription and over-the-counter (OTC) formulations. It commonly is used to treat and prevent superficial wound infections as an OTC antibiotic and also has otic, ophthalmologic, gastroenterologic, urologic, and peritoneal formulations. It also can be used in the dental and veterinary fields and is present in some animal feeds and in trace amounts in some vaccines for humans. Neomycin is a common antibiotic contact allergen, and the most recently reported 2017-2018 North American Contact Dermatitis Group data cycle placed it at number 12 with 5.4% positivity.³⁷ Co-reactions with bacitracin can occur, substantially limiting OTC topical antibiotic options for allergic patients. A safe alternative for patients with neomycin (and bacitracin and polymyxin) contact allergy is prescription mupirocin.

Bacitracin—Bacitracin interferes with peptidoglycan and cell-wall synthesis to treat superficial cutaneous infections. Similar to neomycin, it also can be found in OTC antibiotic ointments as well as in antibacterial bandages. There are several case reports of patients with both type IV delayed hypersensitivity (contact dermatitis) and type I anaphylactic reactions to bacitracin^38-40; patch testers should be aware of this rare association. Bacitracin was positive in 5.5% of patch tested patients in the 2017-2018 North American Contact Dermatitis Group data cycle,³⁷ and as with neomycin, bacitracin also is commonly patch tested in most screening patch test series.

Polymyxin—Polymyxin is a polypeptide topical antibiotic that is used to treat superficial wound infections and can be used in combination with neomycin and/or bacitracin. Historically, it is a less common antibiotic allergen; however, it is now frequently included in comprehensive patch test series, as the frequency of positive reactions seems to be increasing, probably due to polysensitization with neomycin and bacitracin.

Nystatin—Nystatin is an antifungal that binds to ergosterol and disrupts the cell wall. Cases exist of ACD to topical nystatin as well as systemic ACD from oral exposure, though both are quite rare. Authors have surmised that the overall low rates of ACD may be due to poor skin absorption of nystatin, which also can confound patch testing.^41,42 For patients with suspected ACD to nystatin, repeat open application testing also can be performed to confirm allergy.

Imidazole Antifungals—Similar to nystatins, imidazole antifungals also work by disrupting the fungal cell wall. Imidazole antifungal preparations that have been reported to cause ACD include clotrimazole, miconazole, econazole, and isoconazole, and although cross-reactivity patterns have been described, they are not always reproducible with patch testing.⁴³ In one reported case, tioconazole found in an antifungal nail lacquer triggered ACD involving not only the fingers and toes but also the trunk.⁴⁴ Erythema multiforme–like reactions also have been described from topical use.⁴⁵ Commercial patch test preparations of the most common imidazole allergens do exist. Nonimidazole antifungals remain a safe option for allergic patients.

Antihistamines

Antihistamines, or H1-receptor antagonists, are marketed to be applied topically for relief of pruritus associated with allergic cutaneous reactions. Ironically, they are known to be potent sensitizers themselves. There are 6 main chemical classes of antihistamines: phenothiazines, ethylenediamines, ethanolamines, alkylamines, piperazines, and piperidines. Goossens and Linsen⁴⁶ patch tested 12,460 patients from 1978 to 1997 and found the most positive reactions to promethazine (phenothiazine)(n=12), followed by diphenhydramine (ethanolamine)(n=8) and clemizole (benzimidazole)(n=6). The authors also noted cross-reactions between diphenhydramine derivatives and between promethazine and chlorpromazine.⁴⁶

Doxepin is a tricyclic antidepressant with antihistamine activity and is a well-documented sensitizer.^47-52 Taylor et al⁴⁷ evaluated 97 patients with chronic dermatoses, and patch testing revealed 17 (17.5%) positive reactions to doxepin cream, 13 (76.5%) of which were positive reactions to both the commercial cream and the active ingredient. Patch testing using doxepin dilution as low as 0.5% in petrolatum is sufficient to provoke a strong (++) allergic reaction.^50,51 Early-onset ACD following the use of doxepin cream suggests the possibility of prior sensitization, perhaps with a structurally similar phenothiazine drug.⁵¹ A keen suspicion for ACD in patients using doxepin cream for longer than the recommended duration can help make the diagnosis.^49,52

Topical Analgesics

Nonsteroidal Anti-inflammatory Drugs—Ketoprofen is one of the most frequent culprits of photoallergic contact dermatitis. Pruritic, papulovesicular, and bullous lesions typically develop acutely weeks after exposure. Prolonged photosensitivity is common and can last years after discontinuation of the nonsteroidal anti-inflammatory drug.⁵³ Cases of cross-reactions and co-sensitization to structurally similar substances have been reported, including to benzophenone-related chemicals in sunscreen and aldehyde groups in fragrance mix.^53,54

Diclofenac gel generally is well tolerated in the topical treatment of joint pain and inflammation. In the setting of ACD, patients typically present with dermatitis localized to the area of application.⁵⁵ Immediate cessation and avoidance of topical diclofenac are crucial components of management. Although systemic contact dermatitis has been reported with oral diclofenac use,⁵⁶ a recent report suggested that oral diclofenac may be well tolerated for some patients with topical ACD.⁵⁷

Publications on bufexamac-induced ACD mainly consist of international reports, as this medication has been discontinued in the United States. Bufexamac is a highly sensitizing agent that can lead to severe polymorphic eruptions requiring treatment with prednisolone and even hospitalization.⁵⁸ In one Australian case report, a mother developed an edematous, erythematous, papulovesicular eruption on the breast while breastfeeding her baby, who was being treated with bufexamac cream 5% for infantile eczema.⁵⁹ Carprofen-induced photoallergic contact dermatitis is associated with occupational exposure in pharmaceutical workers.^60,61 A few case reports on other nonsteroidal anti-inflammatory drugs, including etofenamate and aceclofenac, have been published.^62,63

Compounded Medications—Compounded topical analgesics, which help to control pain via multiple combined effects, have gained increasing popularity in the management of chronic neuropathic pain disorders. Only a few recent retrospective studies assessing the efficacy and safety of these medications have mentioned suspected allergic cutaneous reactions.^62,63 In 2015, Turrentine et al⁶⁴ reported a case of ACD to cyclobenzaprine in a compound containing ketamine 10%, diclofenac 5%, baclofen 2%, bupivacaine 1%, cyclobenzaprine 2%, gabapentin 6%, ibuprofen 3%, and pentoxifylline 3% in a proprietary cream base. When patients present with suspected ACD to a compounded pain medication, obtaining individual components for patch testing is key to determining the allergic ingredient(s). We suspect that we will see a rise in reports of ACD as these topical compounds become readily adopted in clinical practices.

Patch Testing for Diagnosis

When patients present with symptoms concerning for ACD to medicaments, the astute clinician should promptly stop the suspected topical medication and consider patch testing. For common allergens such as neomycin, bacitracin, or ethylenediamine, commercial patch test preparations exist and should be used; however, for drugs that do not have a commercial patch test preparation, the patient’s product can be applied as is, keeping in mind that certain preparations (such as retinoids) can cause irritant patch test reactions, which may confound the reading. Alternatively, individual ingredients in the medication’s formulation can be requested from the manufacturer or a compounding pharmacy for targeted testing. Suggested concentrations for patch testing based on the literature and expert reference are listed in the Table. The authors (M.R., A.R.A.) frequently rely on an expert reference⁶⁶ to determine ideal concentrations for patch testing. Referral to a specialized patch test clinic may be appropriate.

Final Interpretation

Although their intent is to heal, topical medicaments also can be a source of ACD. The astute clinician should consider ACD when topicals either no longer seem to help the patient or trigger new-onset dermatitis. Patch testing directly with the culprit medicament, or individual medication ingredients when needed, can lead to the diagnosis, though caution is advised. Stay tuned for part 2 of this series in which we will discuss ACD to topical steroids, immunomodulators, and anesthetic medications.

Topical medications frequently are prescribed in dermatology and provide the advantages of direct skin penetration and targeted application while typically sparing patients from systemic effects. Adverse cutaneous effects include allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), photosensitivity, urticaria, hyperpigmentation or hypopigmentation, atrophy, periorificial dermatitis, and acneform eruptions. Allergic contact dermatitis can develop from the active drug or vehicle components.

Patients with medicament ACD often present with symptoms of pruritus and dermatitis at the site of topical application. They may express concern that the medication is no longer working or seems to be making things worse. Certain sites are more prone to developing medicament dermatitis, including the face, groin, and lower legs. Older adults may be more at risk. Other risk factors include pre-existing skin diseases such as stasis dermatitis, acne, psoriasis, atopic dermatitis, and genital dermatoses.¹ A review of 14,911 patch-tested patients from a single referral clinic revealed that 17.4% had iatrogenic contact dermatitis, with the most common culprits being topical antibiotics, antiseptics, and steroids.²

In this 2-part series, we will focus on the active drug as a source of ACD. Part 1 explores ACD associated with acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations.

Acne and Rosacea Medications

Retinoids—Topical retinoids are first-line acne treatments that help normalize skin keratinization. Irritant contact dermatitis from retinoids is a well-known and common side effect. Although far less common than ICD, ACD from topical retinoid use has been reported.^3,4 Reactions to tretinoin are most frequently reported in the literature compared to adapalene gel⁵ and tazarotene foam, which have lower potential for sensitization.⁶ Allergic contact dermatitis also has been reported from retinyl palmitate^7,8 in cosmetic creams and from occupational exposure in settings of industrial vitamin A production.⁹ Both ICD and ACD from topical retinoids can present with pruritus, erythema, and scaling. Given this clinical overlap between ACD and ICD, patch testing is crucial in differentiating the underlying etiology of the dermatitis.

Benzoyl Peroxide—Benzoyl peroxide (BP) is another popular topical acne treatment that targets Cutibacterium acnes, a bacterium often implicated in the pathogenesis of acne vulgaris. Similar to retinoids, ICD is more common than ACD. Several cases of ACD to BP have been reported.^10-14 Occasionally, honey-colored crusting associated with ACD to BP can mimic impetigo.¹⁰ Aside from use of BP as an acne treatment, other potential exposures to BP include bleached flour¹³ and orthopedic bone cement. Occupations at risk for potential BP exposure include dental technicians¹⁵ and those working in plastic manufacturing.

Brimonidine—Brimonidine tartrate is a selective α₂-adrenergic agonist initially used to treat open-angle glaucoma and also is used as a topical treatment for rosacea. Allergic reactions to brimonidine eye drops may present with periorbital hyperpigmentation and pruritic bullous lesions.¹⁶ Case reports of topical brimonidine ACD have demonstrated mixed patch test results, with positive patch tests to Mirvaso (Galderma) as is but negative patch tests to pure brimonidine tartrate 0.33%.^17,18 Ringuet and Houle¹⁹ reported the first known positive patch test reaction to pure topical brimonidine, testing with brimonidine tartrate 1% in petrolatum.^20,21 Clinicians should be attuned to ACD to topical brimonidine in patients previously treated for glaucoma, as prior use of ophthalmic preparations may result in sensitization.^18,20

Antimicrobials

Clindamycin—Clindamycin targets bacterial protein synthesis and is an effective adjunct in the treatment of acne. Despite its widespread and often long-term use, topical clindamycin is a weak sensitizer.²² To date, limited case reports on ACD to topical clindamycin exist.^23-28 Rare clinical patterns of ACD to clindamycin include mimickers of irritant retinoid dermatitis, erythema multiforme, or pustular rosacea.^25,26,29

Metronidazole—Metronidazole is a bactericidal agent that disrupts nucleic acid synthesis with additional anti-inflammatory properties used in the treatment of rosacea. Allergic contact dermatitis to topical metronidazole has been reported.^30-34 In 2006, Beutner at al³⁵ patch tested 215 patients using metronidazole gel 1%, which revealed no positive reactions to indicate contact sensitization. Similarly, Jappe et al³⁶ found no positive reactions to metronidazole 2% in petrolatum in their prospective analysis of 78 rosacea patients, further highlighting the exceptionally low incidence of ACD. Cross-reaction with isothiazolinone, which shares structurally similar properties to metronidazole, has been speculated.^31,34 One patient developed an acute reaction to metronidazole gel 0.75% within 24 hours of application, suggesting that isothiazolinone may act as a sensitizer, though this relationship has not been proven.³¹

Neomycin—Neomycin blocks bacterial protein synthesis and is available in both prescription and over-the-counter (OTC) formulations. It commonly is used to treat and prevent superficial wound infections as an OTC antibiotic and also has otic, ophthalmologic, gastroenterologic, urologic, and peritoneal formulations. It also can be used in the dental and veterinary fields and is present in some animal feeds and in trace amounts in some vaccines for humans. Neomycin is a common antibiotic contact allergen, and the most recently reported 2017-2018 North American Contact Dermatitis Group data cycle placed it at number 12 with 5.4% positivity.³⁷ Co-reactions with bacitracin can occur, substantially limiting OTC topical antibiotic options for allergic patients. A safe alternative for patients with neomycin (and bacitracin and polymyxin) contact allergy is prescription mupirocin.

Bacitracin—Bacitracin interferes with peptidoglycan and cell-wall synthesis to treat superficial cutaneous infections. Similar to neomycin, it also can be found in OTC antibiotic ointments as well as in antibacterial bandages. There are several case reports of patients with both type IV delayed hypersensitivity (contact dermatitis) and type I anaphylactic reactions to bacitracin^38-40; patch testers should be aware of this rare association. Bacitracin was positive in 5.5% of patch tested patients in the 2017-2018 North American Contact Dermatitis Group data cycle,³⁷ and as with neomycin, bacitracin also is commonly patch tested in most screening patch test series.

Polymyxin—Polymyxin is a polypeptide topical antibiotic that is used to treat superficial wound infections and can be used in combination with neomycin and/or bacitracin. Historically, it is a less common antibiotic allergen; however, it is now frequently included in comprehensive patch test series, as the frequency of positive reactions seems to be increasing, probably due to polysensitization with neomycin and bacitracin.

Nystatin—Nystatin is an antifungal that binds to ergosterol and disrupts the cell wall. Cases exist of ACD to topical nystatin as well as systemic ACD from oral exposure, though both are quite rare. Authors have surmised that the overall low rates of ACD may be due to poor skin absorption of nystatin, which also can confound patch testing.^41,42 For patients with suspected ACD to nystatin, repeat open application testing also can be performed to confirm allergy.

Imidazole Antifungals—Similar to nystatins, imidazole antifungals also work by disrupting the fungal cell wall. Imidazole antifungal preparations that have been reported to cause ACD include clotrimazole, miconazole, econazole, and isoconazole, and although cross-reactivity patterns have been described, they are not always reproducible with patch testing.⁴³ In one reported case, tioconazole found in an antifungal nail lacquer triggered ACD involving not only the fingers and toes but also the trunk.⁴⁴ Erythema multiforme–like reactions also have been described from topical use.⁴⁵ Commercial patch test preparations of the most common imidazole allergens do exist. Nonimidazole antifungals remain a safe option for allergic patients.

Antihistamines

Antihistamines, or H1-receptor antagonists, are marketed to be applied topically for relief of pruritus associated with allergic cutaneous reactions. Ironically, they are known to be potent sensitizers themselves. There are 6 main chemical classes of antihistamines: phenothiazines, ethylenediamines, ethanolamines, alkylamines, piperazines, and piperidines. Goossens and Linsen⁴⁶ patch tested 12,460 patients from 1978 to 1997 and found the most positive reactions to promethazine (phenothiazine)(n=12), followed by diphenhydramine (ethanolamine)(n=8) and clemizole (benzimidazole)(n=6). The authors also noted cross-reactions between diphenhydramine derivatives and between promethazine and chlorpromazine.⁴⁶

Doxepin is a tricyclic antidepressant with antihistamine activity and is a well-documented sensitizer.^47-52 Taylor et al⁴⁷ evaluated 97 patients with chronic dermatoses, and patch testing revealed 17 (17.5%) positive reactions to doxepin cream, 13 (76.5%) of which were positive reactions to both the commercial cream and the active ingredient. Patch testing using doxepin dilution as low as 0.5% in petrolatum is sufficient to provoke a strong (++) allergic reaction.^50,51 Early-onset ACD following the use of doxepin cream suggests the possibility of prior sensitization, perhaps with a structurally similar phenothiazine drug.⁵¹ A keen suspicion for ACD in patients using doxepin cream for longer than the recommended duration can help make the diagnosis.^49,52

Topical Analgesics

Nonsteroidal Anti-inflammatory Drugs—Ketoprofen is one of the most frequent culprits of photoallergic contact dermatitis. Pruritic, papulovesicular, and bullous lesions typically develop acutely weeks after exposure. Prolonged photosensitivity is common and can last years after discontinuation of the nonsteroidal anti-inflammatory drug.⁵³ Cases of cross-reactions and co-sensitization to structurally similar substances have been reported, including to benzophenone-related chemicals in sunscreen and aldehyde groups in fragrance mix.^53,54

Diclofenac gel generally is well tolerated in the topical treatment of joint pain and inflammation. In the setting of ACD, patients typically present with dermatitis localized to the area of application.⁵⁵ Immediate cessation and avoidance of topical diclofenac are crucial components of management. Although systemic contact dermatitis has been reported with oral diclofenac use,⁵⁶ a recent report suggested that oral diclofenac may be well tolerated for some patients with topical ACD.⁵⁷

Publications on bufexamac-induced ACD mainly consist of international reports, as this medication has been discontinued in the United States. Bufexamac is a highly sensitizing agent that can lead to severe polymorphic eruptions requiring treatment with prednisolone and even hospitalization.⁵⁸ In one Australian case report, a mother developed an edematous, erythematous, papulovesicular eruption on the breast while breastfeeding her baby, who was being treated with bufexamac cream 5% for infantile eczema.⁵⁹ Carprofen-induced photoallergic contact dermatitis is associated with occupational exposure in pharmaceutical workers.^60,61 A few case reports on other nonsteroidal anti-inflammatory drugs, including etofenamate and aceclofenac, have been published.^62,63

Compounded Medications—Compounded topical analgesics, which help to control pain via multiple combined effects, have gained increasing popularity in the management of chronic neuropathic pain disorders. Only a few recent retrospective studies assessing the efficacy and safety of these medications have mentioned suspected allergic cutaneous reactions.^62,63 In 2015, Turrentine et al⁶⁴ reported a case of ACD to cyclobenzaprine in a compound containing ketamine 10%, diclofenac 5%, baclofen 2%, bupivacaine 1%, cyclobenzaprine 2%, gabapentin 6%, ibuprofen 3%, and pentoxifylline 3% in a proprietary cream base. When patients present with suspected ACD to a compounded pain medication, obtaining individual components for patch testing is key to determining the allergic ingredient(s). We suspect that we will see a rise in reports of ACD as these topical compounds become readily adopted in clinical practices.

Patch Testing for Diagnosis

When patients present with symptoms concerning for ACD to medicaments, the astute clinician should promptly stop the suspected topical medication and consider patch testing. For common allergens such as neomycin, bacitracin, or ethylenediamine, commercial patch test preparations exist and should be used; however, for drugs that do not have a commercial patch test preparation, the patient’s product can be applied as is, keeping in mind that certain preparations (such as retinoids) can cause irritant patch test reactions, which may confound the reading. Alternatively, individual ingredients in the medication’s formulation can be requested from the manufacturer or a compounding pharmacy for targeted testing. Suggested concentrations for patch testing based on the literature and expert reference are listed in the Table. The authors (M.R., A.R.A.) frequently rely on an expert reference⁶⁶ to determine ideal concentrations for patch testing. Referral to a specialized patch test clinic may be appropriate.

Final Interpretation

Although their intent is to heal, topical medicaments also can be a source of ACD. The astute clinician should consider ACD when topicals either no longer seem to help the patient or trigger new-onset dermatitis. Patch testing directly with the culprit medicament, or individual medication ingredients when needed, can lead to the diagnosis, though caution is advised. Stay tuned for part 2 of this series in which we will discuss ACD to topical steroids, immunomodulators, and anesthetic medications.

Topical medications frequently are prescribed in dermatology and provide the advantages of direct skin penetration and targeted application while typically sparing patients from systemic effects. Adverse cutaneous effects include allergic contact dermatitis (ACD), irritant contact dermatitis (ICD), photosensitivity, urticaria, hyperpigmentation or hypopigmentation, atrophy, periorificial dermatitis, and acneform eruptions. Allergic contact dermatitis can develop from the active drug or vehicle components.

Patients with medicament ACD often present with symptoms of pruritus and dermatitis at the site of topical application. They may express concern that the medication is no longer working or seems to be making things worse. Certain sites are more prone to developing medicament dermatitis, including the face, groin, and lower legs. Older adults may be more at risk. Other risk factors include pre-existing skin diseases such as stasis dermatitis, acne, psoriasis, atopic dermatitis, and genital dermatoses.¹ A review of 14,911 patch-tested patients from a single referral clinic revealed that 17.4% had iatrogenic contact dermatitis, with the most common culprits being topical antibiotics, antiseptics, and steroids.²

In this 2-part series, we will focus on the active drug as a source of ACD. Part 1 explores ACD associated with acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations.

Acne and Rosacea Medications

Retinoids—Topical retinoids are first-line acne treatments that help normalize skin keratinization. Irritant contact dermatitis from retinoids is a well-known and common side effect. Although far less common than ICD, ACD from topical retinoid use has been reported.^3,4 Reactions to tretinoin are most frequently reported in the literature compared to adapalene gel⁵ and tazarotene foam, which have lower potential for sensitization.⁶ Allergic contact dermatitis also has been reported from retinyl palmitate^7,8 in cosmetic creams and from occupational exposure in settings of industrial vitamin A production.⁹ Both ICD and ACD from topical retinoids can present with pruritus, erythema, and scaling. Given this clinical overlap between ACD and ICD, patch testing is crucial in differentiating the underlying etiology of the dermatitis.

Benzoyl Peroxide—Benzoyl peroxide (BP) is another popular topical acne treatment that targets Cutibacterium acnes, a bacterium often implicated in the pathogenesis of acne vulgaris. Similar to retinoids, ICD is more common than ACD. Several cases of ACD to BP have been reported.^10-14 Occasionally, honey-colored crusting associated with ACD to BP can mimic impetigo.¹⁰ Aside from use of BP as an acne treatment, other potential exposures to BP include bleached flour¹³ and orthopedic bone cement. Occupations at risk for potential BP exposure include dental technicians¹⁵ and those working in plastic manufacturing.

Brimonidine—Brimonidine tartrate is a selective α₂-adrenergic agonist initially used to treat open-angle glaucoma and also is used as a topical treatment for rosacea. Allergic reactions to brimonidine eye drops may present with periorbital hyperpigmentation and pruritic bullous lesions.¹⁶ Case reports of topical brimonidine ACD have demonstrated mixed patch test results, with positive patch tests to Mirvaso (Galderma) as is but negative patch tests to pure brimonidine tartrate 0.33%.^17,18 Ringuet and Houle¹⁹ reported the first known positive patch test reaction to pure topical brimonidine, testing with brimonidine tartrate 1% in petrolatum.^20,21 Clinicians should be attuned to ACD to topical brimonidine in patients previously treated for glaucoma, as prior use of ophthalmic preparations may result in sensitization.^18,20

Antimicrobials

Clindamycin—Clindamycin targets bacterial protein synthesis and is an effective adjunct in the treatment of acne. Despite its widespread and often long-term use, topical clindamycin is a weak sensitizer.²² To date, limited case reports on ACD to topical clindamycin exist.^23-28 Rare clinical patterns of ACD to clindamycin include mimickers of irritant retinoid dermatitis, erythema multiforme, or pustular rosacea.^25,26,29

Metronidazole—Metronidazole is a bactericidal agent that disrupts nucleic acid synthesis with additional anti-inflammatory properties used in the treatment of rosacea. Allergic contact dermatitis to topical metronidazole has been reported.^30-34 In 2006, Beutner at al³⁵ patch tested 215 patients using metronidazole gel 1%, which revealed no positive reactions to indicate contact sensitization. Similarly, Jappe et al³⁶ found no positive reactions to metronidazole 2% in petrolatum in their prospective analysis of 78 rosacea patients, further highlighting the exceptionally low incidence of ACD. Cross-reaction with isothiazolinone, which shares structurally similar properties to metronidazole, has been speculated.^31,34 One patient developed an acute reaction to metronidazole gel 0.75% within 24 hours of application, suggesting that isothiazolinone may act as a sensitizer, though this relationship has not been proven.³¹

Neomycin—Neomycin blocks bacterial protein synthesis and is available in both prescription and over-the-counter (OTC) formulations. It commonly is used to treat and prevent superficial wound infections as an OTC antibiotic and also has otic, ophthalmologic, gastroenterologic, urologic, and peritoneal formulations. It also can be used in the dental and veterinary fields and is present in some animal feeds and in trace amounts in some vaccines for humans. Neomycin is a common antibiotic contact allergen, and the most recently reported 2017-2018 North American Contact Dermatitis Group data cycle placed it at number 12 with 5.4% positivity.³⁷ Co-reactions with bacitracin can occur, substantially limiting OTC topical antibiotic options for allergic patients. A safe alternative for patients with neomycin (and bacitracin and polymyxin) contact allergy is prescription mupirocin.

Bacitracin—Bacitracin interferes with peptidoglycan and cell-wall synthesis to treat superficial cutaneous infections. Similar to neomycin, it also can be found in OTC antibiotic ointments as well as in antibacterial bandages. There are several case reports of patients with both type IV delayed hypersensitivity (contact dermatitis) and type I anaphylactic reactions to bacitracin^38-40; patch testers should be aware of this rare association. Bacitracin was positive in 5.5% of patch tested patients in the 2017-2018 North American Contact Dermatitis Group data cycle,³⁷ and as with neomycin, bacitracin also is commonly patch tested in most screening patch test series.

Polymyxin—Polymyxin is a polypeptide topical antibiotic that is used to treat superficial wound infections and can be used in combination with neomycin and/or bacitracin. Historically, it is a less common antibiotic allergen; however, it is now frequently included in comprehensive patch test series, as the frequency of positive reactions seems to be increasing, probably due to polysensitization with neomycin and bacitracin.

Nystatin—Nystatin is an antifungal that binds to ergosterol and disrupts the cell wall. Cases exist of ACD to topical nystatin as well as systemic ACD from oral exposure, though both are quite rare. Authors have surmised that the overall low rates of ACD may be due to poor skin absorption of nystatin, which also can confound patch testing.^41,42 For patients with suspected ACD to nystatin, repeat open application testing also can be performed to confirm allergy.

Imidazole Antifungals—Similar to nystatins, imidazole antifungals also work by disrupting the fungal cell wall. Imidazole antifungal preparations that have been reported to cause ACD include clotrimazole, miconazole, econazole, and isoconazole, and although cross-reactivity patterns have been described, they are not always reproducible with patch testing.⁴³ In one reported case, tioconazole found in an antifungal nail lacquer triggered ACD involving not only the fingers and toes but also the trunk.⁴⁴ Erythema multiforme–like reactions also have been described from topical use.⁴⁵ Commercial patch test preparations of the most common imidazole allergens do exist. Nonimidazole antifungals remain a safe option for allergic patients.

Antihistamines

Antihistamines, or H1-receptor antagonists, are marketed to be applied topically for relief of pruritus associated with allergic cutaneous reactions. Ironically, they are known to be potent sensitizers themselves. There are 6 main chemical classes of antihistamines: phenothiazines, ethylenediamines, ethanolamines, alkylamines, piperazines, and piperidines. Goossens and Linsen⁴⁶ patch tested 12,460 patients from 1978 to 1997 and found the most positive reactions to promethazine (phenothiazine)(n=12), followed by diphenhydramine (ethanolamine)(n=8) and clemizole (benzimidazole)(n=6). The authors also noted cross-reactions between diphenhydramine derivatives and between promethazine and chlorpromazine.⁴⁶

Doxepin is a tricyclic antidepressant with antihistamine activity and is a well-documented sensitizer.^47-52 Taylor et al⁴⁷ evaluated 97 patients with chronic dermatoses, and patch testing revealed 17 (17.5%) positive reactions to doxepin cream, 13 (76.5%) of which were positive reactions to both the commercial cream and the active ingredient. Patch testing using doxepin dilution as low as 0.5% in petrolatum is sufficient to provoke a strong (++) allergic reaction.^50,51 Early-onset ACD following the use of doxepin cream suggests the possibility of prior sensitization, perhaps with a structurally similar phenothiazine drug.⁵¹ A keen suspicion for ACD in patients using doxepin cream for longer than the recommended duration can help make the diagnosis.^49,52

Topical Analgesics

Nonsteroidal Anti-inflammatory Drugs—Ketoprofen is one of the most frequent culprits of photoallergic contact dermatitis. Pruritic, papulovesicular, and bullous lesions typically develop acutely weeks after exposure. Prolonged photosensitivity is common and can last years after discontinuation of the nonsteroidal anti-inflammatory drug.⁵³ Cases of cross-reactions and co-sensitization to structurally similar substances have been reported, including to benzophenone-related chemicals in sunscreen and aldehyde groups in fragrance mix.^53,54

Diclofenac gel generally is well tolerated in the topical treatment of joint pain and inflammation. In the setting of ACD, patients typically present with dermatitis localized to the area of application.⁵⁵ Immediate cessation and avoidance of topical diclofenac are crucial components of management. Although systemic contact dermatitis has been reported with oral diclofenac use,⁵⁶ a recent report suggested that oral diclofenac may be well tolerated for some patients with topical ACD.⁵⁷

Publications on bufexamac-induced ACD mainly consist of international reports, as this medication has been discontinued in the United States. Bufexamac is a highly sensitizing agent that can lead to severe polymorphic eruptions requiring treatment with prednisolone and even hospitalization.⁵⁸ In one Australian case report, a mother developed an edematous, erythematous, papulovesicular eruption on the breast while breastfeeding her baby, who was being treated with bufexamac cream 5% for infantile eczema.⁵⁹ Carprofen-induced photoallergic contact dermatitis is associated with occupational exposure in pharmaceutical workers.^60,61 A few case reports on other nonsteroidal anti-inflammatory drugs, including etofenamate and aceclofenac, have been published.^62,63

Compounded Medications—Compounded topical analgesics, which help to control pain via multiple combined effects, have gained increasing popularity in the management of chronic neuropathic pain disorders. Only a few recent retrospective studies assessing the efficacy and safety of these medications have mentioned suspected allergic cutaneous reactions.^62,63 In 2015, Turrentine et al⁶⁴ reported a case of ACD to cyclobenzaprine in a compound containing ketamine 10%, diclofenac 5%, baclofen 2%, bupivacaine 1%, cyclobenzaprine 2%, gabapentin 6%, ibuprofen 3%, and pentoxifylline 3% in a proprietary cream base. When patients present with suspected ACD to a compounded pain medication, obtaining individual components for patch testing is key to determining the allergic ingredient(s). We suspect that we will see a rise in reports of ACD as these topical compounds become readily adopted in clinical practices.

Patch Testing for Diagnosis

When patients present with symptoms concerning for ACD to medicaments, the astute clinician should promptly stop the suspected topical medication and consider patch testing. For common allergens such as neomycin, bacitracin, or ethylenediamine, commercial patch test preparations exist and should be used; however, for drugs that do not have a commercial patch test preparation, the patient’s product can be applied as is, keeping in mind that certain preparations (such as retinoids) can cause irritant patch test reactions, which may confound the reading. Alternatively, individual ingredients in the medication’s formulation can be requested from the manufacturer or a compounding pharmacy for targeted testing. Suggested concentrations for patch testing based on the literature and expert reference are listed in the Table. The authors (M.R., A.R.A.) frequently rely on an expert reference⁶⁶ to determine ideal concentrations for patch testing. Referral to a specialized patch test clinic may be appropriate.

Final Interpretation

Although their intent is to heal, topical medicaments also can be a source of ACD. The astute clinician should consider ACD when topicals either no longer seem to help the patient or trigger new-onset dermatitis. Patch testing directly with the culprit medicament, or individual medication ingredients when needed, can lead to the diagnosis, though caution is advised. Stay tuned for part 2 of this series in which we will discuss ACD to topical steroids, immunomodulators, and anesthetic medications.

The proposed 2022 Medicare physician fee schedule and quality payment program (QPP) regulations were released on July 13, 2021.¹ Final regulations are expected to be released on or around November 1, 2021, but they may be delayed. Multiple national medical organizations, including the College of American Pathologists (CAP), the American Society of Dermatopathology, the American Academy of Dermatology Association (AADA), and the American Medical Association (AMA) Physicians’ Grassroots Network all work together to engage with the Centers for Medicare & Medicaid Services (CMS) to influence these regulations. Stated advocacy priorities include protecting the value of dermatopathology services, mobilizing dermatopathologists for political action, ensuring dermatopathologists can participate in new payment models, strengthening the profession with advocacy on a state level, and conducting socioeconomic research. Is your practice aware and prepared to handle the changes coming in 2022?

2021 Medicare Cuts

The recent revisions and revaluations of the outpatient evaluation and management (E/M) codes² resulted in a considerable redistribution of Medicare dollars in 2021, negatively impacting dermatopathologists and other specialties and services due to budget neutrality required by law (Figure). Important steps were taken to mitigate the 2021 Medicare cuts for all non–office-based dermatopathology services (eg, pathology, surgical services, emergency department).^1,3 Direct engagement by the CAP, American Society of Dermatopathology, and AADA, along with the AMA Physicians’ Grassroots Network resulted in legislative action on December 27, 2020, which directed Medicare to make a 3.75% positive adjustment to the 2021 physician payments. Additionally, the CMS updated the 2021 physician conversion factor to $34.8931, a 3.3% reduction from the 2020 conversion factor rather than $32.41, or a 10.20% decrease. The 2% payment adjustment (sequestration) through December 21, 2021, also was suspended, and Congress and the Biden administration mandated delayed implementation of the inherent complexity add-on code for E/M services (G2211) until 2024.^1,3

Threat of Medicare Cuts in 2022

Based on dermatopathology utilization data, the overall impact on reimbursement for 2022 represents an approximately 5% decrease from 2021 dermatopathology payments (Table 1).^1,4 This represents a 3.75% cut from revaluation of E/M services, and a 1% cut due to changes in practice expense pricing. The estimated change in reimbursement for independent laboratories is a 6% decrease. Advocacy groups have been working to mitigate the 2022 cuts by engaging with Congress and urging them to act before these changes go into effect next year. Keep in mind that approximately half of all pathology Current Procedural Terminology (CPT) codes have been targeted for evaluation by the CMS since 2006.^1,4

Coding for Clinical Pathology Consultation Services

The current clinical pathology consultation services (CPT codes 80500 and 80502) previously were identified as potentially misvalued for review by the AMA Relative Value Scale Update Committee’s (RUC’s) relativity assessment workgroup.⁴ Consequently, the CAP worked with the AMA’s CPT Editorial Panel to delete codes 80500 and 80502, as well as to modernize and create the 4 new clinical pathology consultation codes: 80XX0, 80XX1, 80XX2, and 80XX3. Then the CAP worked with the RUC to develop physician work and practice expense values for the new clinical pathology consultation codes. Once the fee schedule is finalized, pathologists can begin using the new codes to bill these services in 2022 (Table 2).⁴

According to CPT, clinical pathology consultation services may be reported when the following criteria have been met: (1) the pathologist renders a clinical pathology consultation at the request of a physician or qualified health care professional at the same or another institution; (2) the pathology clinical consultation request relating to pathology and laboratory findings or other relevant clinical or diagnostic information requiring additional medical interpretative judgment is made; and (3) these codes are not reported in conjunction with codes 88321, 88323, and 88325.⁴

Proposed 2022 Medicare QPP Requirements

On July 13, 2021, the CMS also published its proposed 2022 QPP proposals that will take effect next year.⁴ According to the proposed regulation, nearly all dermatopathologists will be required to participate in Medicare’s QPP, either through advanced alternative payment models (APMs) or the Merit-based Incentive Payment System (MIPS). The CAP has long advocated for reducing MIPS reporting burdens for dermatopathologists. In this regulation, the CMS is proposing key program changes that move the program forward but also introduce additional complexities; for example, the CMS will move forward with a new participation pathway called MIPS Value Pathways (MVPs). The CMS proposed 7 specific MVPs that align with certain clinical topics; however, it will not implement these MVPs until the 2023 MIPS performance period.

In 2022, dermatopathologists who are eligible for MIPS will have to take action to avoid penalties that reduce future Medicare Part B payments for their services. Performance in MIPS in 2022 affects Medicare Part B payments in 2024 by an increase of 9% to a decrease of 9%.

In its proposed 2022 QPP regulations, the CMS proposed an increase of the performance threshold from 60 MIPS points to 75 MIPS points. It also proposed an increase of the exceptional Performance Threshold from 85 MIPS points to 89 MIPS points.

The CMS also proposed notable scoring changes for quality measures, including removing the 3-point floor for measures that can be scored against a benchmark. These measures would receive 1 to 10 points. Measures without a benchmark or that do not meet case requirements would earn 0 points, with an exception for small practices. The CMS also proposed removing bonus points for reporting additional outcomes and high-priority measures beyond the 1 that is required, as well as establishing a 5-point floor for the first 2 performance periods for new measures, which is in line with the CAP’s advocacy.

The Pathology Specialty Measure Set will remain the same as the 2021 set containing 6 quality measures, including the AADA-stewarded quality measure #440 (skin cancer: biopsy reporting time—pathologist to clinician). Although the CAP recognizes the importance of prompt turnaround of biopsy reports, it also is working with the CMS and the AADA to mitigate the operational challenges dermatopathologists encounter when using this measure. 

Due to advocacy from the CAP, the CMS included a CAP-proposed improvement activity on implementation of a laboratory preparedness plan to support continued or expanded patient care during the COVID-19 pandemic or another public health emergency. This plan should address how the laboratory would maintain or expand access to improve beneficiary health outcomes and reduce health care disparities.

The CAP has actively worked with the CMS to demonstrate the need for more appropriate and alternative measures and improvement activities so that pathologists can more fully participate in MIPS. 

Alternative Payment Models—For those dermatopathologists who practice in an APM, the proposed 2022 QPP makes minimal changes to the advanced APM track while adding transition time for accountable care organizations in the Medicare Shared Savings Program to report on certain quality measures and increasing flexibility related to the program’s quality performance standard.

Cures Act 2021: To Do No Harm

The 21st Century Cures Act (Cures Act) was signed into federal law in 2016. The Office of the National Coordinator for Health Information Technology (ONC) laid the groundwork for patients to have easier access to and control of their health information.⁵ The ONC’s final rule, which went into effect on April 5, 2021, requires that all providers make their office notes, laboratory results, and other diagnostic reports (including dermatopathology reports) available to patients as soon as the physician’s office receives an electronic copy. Penalty for noncompliance has not been determined.

There are information-blocking exceptions, but delaying access to a patient’s report so that a provider can review the result before the patient receives it is not considered an exception.⁶ The exceptions are situational and must be evaluated by the referring clinician or their employer. Documentation of the exception is critical. The specific facts and circumstances associated with your decision to use an exception will be important to include in your documentation. Information blocking necessary to prevent “harm” to a patient or another person requires a reasonable belief that the practice will substantially reduce the risk of harm.⁶

The AMA passed a resolution in June 2021 calling for changes to this rule to allow for a delay of pathology results, advocating to the Office for Civil Rights to revise the harm exception to include psychological distress.⁶ In August 2021, the AADA met with senior officials at the ONC also asking to revise its definition of harm, sharing examples of emotional strain that resulted from receiving results without clinical context.⁷ California enacted a law requiring a delay before a patient receives the result of a malignant diagnosis, giving the clinician time to contact the patient before they see their report.⁸

The Cures Act requirements are about patients accessing their health care information. Always consider what is best for the patient and ensure that your policies and procedures reflect this.⁵

Final Thoughts

It is important to learn and support advocacy priorities and efforts and to join forces to protect your practice. Physician advocacy is no longer an elective pursuit. We need to be involved and engaged through our medical societies to help patients, communities, and ourselves.

The proposed 2022 Medicare physician fee schedule and quality payment program (QPP) regulations were released on July 13, 2021.¹ Final regulations are expected to be released on or around November 1, 2021, but they may be delayed. Multiple national medical organizations, including the College of American Pathologists (CAP), the American Society of Dermatopathology, the American Academy of Dermatology Association (AADA), and the American Medical Association (AMA) Physicians’ Grassroots Network all work together to engage with the Centers for Medicare & Medicaid Services (CMS) to influence these regulations. Stated advocacy priorities include protecting the value of dermatopathology services, mobilizing dermatopathologists for political action, ensuring dermatopathologists can participate in new payment models, strengthening the profession with advocacy on a state level, and conducting socioeconomic research. Is your practice aware and prepared to handle the changes coming in 2022?

2021 Medicare Cuts

The recent revisions and revaluations of the outpatient evaluation and management (E/M) codes² resulted in a considerable redistribution of Medicare dollars in 2021, negatively impacting dermatopathologists and other specialties and services due to budget neutrality required by law (Figure). Important steps were taken to mitigate the 2021 Medicare cuts for all non–office-based dermatopathology services (eg, pathology, surgical services, emergency department).^1,3 Direct engagement by the CAP, American Society of Dermatopathology, and AADA, along with the AMA Physicians’ Grassroots Network resulted in legislative action on December 27, 2020, which directed Medicare to make a 3.75% positive adjustment to the 2021 physician payments. Additionally, the CMS updated the 2021 physician conversion factor to $34.8931, a 3.3% reduction from the 2020 conversion factor rather than $32.41, or a 10.20% decrease. The 2% payment adjustment (sequestration) through December 21, 2021, also was suspended, and Congress and the Biden administration mandated delayed implementation of the inherent complexity add-on code for E/M services (G2211) until 2024.^1,3

Threat of Medicare Cuts in 2022

Based on dermatopathology utilization data, the overall impact on reimbursement for 2022 represents an approximately 5% decrease from 2021 dermatopathology payments (Table 1).^1,4 This represents a 3.75% cut from revaluation of E/M services, and a 1% cut due to changes in practice expense pricing. The estimated change in reimbursement for independent laboratories is a 6% decrease. Advocacy groups have been working to mitigate the 2022 cuts by engaging with Congress and urging them to act before these changes go into effect next year. Keep in mind that approximately half of all pathology Current Procedural Terminology (CPT) codes have been targeted for evaluation by the CMS since 2006.^1,4

Coding for Clinical Pathology Consultation Services

The current clinical pathology consultation services (CPT codes 80500 and 80502) previously were identified as potentially misvalued for review by the AMA Relative Value Scale Update Committee’s (RUC’s) relativity assessment workgroup.⁴ Consequently, the CAP worked with the AMA’s CPT Editorial Panel to delete codes 80500 and 80502, as well as to modernize and create the 4 new clinical pathology consultation codes: 80XX0, 80XX1, 80XX2, and 80XX3. Then the CAP worked with the RUC to develop physician work and practice expense values for the new clinical pathology consultation codes. Once the fee schedule is finalized, pathologists can begin using the new codes to bill these services in 2022 (Table 2).⁴

According to CPT, clinical pathology consultation services may be reported when the following criteria have been met: (1) the pathologist renders a clinical pathology consultation at the request of a physician or qualified health care professional at the same or another institution; (2) the pathology clinical consultation request relating to pathology and laboratory findings or other relevant clinical or diagnostic information requiring additional medical interpretative judgment is made; and (3) these codes are not reported in conjunction with codes 88321, 88323, and 88325.⁴

Proposed 2022 Medicare QPP Requirements

On July 13, 2021, the CMS also published its proposed 2022 QPP proposals that will take effect next year.⁴ According to the proposed regulation, nearly all dermatopathologists will be required to participate in Medicare’s QPP, either through advanced alternative payment models (APMs) or the Merit-based Incentive Payment System (MIPS). The CAP has long advocated for reducing MIPS reporting burdens for dermatopathologists. In this regulation, the CMS is proposing key program changes that move the program forward but also introduce additional complexities; for example, the CMS will move forward with a new participation pathway called MIPS Value Pathways (MVPs). The CMS proposed 7 specific MVPs that align with certain clinical topics; however, it will not implement these MVPs until the 2023 MIPS performance period.

In 2022, dermatopathologists who are eligible for MIPS will have to take action to avoid penalties that reduce future Medicare Part B payments for their services. Performance in MIPS in 2022 affects Medicare Part B payments in 2024 by an increase of 9% to a decrease of 9%.

In its proposed 2022 QPP regulations, the CMS proposed an increase of the performance threshold from 60 MIPS points to 75 MIPS points. It also proposed an increase of the exceptional Performance Threshold from 85 MIPS points to 89 MIPS points.

The CMS also proposed notable scoring changes for quality measures, including removing the 3-point floor for measures that can be scored against a benchmark. These measures would receive 1 to 10 points. Measures without a benchmark or that do not meet case requirements would earn 0 points, with an exception for small practices. The CMS also proposed removing bonus points for reporting additional outcomes and high-priority measures beyond the 1 that is required, as well as establishing a 5-point floor for the first 2 performance periods for new measures, which is in line with the CAP’s advocacy.

The Pathology Specialty Measure Set will remain the same as the 2021 set containing 6 quality measures, including the AADA-stewarded quality measure #440 (skin cancer: biopsy reporting time—pathologist to clinician). Although the CAP recognizes the importance of prompt turnaround of biopsy reports, it also is working with the CMS and the AADA to mitigate the operational challenges dermatopathologists encounter when using this measure. 

Due to advocacy from the CAP, the CMS included a CAP-proposed improvement activity on implementation of a laboratory preparedness plan to support continued or expanded patient care during the COVID-19 pandemic or another public health emergency. This plan should address how the laboratory would maintain or expand access to improve beneficiary health outcomes and reduce health care disparities.

The CAP has actively worked with the CMS to demonstrate the need for more appropriate and alternative measures and improvement activities so that pathologists can more fully participate in MIPS. 

Alternative Payment Models—For those dermatopathologists who practice in an APM, the proposed 2022 QPP makes minimal changes to the advanced APM track while adding transition time for accountable care organizations in the Medicare Shared Savings Program to report on certain quality measures and increasing flexibility related to the program’s quality performance standard.

Cures Act 2021: To Do No Harm

The 21st Century Cures Act (Cures Act) was signed into federal law in 2016. The Office of the National Coordinator for Health Information Technology (ONC) laid the groundwork for patients to have easier access to and control of their health information.⁵ The ONC’s final rule, which went into effect on April 5, 2021, requires that all providers make their office notes, laboratory results, and other diagnostic reports (including dermatopathology reports) available to patients as soon as the physician’s office receives an electronic copy. Penalty for noncompliance has not been determined.

There are information-blocking exceptions, but delaying access to a patient’s report so that a provider can review the result before the patient receives it is not considered an exception.⁶ The exceptions are situational and must be evaluated by the referring clinician or their employer. Documentation of the exception is critical. The specific facts and circumstances associated with your decision to use an exception will be important to include in your documentation. Information blocking necessary to prevent “harm” to a patient or another person requires a reasonable belief that the practice will substantially reduce the risk of harm.⁶

The AMA passed a resolution in June 2021 calling for changes to this rule to allow for a delay of pathology results, advocating to the Office for Civil Rights to revise the harm exception to include psychological distress.⁶ In August 2021, the AADA met with senior officials at the ONC also asking to revise its definition of harm, sharing examples of emotional strain that resulted from receiving results without clinical context.⁷ California enacted a law requiring a delay before a patient receives the result of a malignant diagnosis, giving the clinician time to contact the patient before they see their report.⁸

The Cures Act requirements are about patients accessing their health care information. Always consider what is best for the patient and ensure that your policies and procedures reflect this.⁵

Final Thoughts

It is important to learn and support advocacy priorities and efforts and to join forces to protect your practice. Physician advocacy is no longer an elective pursuit. We need to be involved and engaged through our medical societies to help patients, communities, and ourselves.

The proposed 2022 Medicare physician fee schedule and quality payment program (QPP) regulations were released on July 13, 2021.¹ Final regulations are expected to be released on or around November 1, 2021, but they may be delayed. Multiple national medical organizations, including the College of American Pathologists (CAP), the American Society of Dermatopathology, the American Academy of Dermatology Association (AADA), and the American Medical Association (AMA) Physicians’ Grassroots Network all work together to engage with the Centers for Medicare & Medicaid Services (CMS) to influence these regulations. Stated advocacy priorities include protecting the value of dermatopathology services, mobilizing dermatopathologists for political action, ensuring dermatopathologists can participate in new payment models, strengthening the profession with advocacy on a state level, and conducting socioeconomic research. Is your practice aware and prepared to handle the changes coming in 2022?

2021 Medicare Cuts

The recent revisions and revaluations of the outpatient evaluation and management (E/M) codes² resulted in a considerable redistribution of Medicare dollars in 2021, negatively impacting dermatopathologists and other specialties and services due to budget neutrality required by law (Figure). Important steps were taken to mitigate the 2021 Medicare cuts for all non–office-based dermatopathology services (eg, pathology, surgical services, emergency department).^1,3 Direct engagement by the CAP, American Society of Dermatopathology, and AADA, along with the AMA Physicians’ Grassroots Network resulted in legislative action on December 27, 2020, which directed Medicare to make a 3.75% positive adjustment to the 2021 physician payments. Additionally, the CMS updated the 2021 physician conversion factor to $34.8931, a 3.3% reduction from the 2020 conversion factor rather than $32.41, or a 10.20% decrease. The 2% payment adjustment (sequestration) through December 21, 2021, also was suspended, and Congress and the Biden administration mandated delayed implementation of the inherent complexity add-on code for E/M services (G2211) until 2024.^1,3

Threat of Medicare Cuts in 2022

Based on dermatopathology utilization data, the overall impact on reimbursement for 2022 represents an approximately 5% decrease from 2021 dermatopathology payments (Table 1).^1,4 This represents a 3.75% cut from revaluation of E/M services, and a 1% cut due to changes in practice expense pricing. The estimated change in reimbursement for independent laboratories is a 6% decrease. Advocacy groups have been working to mitigate the 2022 cuts by engaging with Congress and urging them to act before these changes go into effect next year. Keep in mind that approximately half of all pathology Current Procedural Terminology (CPT) codes have been targeted for evaluation by the CMS since 2006.^1,4

Coding for Clinical Pathology Consultation Services

The current clinical pathology consultation services (CPT codes 80500 and 80502) previously were identified as potentially misvalued for review by the AMA Relative Value Scale Update Committee’s (RUC’s) relativity assessment workgroup.⁴ Consequently, the CAP worked with the AMA’s CPT Editorial Panel to delete codes 80500 and 80502, as well as to modernize and create the 4 new clinical pathology consultation codes: 80XX0, 80XX1, 80XX2, and 80XX3. Then the CAP worked with the RUC to develop physician work and practice expense values for the new clinical pathology consultation codes. Once the fee schedule is finalized, pathologists can begin using the new codes to bill these services in 2022 (Table 2).⁴

According to CPT, clinical pathology consultation services may be reported when the following criteria have been met: (1) the pathologist renders a clinical pathology consultation at the request of a physician or qualified health care professional at the same or another institution; (2) the pathology clinical consultation request relating to pathology and laboratory findings or other relevant clinical or diagnostic information requiring additional medical interpretative judgment is made; and (3) these codes are not reported in conjunction with codes 88321, 88323, and 88325.⁴

Proposed 2022 Medicare QPP Requirements

On July 13, 2021, the CMS also published its proposed 2022 QPP proposals that will take effect next year.⁴ According to the proposed regulation, nearly all dermatopathologists will be required to participate in Medicare’s QPP, either through advanced alternative payment models (APMs) or the Merit-based Incentive Payment System (MIPS). The CAP has long advocated for reducing MIPS reporting burdens for dermatopathologists. In this regulation, the CMS is proposing key program changes that move the program forward but also introduce additional complexities; for example, the CMS will move forward with a new participation pathway called MIPS Value Pathways (MVPs). The CMS proposed 7 specific MVPs that align with certain clinical topics; however, it will not implement these MVPs until the 2023 MIPS performance period.

In 2022, dermatopathologists who are eligible for MIPS will have to take action to avoid penalties that reduce future Medicare Part B payments for their services. Performance in MIPS in 2022 affects Medicare Part B payments in 2024 by an increase of 9% to a decrease of 9%.

In its proposed 2022 QPP regulations, the CMS proposed an increase of the performance threshold from 60 MIPS points to 75 MIPS points. It also proposed an increase of the exceptional Performance Threshold from 85 MIPS points to 89 MIPS points.

The CMS also proposed notable scoring changes for quality measures, including removing the 3-point floor for measures that can be scored against a benchmark. These measures would receive 1 to 10 points. Measures without a benchmark or that do not meet case requirements would earn 0 points, with an exception for small practices. The CMS also proposed removing bonus points for reporting additional outcomes and high-priority measures beyond the 1 that is required, as well as establishing a 5-point floor for the first 2 performance periods for new measures, which is in line with the CAP’s advocacy.

The Pathology Specialty Measure Set will remain the same as the 2021 set containing 6 quality measures, including the AADA-stewarded quality measure #440 (skin cancer: biopsy reporting time—pathologist to clinician). Although the CAP recognizes the importance of prompt turnaround of biopsy reports, it also is working with the CMS and the AADA to mitigate the operational challenges dermatopathologists encounter when using this measure. 

Due to advocacy from the CAP, the CMS included a CAP-proposed improvement activity on implementation of a laboratory preparedness plan to support continued or expanded patient care during the COVID-19 pandemic or another public health emergency. This plan should address how the laboratory would maintain or expand access to improve beneficiary health outcomes and reduce health care disparities.

The CAP has actively worked with the CMS to demonstrate the need for more appropriate and alternative measures and improvement activities so that pathologists can more fully participate in MIPS. 

Alternative Payment Models—For those dermatopathologists who practice in an APM, the proposed 2022 QPP makes minimal changes to the advanced APM track while adding transition time for accountable care organizations in the Medicare Shared Savings Program to report on certain quality measures and increasing flexibility related to the program’s quality performance standard.

Cures Act 2021: To Do No Harm

The 21st Century Cures Act (Cures Act) was signed into federal law in 2016. The Office of the National Coordinator for Health Information Technology (ONC) laid the groundwork for patients to have easier access to and control of their health information.⁵ The ONC’s final rule, which went into effect on April 5, 2021, requires that all providers make their office notes, laboratory results, and other diagnostic reports (including dermatopathology reports) available to patients as soon as the physician’s office receives an electronic copy. Penalty for noncompliance has not been determined.

There are information-blocking exceptions, but delaying access to a patient’s report so that a provider can review the result before the patient receives it is not considered an exception.⁶ The exceptions are situational and must be evaluated by the referring clinician or their employer. Documentation of the exception is critical. The specific facts and circumstances associated with your decision to use an exception will be important to include in your documentation. Information blocking necessary to prevent “harm” to a patient or another person requires a reasonable belief that the practice will substantially reduce the risk of harm.⁶

The AMA passed a resolution in June 2021 calling for changes to this rule to allow for a delay of pathology results, advocating to the Office for Civil Rights to revise the harm exception to include psychological distress.⁶ In August 2021, the AADA met with senior officials at the ONC also asking to revise its definition of harm, sharing examples of emotional strain that resulted from receiving results without clinical context.⁷ California enacted a law requiring a delay before a patient receives the result of a malignant diagnosis, giving the clinician time to contact the patient before they see their report.⁸

The Cures Act requirements are about patients accessing their health care information. Always consider what is best for the patient and ensure that your policies and procedures reflect this.⁵

Final Thoughts

It is important to learn and support advocacy priorities and efforts and to join forces to protect your practice. Physician advocacy is no longer an elective pursuit. We need to be involved and engaged through our medical societies to help patients, communities, and ourselves.

Giant hogweed (Heracleum mantegazzianum) is an invasive flowering weed of the family Apiaceae that typically reaches a height of 13 feet, with thick stems; large green leaves; and umbrella-shaped, flat-topped, radial clusters (umbels) of small individual white flowers¹ (Figure 1). Because of the size and beauty of giant hogweed, it was widely planted in 19th century ornamental gardens in the United Kingdom and has since naturalized and spread throughout central Europe, Canada, and the United States.^1,2 The plant most commonly is found in shady areas near rivers and woodlands.¹

Due to the invasive nature of the giant hogweed, its prevalence continues to grow, its eradication remains difficult, and reports of phytophotodermatitis are increasing in number and distribution. In fact, there has been widespread media coverage of the dangers of giant hogweed in the United Kingdom since 2016¹ and in the United States in 2018 and 2019.^3-6

Transmission

Phytophotodermatitis is a type of nonimmunologic dermatitis caused by UV light reacting with a plant-based photosensitizing agent. In the case of giant hogweed, sap from the plant’s fruits, leaves, and stem contain furocoumarins or psoralens.⁷ Upon activation by UVA radiation, furan rings of these compounds create reactive oxygen species and intercalate with DNA pyrimidine bases, which results in cellular death, damage to successive skin layers, and reduced wound healing at the cellular level.⁸ This effect is intensified with increased percutaneous absorption of furocoumarin, which can result from high temperature, humidity, skin infection, lack of protective clothing, and moist conditions.⁹

The highest concentration of phototoxic compounds is found in giant hogweed from June through August,⁷ which, in combination with people increasing their outdoor activity in the summer, results in a greater prevalence and severity of H mantegazzianum phytophotodermatitis during summer months.

Presentation

Phytophotodermatitis caused by giant hogweed can range from burning and erythema to full-thickness chemical burns that require surgical debridement and skin grafting.⁸ After exposure to the offending agent, a harmful skin reaction can start within 15 minutes. After a latent period of approximately 24 hours, erythema, edema, and bullae can appear and generally peak by 72 hours.¹⁰ In addition to cutaneous injury, inhalation of giant hogweed traces can result in obstructive pulmonary symptoms. Eye contact can result in blindness.⁹

In addition to the rash caused by giant hogweed, a “weed-wacker dermatitis” or “strimmer rash” can be caused by the similar-appearing but smaller common hogweed (Heracleum sphondylium). Common hogweed is highly prevalent in the United States and often is confused with the larger giant hogweed because of tall stems and white, flat-topped flowers.

Management

Following contact with giant hogweed, a person should immediately avoid UV exposure and rinse the area with soap and water. UV radiation must be avoided for at least 48 hours. If erythema occurs, a topical steroid can be applied to the affected area; pain can be alleviated by a nonsteroidal anti-inflammatory drug.⁹

Further treatment might be required if bullous lesions are present. Small blisters can be punctured and drained; however, large blisters, extensive epidermal-dermal separation, and large areas of detached epidermis should simply be cleansed and dressed. An oral steroid also can be used to reduce inflammation in moderate and severe cases. Full-thickness injury might require surgical intervention.⁸

Clinical Case

A 27-year-old male landscaper presented to the emergency department with an increasingly painful blistering rash on the arms and neck of 1 day’s duration. He noticed bright red skin and blisters 18 to 24 hours after trimming what he identified as shoulder-high giant hogweed plants. Neither he nor his coworkers were wearing sunscreen or protective clothing as they cleared the plants for several hours. His coworkers developed similar rashes, but his rash was the most severe, requiring treatment in the emergency department.

Physical examination showed innumerable 2- to 10-mm, tense vesicles and bullae on a background of blanching erythema in a striking photodistribution along the neck (Figure 2) and arms (Figure 3). He had notable edema of both arms and several large 3- to 4-cm bullae on the ventral aspects of the forearms.

The patient was diagnosed with severe phytophotodermatitis secondary to contact with H mantegazzianum and was started on oral prednisone 70 mg daily (1 mg/kg/d), which was decreased by 10 mg every 3 days until the course of treatment was complete. He also was instructed to apply mupirocin ointment to open areas and petroleum jelly to intact skin. Additionally, he was advised to practice strict photoprotection for the near and distant future.

Within several days after treatment began, the phytophotodermatitis dramatically improved, with complete resolution in 1 week. Postinflammatory hyperpigmentation resolved after several weeks.

Giant hogweed (Heracleum mantegazzianum) is an invasive flowering weed of the family Apiaceae that typically reaches a height of 13 feet, with thick stems; large green leaves; and umbrella-shaped, flat-topped, radial clusters (umbels) of small individual white flowers¹ (Figure 1). Because of the size and beauty of giant hogweed, it was widely planted in 19th century ornamental gardens in the United Kingdom and has since naturalized and spread throughout central Europe, Canada, and the United States.^1,2 The plant most commonly is found in shady areas near rivers and woodlands.¹

Due to the invasive nature of the giant hogweed, its prevalence continues to grow, its eradication remains difficult, and reports of phytophotodermatitis are increasing in number and distribution. In fact, there has been widespread media coverage of the dangers of giant hogweed in the United Kingdom since 2016¹ and in the United States in 2018 and 2019.^3-6

Transmission

Phytophotodermatitis is a type of nonimmunologic dermatitis caused by UV light reacting with a plant-based photosensitizing agent. In the case of giant hogweed, sap from the plant’s fruits, leaves, and stem contain furocoumarins or psoralens.⁷ Upon activation by UVA radiation, furan rings of these compounds create reactive oxygen species and intercalate with DNA pyrimidine bases, which results in cellular death, damage to successive skin layers, and reduced wound healing at the cellular level.⁸ This effect is intensified with increased percutaneous absorption of furocoumarin, which can result from high temperature, humidity, skin infection, lack of protective clothing, and moist conditions.⁹

The highest concentration of phototoxic compounds is found in giant hogweed from June through August,⁷ which, in combination with people increasing their outdoor activity in the summer, results in a greater prevalence and severity of H mantegazzianum phytophotodermatitis during summer months.

Presentation

Phytophotodermatitis caused by giant hogweed can range from burning and erythema to full-thickness chemical burns that require surgical debridement and skin grafting.⁸ After exposure to the offending agent, a harmful skin reaction can start within 15 minutes. After a latent period of approximately 24 hours, erythema, edema, and bullae can appear and generally peak by 72 hours.¹⁰ In addition to cutaneous injury, inhalation of giant hogweed traces can result in obstructive pulmonary symptoms. Eye contact can result in blindness.⁹

In addition to the rash caused by giant hogweed, a “weed-wacker dermatitis” or “strimmer rash” can be caused by the similar-appearing but smaller common hogweed (Heracleum sphondylium). Common hogweed is highly prevalent in the United States and often is confused with the larger giant hogweed because of tall stems and white, flat-topped flowers.

Management

Following contact with giant hogweed, a person should immediately avoid UV exposure and rinse the area with soap and water. UV radiation must be avoided for at least 48 hours. If erythema occurs, a topical steroid can be applied to the affected area; pain can be alleviated by a nonsteroidal anti-inflammatory drug.⁹

Further treatment might be required if bullous lesions are present. Small blisters can be punctured and drained; however, large blisters, extensive epidermal-dermal separation, and large areas of detached epidermis should simply be cleansed and dressed. An oral steroid also can be used to reduce inflammation in moderate and severe cases. Full-thickness injury might require surgical intervention.⁸

Clinical Case

A 27-year-old male landscaper presented to the emergency department with an increasingly painful blistering rash on the arms and neck of 1 day’s duration. He noticed bright red skin and blisters 18 to 24 hours after trimming what he identified as shoulder-high giant hogweed plants. Neither he nor his coworkers were wearing sunscreen or protective clothing as they cleared the plants for several hours. His coworkers developed similar rashes, but his rash was the most severe, requiring treatment in the emergency department.

Physical examination showed innumerable 2- to 10-mm, tense vesicles and bullae on a background of blanching erythema in a striking photodistribution along the neck (Figure 2) and arms (Figure 3). He had notable edema of both arms and several large 3- to 4-cm bullae on the ventral aspects of the forearms.

The patient was diagnosed with severe phytophotodermatitis secondary to contact with H mantegazzianum and was started on oral prednisone 70 mg daily (1 mg/kg/d), which was decreased by 10 mg every 3 days until the course of treatment was complete. He also was instructed to apply mupirocin ointment to open areas and petroleum jelly to intact skin. Additionally, he was advised to practice strict photoprotection for the near and distant future.

Within several days after treatment began, the phytophotodermatitis dramatically improved, with complete resolution in 1 week. Postinflammatory hyperpigmentation resolved after several weeks.

Giant hogweed (Heracleum mantegazzianum) is an invasive flowering weed of the family Apiaceae that typically reaches a height of 13 feet, with thick stems; large green leaves; and umbrella-shaped, flat-topped, radial clusters (umbels) of small individual white flowers¹ (Figure 1). Because of the size and beauty of giant hogweed, it was widely planted in 19th century ornamental gardens in the United Kingdom and has since naturalized and spread throughout central Europe, Canada, and the United States.^1,2 The plant most commonly is found in shady areas near rivers and woodlands.¹

Due to the invasive nature of the giant hogweed, its prevalence continues to grow, its eradication remains difficult, and reports of phytophotodermatitis are increasing in number and distribution. In fact, there has been widespread media coverage of the dangers of giant hogweed in the United Kingdom since 2016¹ and in the United States in 2018 and 2019.^3-6

Transmission

Phytophotodermatitis is a type of nonimmunologic dermatitis caused by UV light reacting with a plant-based photosensitizing agent. In the case of giant hogweed, sap from the plant’s fruits, leaves, and stem contain furocoumarins or psoralens.⁷ Upon activation by UVA radiation, furan rings of these compounds create reactive oxygen species and intercalate with DNA pyrimidine bases, which results in cellular death, damage to successive skin layers, and reduced wound healing at the cellular level.⁸ This effect is intensified with increased percutaneous absorption of furocoumarin, which can result from high temperature, humidity, skin infection, lack of protective clothing, and moist conditions.⁹

The highest concentration of phototoxic compounds is found in giant hogweed from June through August,⁷ which, in combination with people increasing their outdoor activity in the summer, results in a greater prevalence and severity of H mantegazzianum phytophotodermatitis during summer months.

Presentation

Phytophotodermatitis caused by giant hogweed can range from burning and erythema to full-thickness chemical burns that require surgical debridement and skin grafting.⁸ After exposure to the offending agent, a harmful skin reaction can start within 15 minutes. After a latent period of approximately 24 hours, erythema, edema, and bullae can appear and generally peak by 72 hours.¹⁰ In addition to cutaneous injury, inhalation of giant hogweed traces can result in obstructive pulmonary symptoms. Eye contact can result in blindness.⁹

In addition to the rash caused by giant hogweed, a “weed-wacker dermatitis” or “strimmer rash” can be caused by the similar-appearing but smaller common hogweed (Heracleum sphondylium). Common hogweed is highly prevalent in the United States and often is confused with the larger giant hogweed because of tall stems and white, flat-topped flowers.

Management

Following contact with giant hogweed, a person should immediately avoid UV exposure and rinse the area with soap and water. UV radiation must be avoided for at least 48 hours. If erythema occurs, a topical steroid can be applied to the affected area; pain can be alleviated by a nonsteroidal anti-inflammatory drug.⁹

Further treatment might be required if bullous lesions are present. Small blisters can be punctured and drained; however, large blisters, extensive epidermal-dermal separation, and large areas of detached epidermis should simply be cleansed and dressed. An oral steroid also can be used to reduce inflammation in moderate and severe cases. Full-thickness injury might require surgical intervention.⁸

Clinical Case

A 27-year-old male landscaper presented to the emergency department with an increasingly painful blistering rash on the arms and neck of 1 day’s duration. He noticed bright red skin and blisters 18 to 24 hours after trimming what he identified as shoulder-high giant hogweed plants. Neither he nor his coworkers were wearing sunscreen or protective clothing as they cleared the plants for several hours. His coworkers developed similar rashes, but his rash was the most severe, requiring treatment in the emergency department.

Physical examination showed innumerable 2- to 10-mm, tense vesicles and bullae on a background of blanching erythema in a striking photodistribution along the neck (Figure 2) and arms (Figure 3). He had notable edema of both arms and several large 3- to 4-cm bullae on the ventral aspects of the forearms.

The patient was diagnosed with severe phytophotodermatitis secondary to contact with H mantegazzianum and was started on oral prednisone 70 mg daily (1 mg/kg/d), which was decreased by 10 mg every 3 days until the course of treatment was complete. He also was instructed to apply mupirocin ointment to open areas and petroleum jelly to intact skin. Additionally, he was advised to practice strict photoprotection for the near and distant future.

Within several days after treatment began, the phytophotodermatitis dramatically improved, with complete resolution in 1 week. Postinflammatory hyperpigmentation resolved after several weeks.