Hospital Consult

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The World Health Organization defines malnutrition as deficiencies, excesses, or imbalances in an individual’s intake of energy and/or nutrients.¹ This review will focus on undernutrition, which may result from macronutrient or micronutrient deficiencies. Undernutrition in the hospitalized patient is a common yet underrecognized phenomenon, with an estimated prevalence of 20% to 50% worldwide.² Malnutrition is an independent risk factor for patient morbidity and mortality and has been associated with increased health care costs.³ Nutritional deficiencies may arise from inadequate nutrient intake, abnormal nutrient absorption, or improper nutrient utilization.⁴ Unfortunately, no standardized algorithm for screening and diagnosing patients with malnutrition exists, making early physical examination findings of utmost importance. Herein, we present a review of acquired nutritional deficiency dermatoses in the inpatient setting.

Protein-Energy Malnutrition

Protein-energy malnutrition (PEM) refers to a set of related disorders that include marasmus, kwashiorkor (KW), and marasmic KW. These conditions frequently are seen in developing countries but also have been reported in developed nations.⁵ Marasmus occurs from a chronic deficiency of protein and calories. Decreased insulin production and unopposed catabolism result in sarcopenia and loss of bone and subcutaneous fat.⁶ Affected patients include children who are less than 60% ideal body weight (IBW) without edema or hypoproteinemia.⁷ Kwashiorkor is the edematous form of PEM that develops from isolated protein deficiency, resulting in edema, diarrhea, and immunosuppression.⁶ Micronutrient deficiencies, oxidative stress, slow protein catabolism, and excess antidiuretic hormone have been proposed as potential drivers of KW.⁸ Kwashiorkor affects children between 60% and 80% IBW. Marasmic KW has features of both diseases, including children who are less than 60% IBW but with associated edema and/or hypoproteinemia.⁹

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Although PEM is uncommon in adults, hospitalized patients carry many predisposing risk factors, including infections, malabsorptive conditions, psychiatric disease, and chronic illness (eTable). Patients with chronic infections present with findings consistent with marasmic KW due to lean body mass loss.

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Zinc Deficiency

Zinc is an essential trace element that provides regulatory, structural, and catalytic functions across multiple biochemical pathways⁶ and serves as an enzymatic cofactor and key component for numerous transcription factors.¹⁷ Zinc is derived from food sources, and its concentration correlates with protein content.¹⁸ Zinc is found in both animal and plant-based proteins, albeit with a lower oral bioavailability in the latter. Zinc deficiency may be inherited or acquired. Primary acrodermatitis enteropathica is an autosomal-recessive disorder of the solute carrier family 39 member 4 gene, SLC39A4 (encodes zinc transporter ZIP4 on enterocytes); the result is abnormal zinc absorption from the small intestine.¹⁸

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Acquired zinc deficiency occurs from decreased dietary zinc intake, impaired intestinal zinc absorption, excessive zinc elimination, or systemic states of high catabolism or low albumin (eTable). Total parenteral nutrition–associated deficiency has arisen when nutritional formulations did not contain trace elements during national shortages or when prolonged TPN was not anticipated and trace elements were removed.¹⁹ Zinc levels may already be low in patients with chronic illness or inflammation, so even a short period on TPN can precipitate deficiency.^18,19 Diets high in phytate may result in zinc deficiency, as phytate impairs intestinal zinc absorption.²⁰ Approximately 15% of patients with inflammatory bowel disease experienced zinc deficiency worldwide.²¹ In Crohn disease, zinc deficiency has been associated with active intestinal inflammation, increased risk for hospitalization, surgeries, and disease-related complications.^22,23

Medications such as antiepileptics, antimetabolites, or penicillamine may induce zinc deficiency, highlighting the importance of medication review for hospitalized patients (eTable). Catabolic states, frequently encountered in hospitalized patients, increase the risk for zinc deficiency.²⁴ Patients with necrolytic migratory erythema (associated with pancreatic glucagonomas) often experience low serum zinc levels.²⁵

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The skin is the third most zinc-abundant tissue in the human body. Within keratinocytes, zinc is critical to normal proliferation and suppression of inflammation.¹⁷ Zinc also plays an important role in cutaneous immune function.²⁶ Zinc deficiency presents with sharply demarcated, flaccid pustules and bullae that erode into scaly, pink, eczematous or psoriasiform plaques. Lesions are found preferentially in acral and periorificial sites, often with crusting and exudate. The groin and flexural surfaces may be affected. Erosions often become secondarily impetiginized. Other cutaneous findings include angular cheilitis, stomatitis, glossitis, paronychia, onychodystrophy, generalized alopecia, and delayed wound healing.²⁶ Histopathology of skin lesions is characterized by granular layer loss, epidermal pallor, confluent parakeratosis, spongiosis, dyskeratosis, and psoriasiform hyperplasia.²⁷ Acquired bullous acrodermatitis enteropathica has been reported as a histologic mimicker of pemphigus foliaceous in patients on TPN.²⁸

Diagnosis of zinc deficiency is made by measuring plasma zinc levels. Fasting levels should be drawn in the morning, as they can fluctuate based on the time of day, stress levels, or inflammation.⁶ Sample hemolysis and anticoagulants high in zinc may falsely elevate plasma zinc. A normal zinc level is greater than 70 µg/dL; however, normal levels do not rule out deficiency.¹⁸ Measurement of zinc-dependent enzymes, such as alkaline phosphatase, can be a quick way to assess zinc status. Serum albumin also should be measured; because zinc is carried by albumin in the blood, hypoalbuminemia may result in secondary zinc deficiency.¹⁸

Zinc replacement therapy is largely through oral supplementation and should start at 0.5 to 2.0 mg/kg/d in adults with acquired disease.^29,30 Zinc sulfate is the most affordable and is the supplement of choice, with 50 mg of elemental zinc per 220 mg of zinc sulfate (~23% elemental zinc).³¹ Alternative zinc salts, such as zinc gluconate (13% elemental zinc), may be used. Patients with malabsorptive disorders often require parenteral supplementation.³² Clinical symptoms often will resolve within 1 to 2 weeks of supplementation.²⁹ In patients with primary acrodermatitis enteropathica, lifelong supplementation with 3 mg/kg/d elemental zinc should occur.⁶ Calcium and folate may reduce zinc absorption, while zinc supplementation can interfere with copper and iron absorption.³³

Iron Deficiency

Iron is an essential component of the hemoglobin molecule. Iron homeostasis and metabolism are tightly regulated processes that drive erythropoiesis. Only 5% to 10% of dietary iron is absorbed through nutrition, while the remainder is recycled from red cell breakdown. Both normal iron levels and iron deficiency (ID) are defined by age and gender.³⁴ Iron-deficiency anemia (IDA) is one of the most common cause-specific anemias worldwide.³⁵

Fatigue is the most common and earliest symptom of ID. In a single study, pallor was predictive of anemia in hospitalized patients; however, absence of pallor did not rule out anemia.³⁴ Dyspnea on exertion, tachycardia, dysphagia, and pica also may be reported. Cutaneous manifestations include koilonychia (Figure 2), glossitis, pruritus, angular cheilitis, and telogen effluvium. Plummer-Vinson syndrome is characterized by microcytic anemia, glossitis, and dysphagia.

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Iron deficiency can be present despite a normal hemoglobin level. Serum ferritin and percentage transferrin saturation are key to early identification of IDA.³⁵ Ferritin levels lower than 30 µg/L confirm the diagnosis. Decreased transferrin saturation and increased total iron binding capacity aid in the diagnosis of IDA. Serum ferritin is an acute-phase reactant, and levels may be falsely elevated in the setting of inflammation or infection.

Essential Fatty Acid Deficiency

Essential fatty acids (EFAs) including linoleic and α-linolenic acid cannot be synthesized by the human body and must be obtained through diet (mostly plant oils). Essential fatty acids have various functions, including maintaining phospholipid membrane integrity, forming prostaglandins and leukotrienes, and storing energy.⁴⁰ Essential fatty acids are important in the structure and function of the stratum corneum and are crucial in maintaining epidermal barrier function.⁴¹ Increased epidermal permeability and transepidermal water loss may be the first signs of EFA deficiency (EFAD).⁴²

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The cutaneous manifestations of EFAD include xerosis, weeping eczematous plaques, and erosions in intertriginous sites. The lesions may progress to widespread desquamation and erythema. With time, the skin can become thick and leathery. Alopecia may occur, and hair may depigment.⁷ Additional findings include poor wound healing and increased susceptibility to infections.^43,44

Essential fatty acid deficiency may occur when dietary fat intake is severely restricted or in malabsorptive states.^45,46 It develops in patients on prolonged TPN, typically when receiving fat-restricted nutrition,^47,48 as occurs in hypertriglyceridemia.⁴⁷ Essential fatty acid deficiency has developed in patients on TPN containing EFAs,⁴⁷ as the introduction of novel intravenous lipid emulsions has resulted in varying proportions of EFA.⁴⁰ Premature neonates are particularly at risk for EFAD.⁴⁹

The diagnosis of EFAD involves the measurement of the triene to tetraene ratio. A ratio of more than 0.2 suggests EFAD, but the clinical signs are not seen until the ratio is over 0.4.⁴⁰ Low plasma levels of linoleic, linolenic, and arachidonic acids also are seen. Elevated liver function tests are supportive of the diagnosis. Biochemical findings typically are seen before cutaneous manifestations.⁴⁰

Treatment of EFAD includes topical, oral, or intravenous replacement of EFAs. Improvement of EFAD with the application of topical linoleic acid to the skin has been reported.⁵⁰ Patients receiving TPN should undergo assessment of parenteral lipid emulsion to ensure adequate fatty acid composition.

Vitamin A Deficiency

Vitamin A (retinol) is a fat-soluble vitamin that plays a critical role in keratinization, epithelial proliferation, and cellular differentiation.⁶ Vitamin A is found in animal products as retinyl esters and in plants as beta-carotene. Vitamin A has 2 clinically important forms: all-trans retinoic acid and 11-cis-retinal. All-trans retinoic acid is involved in cellular differentiation and regulating gene transcription, while 11-cis-retinal is key to rhodopsin generation required for vision. Vitamin A deficiency presents with early ophthalmologic findings, specifically nyctalopia, or delayed adaptation to the dark.⁵¹ Xerophthalmia, abnormal conjunctival keratinization, and Bitot spots subsequently develop and may progress to corneal ulceration and blindness.⁶

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Vitamin A deficiency manifests in the skin as follicular hyperkeratosis, or phrynoderma. Notably, numerous other micronutrient deficiencies may result in phrynoderma. Clinically, multiple pigmented keratotic papules of various sizes, many with a central keratinous plug, are distributed symmetrically on the extensor elbows, knees, shoulders, buttocks, and extremities. The skin surrounding these lesions may be scaly and hyperpigmented.⁵² Generalized xerosis without preceding nyctalopia has been reported.⁵³ Accompanying pityriasis alba may develop.⁵² Lesions on the face may mimic acne, while lesions on the extremities may simulate a perforating disorder. Histopathology of phrynoderma reveals epidermal hyperkeratosis, follicular hyperkeratosis, and follicular plugging.⁵²

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Vitamin A deficiency can be diagnosed by measuring serum retinol levels, with levels lower than 20 µg/dL being diagnostic of deficiency.⁵⁶ Decreased serum retinol in patients hospitalized with flaring irritable bowel disorder has been repeatedly reported.^57-59 Notably, serum retinol concentration does not decline until liver reserves of vitamin A are nearing exhaustion.³³

The US Food and Drug Administration requires manufacturers to list retinol activity equivalents on labels. One international unit of retinol is equivalent to 0.3 µg of retinol activity equivalents.⁶⁰ The treatment of vitamin A deficiency involves high-dose oral supplementation when possible.⁶¹ Although dependent on age, the treatment dose for most adults with vitamin A deficiency is 3000 µg (10,000 IU) once daily.

Phrynoderma has been specifically treated with salicylic acid ointment 3% and intramuscular vitamin A.⁶² Topical urea cream also may treat phrynoderma.⁶³

Vitamin B₂

Vitamin B₂ (riboflavin) is absorbed in the small intestine and converted into 2 biologically active forms—flavin adenine dinucleotide and flavin mononucleotide—which serve as cofactors in metabolic and oxidation-reduction reactions. Malabsorptive disorders and bowel resection can lead to riboflavin deficiency.⁶⁴ Other at-risk populations include those with restrictive diets,⁶⁵ psychiatric illness, or systemic illness (eTable). Riboflavin can be degraded by light (deficiency has been reported after phototherapy for neonatal jaundice⁶⁶) and following boric acid ingestion.⁶⁷ Medications, including long-term treatment with antiepileptics, may lead to riboflavin deficiency.⁶⁸

Riboflavin is critical to maintaining collagen production. Riboflavin deficiency may manifest clinically with extensive seborrheiclike dermatitis,⁴⁴ intertrigolike dermatitis,⁶⁹ or oral-ocular-genital syndrome.⁷⁰ Angular cheilitis may accompany an atrophic tongue that is deep red in color. The scrotum is characteristically involved in men, with confluent dermatitis extending onto the thighs and sparing the midline. Red papules and painful fissures may develop. Balanitis and phimosis have been reported. Testing for riboflavin deficiency should be considered in patients with refractory seborrheic dermatitis.

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Riboflavin stores are assessed by the erythrocyte glutathione reductase activity coefficient.⁴⁴ A level of 1.4 or higher is consistent with deficiency. Serum riboflavin levels, performed after a 12-hour fast, may support the diagnosis but are less sensitive. Patients with glucose-6-phosphate deficiency cannot be assessed via the erythrocyte glutathione reductase activity coefficient and may instead require evaluation of 24-hour urine riboflavin level.⁴⁴

Vitamin B₃

Vitamin B₃ (niacin, nicotinamide, nicotinic acid) is found in plant and animal products or can be derived from its amino acid precursor tryptophan. Niacin deficiency results in pellagra, characterized by dermatitis, dementia, and diarrhea.⁷¹ The most prominent feature is a symmetrically distributed photosensitive dermatitis of the face, neck (called Casal necklace)(Figure 3), chest, dorsal hands, and extensor arms. The eruption may begin with erythema, vesicles, or bullae (wet pellagra) and evolve into thick, hyperpigmented, scaling plaques.⁷¹ The skin may take on a copper tone and become atrophic.⁷² Dull erythema with overlying yellow powdery scale (called sulfur flakes) at follicular orifices has been described on the nasal bridge.⁷³

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Causes of niacin deficiency include malabsorptive conditions, malignancy (including carcinoid tumors), parenteral nutrition, psychiatric disease,^74,75 and restrictive diets (eTable).⁷⁶ Carcinoid tumors divert tryptophan to serotonin resulting in niacin deficiency.⁷⁷

The diagnosis of niacin deficiency is based on clinical findings and response to supplementation.⁷⁵ Low niacin urinary metabolites (N-methylnicotinamide and 2-pyridone) may aid in diagnosis.⁶ Treatment generally includes oral nicotinamide 100 mg every 6 hours; the dose can then be tapered to 50 mg every 8 to 12 hours until symptoms resolve. Severe deficiency may require parenteral nicotinamide 1 g 3 to 4 times daily.⁷⁵

Vitamin B₆

Vitamin B₆ (pyridoxine, pyridoxamine, pyridoxal) is found in whole grains and plant and animal products. Vitamin B₆ functions as a coenzyme in many metabolic pathways and is involved in the conversion of tryptophan to niacin.⁴⁴ Absorption requires hydrolysis by intestinal phosphates and transport to the liver for rephosphorylation prior to release in active form.⁶

Cutaneous findings associated with vitamin B₆ deficiency include periorificial and perineal seborrheic dermatitis,⁷⁸ angular stomatitis, and cheilitis, with associated burning, redness, and tongue edema.⁶ Vitamin B₆ deficiency is a rarely reported cause of burning mouth syndrome.⁷⁹ Because vitamin B₆ is involved in the conversion of tryptophan to niacin, deficiency also may present with pellagralike findings.⁷⁰ Other clinical symptoms are outlined in the eTable.^80,81

Conditions that increase risk for vitamin B₆ deficiency are highlighted in the eTable and include malabsorptive disorders; psychiatric illness⁸²; and chronic disease, especially end-stage renal disease.⁸³ Vitamin B₆ deficiency associated with chronic alcohol use is due to both inadequate vitamin B₆ intake as well as reduced hepatic storage.⁷⁸ Medications such as isoniazid, hydralazine, and oral contraceptives may decrease vitamin B₆ levels (eTable).⁸²

Vitamin B₆ can be measured in the plasma as pyridoxal 5′-phosphate. Plasma concentrations of less than 20 nmol/L are suggestive of deficiency.⁸² Indirect tests include tryptophan and methionine loading.⁶ The treatment of vitamin B₆ deficiency is determined by symptom severity. Recommendations for oral supplementation range from 25 to 600 mg daily.⁸² Symptoms typically improve on 100 mg daily.⁶

Vitamins B₉ and B₁₂

Deficiencies of vitamins B₉ (folic acid, folate) and B₁₂ (cobalamin) have similar clinical presentations. Folate is essential in the metabolism of amino acids, purines, and pyrimidines.⁶ Cobalamin, found in animal products, is a cofactor for methionine synthase and methylmalonyl-CoA mutase.⁸⁴ Megaloblastic anemia is the main finding in folate or cobalamin deficiency. Neurologic findings only accompany cobalamin deficiency. Risk factors for folate deficiency include malabsorptive conditions,⁶ chronic alcohol use,⁸⁵ and antifolate medication use (eTable).⁶

Cobalamin absorption requires gastric acid and intrinsic factor binding in the duodenum. Deficiency may occur from strict diets, psychiatric illness, old age,⁸⁶ decreased gastric acid secretion,⁸⁷ abnormal intrinsic factor function, or intestinal infections.⁶

Generalized cutaneous hyperpigmentation may be the first manifestation of vitamins B₉ and B₁₂ deficiency.⁸⁸ Typically accentuated in acral creases and the oral cavity, pigmentation may mimic Addison disease. Hair depigmentation and linear streaking of the nails are reported.⁸⁴ The tongue becomes painful and red with atrophy of the filiform papillae (Hunter glossitis).⁷⁸ Linear lesions on the tongue and hard palate may serve as an early sign of cobalamin deficiency.⁸⁹

Folate deficiency is diagnosed by measuring the plasma folate level; coincidental cobalamin deficiency should be excluded. Deficiency is managed with oral supplementation (when possible) with 1 to 5 mg of folate daily.⁶ Cobalamin deficiency is based on low serum levels (<150 pg/mL is diagnostic).⁸⁶ Cobalamin deficiency may take years to develop, as vitamin B₁₂ exists in large body stores.⁶ Serum methylmalonic acid may be elevated in patients with clinical features but normal-low serum vitamin B₁₂ level.⁸⁶ Treatment of vitamin B₁₂ deficiency is with oral (2 mg once daily) or parenteral (1 mg every 4 weeks then maintained at once monthly) cyanocobalamin. For patients with neurologic symptoms, intramuscular injection should be given.⁸⁶ The underlying cause of deficiency must be elucidated and treated.

Vitamin C Deficiency

Vitamin C (ascorbic acid) is an essential cofactor for the hydroxylation of proline and lysine residues in collagen synthesis. Plant-based foods are the main dietary source of vitamin C, and deficiency presents clinically as scurvy. Cutaneous findings include follicular hyperkeratosis, perifollicular petechiae, and curled hair shafts (corkscrew hairs)(Figure 4). Ecchymoses of the lower extremities, forearms, and abdomen may be seen. Nodules representing intramuscular and subcutaneous hemorrhage can be present.⁹⁰ Woody edema may mimic cellulitis, while lower extremity hemorrhage may mimic vasculitis. Gingival hyperplasia, hemorrhage, and edema may occur,⁹⁰ along with linear splinter hemorrhages.⁹¹

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Hypovitaminosis C has been routinely demonstrated in hospitalized patients.⁹² Scurvy may occur in patients on strict diets,⁹³ chronic alcohol use,⁹⁴ psychiatric illness,⁹⁵ or gastrointestinal tract disease (eTable).^96-99 Those with low socioeconomic status⁷⁰ or dementia¹⁰⁰ as well as the elderly also are at risk.¹⁰¹ Scurvy has developed in patients with iron overload and those who are on hemodialysis⁴⁴ as well as in association with nilotinib use.¹⁰² Patients with chronic mucous membrane graft-vs-host disease may exhibit vitamin C deficiency.¹⁰³

Scurvy is a clinical diagnosis. Vitamin C levels normalize quickly with supplementation. Cutaneous biopsy will exhibit follicular hyperkeratosis, perifollicular hemorrhage, and fibrosis.⁹¹

Oral ascorbic acid supplementation should be initiated at 500 to 1000 mg daily in adults.¹⁰⁴ The cause of deficiency should be identified, and further supplementation should be decided based on patient risk factors. Lifestyle modifications, such as cessation of smoking and chronic alcohol use, is recommended. The diagnosis of scurvy should prompt workup for additional nutrient deficiencies.

Final Thoughts

Dermatologists play an important role in the early recognition of nutritional deficiencies, as cutaneous manifestations often are the first clue to diagnosis. Nutritional deficiencies are common yet underrecognized in the hospitalized patient and serve as an independent risk factor for patient morbidity and mortality.³ Awareness of the cutaneous manifestations of undernutrition as well as the risk factors for nutritional deficiency may expedite diagnosis and supplementation, thereby improving outcomes for hospitalized patients.

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The World Health Organization defines malnutrition as deficiencies, excesses, or imbalances in an individual’s intake of energy and/or nutrients.¹ This review will focus on undernutrition, which may result from macronutrient or micronutrient deficiencies. Undernutrition in the hospitalized patient is a common yet underrecognized phenomenon, with an estimated prevalence of 20% to 50% worldwide.² Malnutrition is an independent risk factor for patient morbidity and mortality and has been associated with increased health care costs.³ Nutritional deficiencies may arise from inadequate nutrient intake, abnormal nutrient absorption, or improper nutrient utilization.⁴ Unfortunately, no standardized algorithm for screening and diagnosing patients with malnutrition exists, making early physical examination findings of utmost importance. Herein, we present a review of acquired nutritional deficiency dermatoses in the inpatient setting.

Protein-Energy Malnutrition

Protein-energy malnutrition (PEM) refers to a set of related disorders that include marasmus, kwashiorkor (KW), and marasmic KW. These conditions frequently are seen in developing countries but also have been reported in developed nations.⁵ Marasmus occurs from a chronic deficiency of protein and calories. Decreased insulin production and unopposed catabolism result in sarcopenia and loss of bone and subcutaneous fat.⁶ Affected patients include children who are less than 60% ideal body weight (IBW) without edema or hypoproteinemia.⁷ Kwashiorkor is the edematous form of PEM that develops from isolated protein deficiency, resulting in edema, diarrhea, and immunosuppression.⁶ Micronutrient deficiencies, oxidative stress, slow protein catabolism, and excess antidiuretic hormone have been proposed as potential drivers of KW.⁸ Kwashiorkor affects children between 60% and 80% IBW. Marasmic KW has features of both diseases, including children who are less than 60% IBW but with associated edema and/or hypoproteinemia.⁹

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Although PEM is uncommon in adults, hospitalized patients carry many predisposing risk factors, including infections, malabsorptive conditions, psychiatric disease, and chronic illness (eTable). Patients with chronic infections present with findings consistent with marasmic KW due to lean body mass loss.

CT105006296_eTable.jpg

Hoffman_June_2020_1.jpg

Zinc Deficiency

Zinc is an essential trace element that provides regulatory, structural, and catalytic functions across multiple biochemical pathways⁶ and serves as an enzymatic cofactor and key component for numerous transcription factors.¹⁷ Zinc is derived from food sources, and its concentration correlates with protein content.¹⁸ Zinc is found in both animal and plant-based proteins, albeit with a lower oral bioavailability in the latter. Zinc deficiency may be inherited or acquired. Primary acrodermatitis enteropathica is an autosomal-recessive disorder of the solute carrier family 39 member 4 gene, SLC39A4 (encodes zinc transporter ZIP4 on enterocytes); the result is abnormal zinc absorption from the small intestine.¹⁸

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Acquired zinc deficiency occurs from decreased dietary zinc intake, impaired intestinal zinc absorption, excessive zinc elimination, or systemic states of high catabolism or low albumin (eTable). Total parenteral nutrition–associated deficiency has arisen when nutritional formulations did not contain trace elements during national shortages or when prolonged TPN was not anticipated and trace elements were removed.¹⁹ Zinc levels may already be low in patients with chronic illness or inflammation, so even a short period on TPN can precipitate deficiency.^18,19 Diets high in phytate may result in zinc deficiency, as phytate impairs intestinal zinc absorption.²⁰ Approximately 15% of patients with inflammatory bowel disease experienced zinc deficiency worldwide.²¹ In Crohn disease, zinc deficiency has been associated with active intestinal inflammation, increased risk for hospitalization, surgeries, and disease-related complications.^22,23

Medications such as antiepileptics, antimetabolites, or penicillamine may induce zinc deficiency, highlighting the importance of medication review for hospitalized patients (eTable). Catabolic states, frequently encountered in hospitalized patients, increase the risk for zinc deficiency.²⁴ Patients with necrolytic migratory erythema (associated with pancreatic glucagonomas) often experience low serum zinc levels.²⁵

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The skin is the third most zinc-abundant tissue in the human body. Within keratinocytes, zinc is critical to normal proliferation and suppression of inflammation.¹⁷ Zinc also plays an important role in cutaneous immune function.²⁶ Zinc deficiency presents with sharply demarcated, flaccid pustules and bullae that erode into scaly, pink, eczematous or psoriasiform plaques. Lesions are found preferentially in acral and periorificial sites, often with crusting and exudate. The groin and flexural surfaces may be affected. Erosions often become secondarily impetiginized. Other cutaneous findings include angular cheilitis, stomatitis, glossitis, paronychia, onychodystrophy, generalized alopecia, and delayed wound healing.²⁶ Histopathology of skin lesions is characterized by granular layer loss, epidermal pallor, confluent parakeratosis, spongiosis, dyskeratosis, and psoriasiform hyperplasia.²⁷ Acquired bullous acrodermatitis enteropathica has been reported as a histologic mimicker of pemphigus foliaceous in patients on TPN.²⁸

Diagnosis of zinc deficiency is made by measuring plasma zinc levels. Fasting levels should be drawn in the morning, as they can fluctuate based on the time of day, stress levels, or inflammation.⁶ Sample hemolysis and anticoagulants high in zinc may falsely elevate plasma zinc. A normal zinc level is greater than 70 µg/dL; however, normal levels do not rule out deficiency.¹⁸ Measurement of zinc-dependent enzymes, such as alkaline phosphatase, can be a quick way to assess zinc status. Serum albumin also should be measured; because zinc is carried by albumin in the blood, hypoalbuminemia may result in secondary zinc deficiency.¹⁸

Zinc replacement therapy is largely through oral supplementation and should start at 0.5 to 2.0 mg/kg/d in adults with acquired disease.^29,30 Zinc sulfate is the most affordable and is the supplement of choice, with 50 mg of elemental zinc per 220 mg of zinc sulfate (~23% elemental zinc).³¹ Alternative zinc salts, such as zinc gluconate (13% elemental zinc), may be used. Patients with malabsorptive disorders often require parenteral supplementation.³² Clinical symptoms often will resolve within 1 to 2 weeks of supplementation.²⁹ In patients with primary acrodermatitis enteropathica, lifelong supplementation with 3 mg/kg/d elemental zinc should occur.⁶ Calcium and folate may reduce zinc absorption, while zinc supplementation can interfere with copper and iron absorption.³³

Iron Deficiency

Iron is an essential component of the hemoglobin molecule. Iron homeostasis and metabolism are tightly regulated processes that drive erythropoiesis. Only 5% to 10% of dietary iron is absorbed through nutrition, while the remainder is recycled from red cell breakdown. Both normal iron levels and iron deficiency (ID) are defined by age and gender.³⁴ Iron-deficiency anemia (IDA) is one of the most common cause-specific anemias worldwide.³⁵

Fatigue is the most common and earliest symptom of ID. In a single study, pallor was predictive of anemia in hospitalized patients; however, absence of pallor did not rule out anemia.³⁴ Dyspnea on exertion, tachycardia, dysphagia, and pica also may be reported. Cutaneous manifestations include koilonychia (Figure 2), glossitis, pruritus, angular cheilitis, and telogen effluvium. Plummer-Vinson syndrome is characterized by microcytic anemia, glossitis, and dysphagia.

Hoffman_June_2020_2.jpg

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Iron deficiency can be present despite a normal hemoglobin level. Serum ferritin and percentage transferrin saturation are key to early identification of IDA.³⁵ Ferritin levels lower than 30 µg/L confirm the diagnosis. Decreased transferrin saturation and increased total iron binding capacity aid in the diagnosis of IDA. Serum ferritin is an acute-phase reactant, and levels may be falsely elevated in the setting of inflammation or infection.

Essential Fatty Acid Deficiency

Essential fatty acids (EFAs) including linoleic and α-linolenic acid cannot be synthesized by the human body and must be obtained through diet (mostly plant oils). Essential fatty acids have various functions, including maintaining phospholipid membrane integrity, forming prostaglandins and leukotrienes, and storing energy.⁴⁰ Essential fatty acids are important in the structure and function of the stratum corneum and are crucial in maintaining epidermal barrier function.⁴¹ Increased epidermal permeability and transepidermal water loss may be the first signs of EFA deficiency (EFAD).⁴²

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The cutaneous manifestations of EFAD include xerosis, weeping eczematous plaques, and erosions in intertriginous sites. The lesions may progress to widespread desquamation and erythema. With time, the skin can become thick and leathery. Alopecia may occur, and hair may depigment.⁷ Additional findings include poor wound healing and increased susceptibility to infections.^43,44

Essential fatty acid deficiency may occur when dietary fat intake is severely restricted or in malabsorptive states.^45,46 It develops in patients on prolonged TPN, typically when receiving fat-restricted nutrition,^47,48 as occurs in hypertriglyceridemia.⁴⁷ Essential fatty acid deficiency has developed in patients on TPN containing EFAs,⁴⁷ as the introduction of novel intravenous lipid emulsions has resulted in varying proportions of EFA.⁴⁰ Premature neonates are particularly at risk for EFAD.⁴⁹

The diagnosis of EFAD involves the measurement of the triene to tetraene ratio. A ratio of more than 0.2 suggests EFAD, but the clinical signs are not seen until the ratio is over 0.4.⁴⁰ Low plasma levels of linoleic, linolenic, and arachidonic acids also are seen. Elevated liver function tests are supportive of the diagnosis. Biochemical findings typically are seen before cutaneous manifestations.⁴⁰

Treatment of EFAD includes topical, oral, or intravenous replacement of EFAs. Improvement of EFAD with the application of topical linoleic acid to the skin has been reported.⁵⁰ Patients receiving TPN should undergo assessment of parenteral lipid emulsion to ensure adequate fatty acid composition.

Vitamin A Deficiency

Vitamin A (retinol) is a fat-soluble vitamin that plays a critical role in keratinization, epithelial proliferation, and cellular differentiation.⁶ Vitamin A is found in animal products as retinyl esters and in plants as beta-carotene. Vitamin A has 2 clinically important forms: all-trans retinoic acid and 11-cis-retinal. All-trans retinoic acid is involved in cellular differentiation and regulating gene transcription, while 11-cis-retinal is key to rhodopsin generation required for vision. Vitamin A deficiency presents with early ophthalmologic findings, specifically nyctalopia, or delayed adaptation to the dark.⁵¹ Xerophthalmia, abnormal conjunctival keratinization, and Bitot spots subsequently develop and may progress to corneal ulceration and blindness.⁶

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Vitamin A deficiency manifests in the skin as follicular hyperkeratosis, or phrynoderma. Notably, numerous other micronutrient deficiencies may result in phrynoderma. Clinically, multiple pigmented keratotic papules of various sizes, many with a central keratinous plug, are distributed symmetrically on the extensor elbows, knees, shoulders, buttocks, and extremities. The skin surrounding these lesions may be scaly and hyperpigmented.⁵² Generalized xerosis without preceding nyctalopia has been reported.⁵³ Accompanying pityriasis alba may develop.⁵² Lesions on the face may mimic acne, while lesions on the extremities may simulate a perforating disorder. Histopathology of phrynoderma reveals epidermal hyperkeratosis, follicular hyperkeratosis, and follicular plugging.⁵²

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Vitamin A deficiency can be diagnosed by measuring serum retinol levels, with levels lower than 20 µg/dL being diagnostic of deficiency.⁵⁶ Decreased serum retinol in patients hospitalized with flaring irritable bowel disorder has been repeatedly reported.^57-59 Notably, serum retinol concentration does not decline until liver reserves of vitamin A are nearing exhaustion.³³

The US Food and Drug Administration requires manufacturers to list retinol activity equivalents on labels. One international unit of retinol is equivalent to 0.3 µg of retinol activity equivalents.⁶⁰ The treatment of vitamin A deficiency involves high-dose oral supplementation when possible.⁶¹ Although dependent on age, the treatment dose for most adults with vitamin A deficiency is 3000 µg (10,000 IU) once daily.

Phrynoderma has been specifically treated with salicylic acid ointment 3% and intramuscular vitamin A.⁶² Topical urea cream also may treat phrynoderma.⁶³

Vitamin B₂

Vitamin B₂ (riboflavin) is absorbed in the small intestine and converted into 2 biologically active forms—flavin adenine dinucleotide and flavin mononucleotide—which serve as cofactors in metabolic and oxidation-reduction reactions. Malabsorptive disorders and bowel resection can lead to riboflavin deficiency.⁶⁴ Other at-risk populations include those with restrictive diets,⁶⁵ psychiatric illness, or systemic illness (eTable). Riboflavin can be degraded by light (deficiency has been reported after phototherapy for neonatal jaundice⁶⁶) and following boric acid ingestion.⁶⁷ Medications, including long-term treatment with antiepileptics, may lead to riboflavin deficiency.⁶⁸

Riboflavin is critical to maintaining collagen production. Riboflavin deficiency may manifest clinically with extensive seborrheiclike dermatitis,⁴⁴ intertrigolike dermatitis,⁶⁹ or oral-ocular-genital syndrome.⁷⁰ Angular cheilitis may accompany an atrophic tongue that is deep red in color. The scrotum is characteristically involved in men, with confluent dermatitis extending onto the thighs and sparing the midline. Red papules and painful fissures may develop. Balanitis and phimosis have been reported. Testing for riboflavin deficiency should be considered in patients with refractory seborrheic dermatitis.

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Riboflavin stores are assessed by the erythrocyte glutathione reductase activity coefficient.⁴⁴ A level of 1.4 or higher is consistent with deficiency. Serum riboflavin levels, performed after a 12-hour fast, may support the diagnosis but are less sensitive. Patients with glucose-6-phosphate deficiency cannot be assessed via the erythrocyte glutathione reductase activity coefficient and may instead require evaluation of 24-hour urine riboflavin level.⁴⁴

Vitamin B₃

Vitamin B₃ (niacin, nicotinamide, nicotinic acid) is found in plant and animal products or can be derived from its amino acid precursor tryptophan. Niacin deficiency results in pellagra, characterized by dermatitis, dementia, and diarrhea.⁷¹ The most prominent feature is a symmetrically distributed photosensitive dermatitis of the face, neck (called Casal necklace)(Figure 3), chest, dorsal hands, and extensor arms. The eruption may begin with erythema, vesicles, or bullae (wet pellagra) and evolve into thick, hyperpigmented, scaling plaques.⁷¹ The skin may take on a copper tone and become atrophic.⁷² Dull erythema with overlying yellow powdery scale (called sulfur flakes) at follicular orifices has been described on the nasal bridge.⁷³

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Causes of niacin deficiency include malabsorptive conditions, malignancy (including carcinoid tumors), parenteral nutrition, psychiatric disease,^74,75 and restrictive diets (eTable).⁷⁶ Carcinoid tumors divert tryptophan to serotonin resulting in niacin deficiency.⁷⁷

The diagnosis of niacin deficiency is based on clinical findings and response to supplementation.⁷⁵ Low niacin urinary metabolites (N-methylnicotinamide and 2-pyridone) may aid in diagnosis.⁶ Treatment generally includes oral nicotinamide 100 mg every 6 hours; the dose can then be tapered to 50 mg every 8 to 12 hours until symptoms resolve. Severe deficiency may require parenteral nicotinamide 1 g 3 to 4 times daily.⁷⁵

Vitamin B₆

Vitamin B₆ (pyridoxine, pyridoxamine, pyridoxal) is found in whole grains and plant and animal products. Vitamin B₆ functions as a coenzyme in many metabolic pathways and is involved in the conversion of tryptophan to niacin.⁴⁴ Absorption requires hydrolysis by intestinal phosphates and transport to the liver for rephosphorylation prior to release in active form.⁶

Cutaneous findings associated with vitamin B₆ deficiency include periorificial and perineal seborrheic dermatitis,⁷⁸ angular stomatitis, and cheilitis, with associated burning, redness, and tongue edema.⁶ Vitamin B₆ deficiency is a rarely reported cause of burning mouth syndrome.⁷⁹ Because vitamin B₆ is involved in the conversion of tryptophan to niacin, deficiency also may present with pellagralike findings.⁷⁰ Other clinical symptoms are outlined in the eTable.^80,81

Conditions that increase risk for vitamin B₆ deficiency are highlighted in the eTable and include malabsorptive disorders; psychiatric illness⁸²; and chronic disease, especially end-stage renal disease.⁸³ Vitamin B₆ deficiency associated with chronic alcohol use is due to both inadequate vitamin B₆ intake as well as reduced hepatic storage.⁷⁸ Medications such as isoniazid, hydralazine, and oral contraceptives may decrease vitamin B₆ levels (eTable).⁸²

Vitamin B₆ can be measured in the plasma as pyridoxal 5′-phosphate. Plasma concentrations of less than 20 nmol/L are suggestive of deficiency.⁸² Indirect tests include tryptophan and methionine loading.⁶ The treatment of vitamin B₆ deficiency is determined by symptom severity. Recommendations for oral supplementation range from 25 to 600 mg daily.⁸² Symptoms typically improve on 100 mg daily.⁶

Vitamins B₉ and B₁₂

Deficiencies of vitamins B₉ (folic acid, folate) and B₁₂ (cobalamin) have similar clinical presentations. Folate is essential in the metabolism of amino acids, purines, and pyrimidines.⁶ Cobalamin, found in animal products, is a cofactor for methionine synthase and methylmalonyl-CoA mutase.⁸⁴ Megaloblastic anemia is the main finding in folate or cobalamin deficiency. Neurologic findings only accompany cobalamin deficiency. Risk factors for folate deficiency include malabsorptive conditions,⁶ chronic alcohol use,⁸⁵ and antifolate medication use (eTable).⁶

Cobalamin absorption requires gastric acid and intrinsic factor binding in the duodenum. Deficiency may occur from strict diets, psychiatric illness, old age,⁸⁶ decreased gastric acid secretion,⁸⁷ abnormal intrinsic factor function, or intestinal infections.⁶

Generalized cutaneous hyperpigmentation may be the first manifestation of vitamins B₉ and B₁₂ deficiency.⁸⁸ Typically accentuated in acral creases and the oral cavity, pigmentation may mimic Addison disease. Hair depigmentation and linear streaking of the nails are reported.⁸⁴ The tongue becomes painful and red with atrophy of the filiform papillae (Hunter glossitis).⁷⁸ Linear lesions on the tongue and hard palate may serve as an early sign of cobalamin deficiency.⁸⁹

Folate deficiency is diagnosed by measuring the plasma folate level; coincidental cobalamin deficiency should be excluded. Deficiency is managed with oral supplementation (when possible) with 1 to 5 mg of folate daily.⁶ Cobalamin deficiency is based on low serum levels (<150 pg/mL is diagnostic).⁸⁶ Cobalamin deficiency may take years to develop, as vitamin B₁₂ exists in large body stores.⁶ Serum methylmalonic acid may be elevated in patients with clinical features but normal-low serum vitamin B₁₂ level.⁸⁶ Treatment of vitamin B₁₂ deficiency is with oral (2 mg once daily) or parenteral (1 mg every 4 weeks then maintained at once monthly) cyanocobalamin. For patients with neurologic symptoms, intramuscular injection should be given.⁸⁶ The underlying cause of deficiency must be elucidated and treated.

Vitamin C Deficiency

Vitamin C (ascorbic acid) is an essential cofactor for the hydroxylation of proline and lysine residues in collagen synthesis. Plant-based foods are the main dietary source of vitamin C, and deficiency presents clinically as scurvy. Cutaneous findings include follicular hyperkeratosis, perifollicular petechiae, and curled hair shafts (corkscrew hairs)(Figure 4). Ecchymoses of the lower extremities, forearms, and abdomen may be seen. Nodules representing intramuscular and subcutaneous hemorrhage can be present.⁹⁰ Woody edema may mimic cellulitis, while lower extremity hemorrhage may mimic vasculitis. Gingival hyperplasia, hemorrhage, and edema may occur,⁹⁰ along with linear splinter hemorrhages.⁹¹

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Hypovitaminosis C has been routinely demonstrated in hospitalized patients.⁹² Scurvy may occur in patients on strict diets,⁹³ chronic alcohol use,⁹⁴ psychiatric illness,⁹⁵ or gastrointestinal tract disease (eTable).^96-99 Those with low socioeconomic status⁷⁰ or dementia¹⁰⁰ as well as the elderly also are at risk.¹⁰¹ Scurvy has developed in patients with iron overload and those who are on hemodialysis⁴⁴ as well as in association with nilotinib use.¹⁰² Patients with chronic mucous membrane graft-vs-host disease may exhibit vitamin C deficiency.¹⁰³

Scurvy is a clinical diagnosis. Vitamin C levels normalize quickly with supplementation. Cutaneous biopsy will exhibit follicular hyperkeratosis, perifollicular hemorrhage, and fibrosis.⁹¹

Oral ascorbic acid supplementation should be initiated at 500 to 1000 mg daily in adults.¹⁰⁴ The cause of deficiency should be identified, and further supplementation should be decided based on patient risk factors. Lifestyle modifications, such as cessation of smoking and chronic alcohol use, is recommended. The diagnosis of scurvy should prompt workup for additional nutrient deficiencies.

Final Thoughts

Dermatologists play an important role in the early recognition of nutritional deficiencies, as cutaneous manifestations often are the first clue to diagnosis. Nutritional deficiencies are common yet underrecognized in the hospitalized patient and serve as an independent risk factor for patient morbidity and mortality.³ Awareness of the cutaneous manifestations of undernutrition as well as the risk factors for nutritional deficiency may expedite diagnosis and supplementation, thereby improving outcomes for hospitalized patients.

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The World Health Organization defines malnutrition as deficiencies, excesses, or imbalances in an individual’s intake of energy and/or nutrients.¹ This review will focus on undernutrition, which may result from macronutrient or micronutrient deficiencies. Undernutrition in the hospitalized patient is a common yet underrecognized phenomenon, with an estimated prevalence of 20% to 50% worldwide.² Malnutrition is an independent risk factor for patient morbidity and mortality and has been associated with increased health care costs.³ Nutritional deficiencies may arise from inadequate nutrient intake, abnormal nutrient absorption, or improper nutrient utilization.⁴ Unfortunately, no standardized algorithm for screening and diagnosing patients with malnutrition exists, making early physical examination findings of utmost importance. Herein, we present a review of acquired nutritional deficiency dermatoses in the inpatient setting.

Protein-Energy Malnutrition

Protein-energy malnutrition (PEM) refers to a set of related disorders that include marasmus, kwashiorkor (KW), and marasmic KW. These conditions frequently are seen in developing countries but also have been reported in developed nations.⁵ Marasmus occurs from a chronic deficiency of protein and calories. Decreased insulin production and unopposed catabolism result in sarcopenia and loss of bone and subcutaneous fat.⁶ Affected patients include children who are less than 60% ideal body weight (IBW) without edema or hypoproteinemia.⁷ Kwashiorkor is the edematous form of PEM that develops from isolated protein deficiency, resulting in edema, diarrhea, and immunosuppression.⁶ Micronutrient deficiencies, oxidative stress, slow protein catabolism, and excess antidiuretic hormone have been proposed as potential drivers of KW.⁸ Kwashiorkor affects children between 60% and 80% IBW. Marasmic KW has features of both diseases, including children who are less than 60% IBW but with associated edema and/or hypoproteinemia.⁹

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Although PEM is uncommon in adults, hospitalized patients carry many predisposing risk factors, including infections, malabsorptive conditions, psychiatric disease, and chronic illness (eTable). Patients with chronic infections present with findings consistent with marasmic KW due to lean body mass loss.

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Zinc Deficiency

Zinc is an essential trace element that provides regulatory, structural, and catalytic functions across multiple biochemical pathways⁶ and serves as an enzymatic cofactor and key component for numerous transcription factors.¹⁷ Zinc is derived from food sources, and its concentration correlates with protein content.¹⁸ Zinc is found in both animal and plant-based proteins, albeit with a lower oral bioavailability in the latter. Zinc deficiency may be inherited or acquired. Primary acrodermatitis enteropathica is an autosomal-recessive disorder of the solute carrier family 39 member 4 gene, SLC39A4 (encodes zinc transporter ZIP4 on enterocytes); the result is abnormal zinc absorption from the small intestine.¹⁸

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Acquired zinc deficiency occurs from decreased dietary zinc intake, impaired intestinal zinc absorption, excessive zinc elimination, or systemic states of high catabolism or low albumin (eTable). Total parenteral nutrition–associated deficiency has arisen when nutritional formulations did not contain trace elements during national shortages or when prolonged TPN was not anticipated and trace elements were removed.¹⁹ Zinc levels may already be low in patients with chronic illness or inflammation, so even a short period on TPN can precipitate deficiency.^18,19 Diets high in phytate may result in zinc deficiency, as phytate impairs intestinal zinc absorption.²⁰ Approximately 15% of patients with inflammatory bowel disease experienced zinc deficiency worldwide.²¹ In Crohn disease, zinc deficiency has been associated with active intestinal inflammation, increased risk for hospitalization, surgeries, and disease-related complications.^22,23

Medications such as antiepileptics, antimetabolites, or penicillamine may induce zinc deficiency, highlighting the importance of medication review for hospitalized patients (eTable). Catabolic states, frequently encountered in hospitalized patients, increase the risk for zinc deficiency.²⁴ Patients with necrolytic migratory erythema (associated with pancreatic glucagonomas) often experience low serum zinc levels.²⁵

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The skin is the third most zinc-abundant tissue in the human body. Within keratinocytes, zinc is critical to normal proliferation and suppression of inflammation.¹⁷ Zinc also plays an important role in cutaneous immune function.²⁶ Zinc deficiency presents with sharply demarcated, flaccid pustules and bullae that erode into scaly, pink, eczematous or psoriasiform plaques. Lesions are found preferentially in acral and periorificial sites, often with crusting and exudate. The groin and flexural surfaces may be affected. Erosions often become secondarily impetiginized. Other cutaneous findings include angular cheilitis, stomatitis, glossitis, paronychia, onychodystrophy, generalized alopecia, and delayed wound healing.²⁶ Histopathology of skin lesions is characterized by granular layer loss, epidermal pallor, confluent parakeratosis, spongiosis, dyskeratosis, and psoriasiform hyperplasia.²⁷ Acquired bullous acrodermatitis enteropathica has been reported as a histologic mimicker of pemphigus foliaceous in patients on TPN.²⁸

Diagnosis of zinc deficiency is made by measuring plasma zinc levels. Fasting levels should be drawn in the morning, as they can fluctuate based on the time of day, stress levels, or inflammation.⁶ Sample hemolysis and anticoagulants high in zinc may falsely elevate plasma zinc. A normal zinc level is greater than 70 µg/dL; however, normal levels do not rule out deficiency.¹⁸ Measurement of zinc-dependent enzymes, such as alkaline phosphatase, can be a quick way to assess zinc status. Serum albumin also should be measured; because zinc is carried by albumin in the blood, hypoalbuminemia may result in secondary zinc deficiency.¹⁸

Zinc replacement therapy is largely through oral supplementation and should start at 0.5 to 2.0 mg/kg/d in adults with acquired disease.^29,30 Zinc sulfate is the most affordable and is the supplement of choice, with 50 mg of elemental zinc per 220 mg of zinc sulfate (~23% elemental zinc).³¹ Alternative zinc salts, such as zinc gluconate (13% elemental zinc), may be used. Patients with malabsorptive disorders often require parenteral supplementation.³² Clinical symptoms often will resolve within 1 to 2 weeks of supplementation.²⁹ In patients with primary acrodermatitis enteropathica, lifelong supplementation with 3 mg/kg/d elemental zinc should occur.⁶ Calcium and folate may reduce zinc absorption, while zinc supplementation can interfere with copper and iron absorption.³³

Iron Deficiency

Iron is an essential component of the hemoglobin molecule. Iron homeostasis and metabolism are tightly regulated processes that drive erythropoiesis. Only 5% to 10% of dietary iron is absorbed through nutrition, while the remainder is recycled from red cell breakdown. Both normal iron levels and iron deficiency (ID) are defined by age and gender.³⁴ Iron-deficiency anemia (IDA) is one of the most common cause-specific anemias worldwide.³⁵

Fatigue is the most common and earliest symptom of ID. In a single study, pallor was predictive of anemia in hospitalized patients; however, absence of pallor did not rule out anemia.³⁴ Dyspnea on exertion, tachycardia, dysphagia, and pica also may be reported. Cutaneous manifestations include koilonychia (Figure 2), glossitis, pruritus, angular cheilitis, and telogen effluvium. Plummer-Vinson syndrome is characterized by microcytic anemia, glossitis, and dysphagia.

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Iron deficiency can be present despite a normal hemoglobin level. Serum ferritin and percentage transferrin saturation are key to early identification of IDA.³⁵ Ferritin levels lower than 30 µg/L confirm the diagnosis. Decreased transferrin saturation and increased total iron binding capacity aid in the diagnosis of IDA. Serum ferritin is an acute-phase reactant, and levels may be falsely elevated in the setting of inflammation or infection.

Essential Fatty Acid Deficiency

Essential fatty acids (EFAs) including linoleic and α-linolenic acid cannot be synthesized by the human body and must be obtained through diet (mostly plant oils). Essential fatty acids have various functions, including maintaining phospholipid membrane integrity, forming prostaglandins and leukotrienes, and storing energy.⁴⁰ Essential fatty acids are important in the structure and function of the stratum corneum and are crucial in maintaining epidermal barrier function.⁴¹ Increased epidermal permeability and transepidermal water loss may be the first signs of EFA deficiency (EFAD).⁴²

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The cutaneous manifestations of EFAD include xerosis, weeping eczematous plaques, and erosions in intertriginous sites. The lesions may progress to widespread desquamation and erythema. With time, the skin can become thick and leathery. Alopecia may occur, and hair may depigment.⁷ Additional findings include poor wound healing and increased susceptibility to infections.^43,44

Essential fatty acid deficiency may occur when dietary fat intake is severely restricted or in malabsorptive states.^45,46 It develops in patients on prolonged TPN, typically when receiving fat-restricted nutrition,^47,48 as occurs in hypertriglyceridemia.⁴⁷ Essential fatty acid deficiency has developed in patients on TPN containing EFAs,⁴⁷ as the introduction of novel intravenous lipid emulsions has resulted in varying proportions of EFA.⁴⁰ Premature neonates are particularly at risk for EFAD.⁴⁹

The diagnosis of EFAD involves the measurement of the triene to tetraene ratio. A ratio of more than 0.2 suggests EFAD, but the clinical signs are not seen until the ratio is over 0.4.⁴⁰ Low plasma levels of linoleic, linolenic, and arachidonic acids also are seen. Elevated liver function tests are supportive of the diagnosis. Biochemical findings typically are seen before cutaneous manifestations.⁴⁰

Treatment of EFAD includes topical, oral, or intravenous replacement of EFAs. Improvement of EFAD with the application of topical linoleic acid to the skin has been reported.⁵⁰ Patients receiving TPN should undergo assessment of parenteral lipid emulsion to ensure adequate fatty acid composition.

Vitamin A Deficiency

Vitamin A (retinol) is a fat-soluble vitamin that plays a critical role in keratinization, epithelial proliferation, and cellular differentiation.⁶ Vitamin A is found in animal products as retinyl esters and in plants as beta-carotene. Vitamin A has 2 clinically important forms: all-trans retinoic acid and 11-cis-retinal. All-trans retinoic acid is involved in cellular differentiation and regulating gene transcription, while 11-cis-retinal is key to rhodopsin generation required for vision. Vitamin A deficiency presents with early ophthalmologic findings, specifically nyctalopia, or delayed adaptation to the dark.⁵¹ Xerophthalmia, abnormal conjunctival keratinization, and Bitot spots subsequently develop and may progress to corneal ulceration and blindness.⁶

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Vitamin A deficiency manifests in the skin as follicular hyperkeratosis, or phrynoderma. Notably, numerous other micronutrient deficiencies may result in phrynoderma. Clinically, multiple pigmented keratotic papules of various sizes, many with a central keratinous plug, are distributed symmetrically on the extensor elbows, knees, shoulders, buttocks, and extremities. The skin surrounding these lesions may be scaly and hyperpigmented.⁵² Generalized xerosis without preceding nyctalopia has been reported.⁵³ Accompanying pityriasis alba may develop.⁵² Lesions on the face may mimic acne, while lesions on the extremities may simulate a perforating disorder. Histopathology of phrynoderma reveals epidermal hyperkeratosis, follicular hyperkeratosis, and follicular plugging.⁵²

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Vitamin A deficiency can be diagnosed by measuring serum retinol levels, with levels lower than 20 µg/dL being diagnostic of deficiency.⁵⁶ Decreased serum retinol in patients hospitalized with flaring irritable bowel disorder has been repeatedly reported.^57-59 Notably, serum retinol concentration does not decline until liver reserves of vitamin A are nearing exhaustion.³³

The US Food and Drug Administration requires manufacturers to list retinol activity equivalents on labels. One international unit of retinol is equivalent to 0.3 µg of retinol activity equivalents.⁶⁰ The treatment of vitamin A deficiency involves high-dose oral supplementation when possible.⁶¹ Although dependent on age, the treatment dose for most adults with vitamin A deficiency is 3000 µg (10,000 IU) once daily.

Phrynoderma has been specifically treated with salicylic acid ointment 3% and intramuscular vitamin A.⁶² Topical urea cream also may treat phrynoderma.⁶³

Vitamin B₂

Vitamin B₂ (riboflavin) is absorbed in the small intestine and converted into 2 biologically active forms—flavin adenine dinucleotide and flavin mononucleotide—which serve as cofactors in metabolic and oxidation-reduction reactions. Malabsorptive disorders and bowel resection can lead to riboflavin deficiency.⁶⁴ Other at-risk populations include those with restrictive diets,⁶⁵ psychiatric illness, or systemic illness (eTable). Riboflavin can be degraded by light (deficiency has been reported after phototherapy for neonatal jaundice⁶⁶) and following boric acid ingestion.⁶⁷ Medications, including long-term treatment with antiepileptics, may lead to riboflavin deficiency.⁶⁸

Riboflavin is critical to maintaining collagen production. Riboflavin deficiency may manifest clinically with extensive seborrheiclike dermatitis,⁴⁴ intertrigolike dermatitis,⁶⁹ or oral-ocular-genital syndrome.⁷⁰ Angular cheilitis may accompany an atrophic tongue that is deep red in color. The scrotum is characteristically involved in men, with confluent dermatitis extending onto the thighs and sparing the midline. Red papules and painful fissures may develop. Balanitis and phimosis have been reported. Testing for riboflavin deficiency should be considered in patients with refractory seborrheic dermatitis.

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Riboflavin stores are assessed by the erythrocyte glutathione reductase activity coefficient.⁴⁴ A level of 1.4 or higher is consistent with deficiency. Serum riboflavin levels, performed after a 12-hour fast, may support the diagnosis but are less sensitive. Patients with glucose-6-phosphate deficiency cannot be assessed via the erythrocyte glutathione reductase activity coefficient and may instead require evaluation of 24-hour urine riboflavin level.⁴⁴

Vitamin B₃

Vitamin B₃ (niacin, nicotinamide, nicotinic acid) is found in plant and animal products or can be derived from its amino acid precursor tryptophan. Niacin deficiency results in pellagra, characterized by dermatitis, dementia, and diarrhea.⁷¹ The most prominent feature is a symmetrically distributed photosensitive dermatitis of the face, neck (called Casal necklace)(Figure 3), chest, dorsal hands, and extensor arms. The eruption may begin with erythema, vesicles, or bullae (wet pellagra) and evolve into thick, hyperpigmented, scaling plaques.⁷¹ The skin may take on a copper tone and become atrophic.⁷² Dull erythema with overlying yellow powdery scale (called sulfur flakes) at follicular orifices has been described on the nasal bridge.⁷³

Hoffman_June_2020_3.jpg

Causes of niacin deficiency include malabsorptive conditions, malignancy (including carcinoid tumors), parenteral nutrition, psychiatric disease,^74,75 and restrictive diets (eTable).⁷⁶ Carcinoid tumors divert tryptophan to serotonin resulting in niacin deficiency.⁷⁷

The diagnosis of niacin deficiency is based on clinical findings and response to supplementation.⁷⁵ Low niacin urinary metabolites (N-methylnicotinamide and 2-pyridone) may aid in diagnosis.⁶ Treatment generally includes oral nicotinamide 100 mg every 6 hours; the dose can then be tapered to 50 mg every 8 to 12 hours until symptoms resolve. Severe deficiency may require parenteral nicotinamide 1 g 3 to 4 times daily.⁷⁵

Vitamin B₆

Vitamin B₆ (pyridoxine, pyridoxamine, pyridoxal) is found in whole grains and plant and animal products. Vitamin B₆ functions as a coenzyme in many metabolic pathways and is involved in the conversion of tryptophan to niacin.⁴⁴ Absorption requires hydrolysis by intestinal phosphates and transport to the liver for rephosphorylation prior to release in active form.⁶

Cutaneous findings associated with vitamin B₆ deficiency include periorificial and perineal seborrheic dermatitis,⁷⁸ angular stomatitis, and cheilitis, with associated burning, redness, and tongue edema.⁶ Vitamin B₆ deficiency is a rarely reported cause of burning mouth syndrome.⁷⁹ Because vitamin B₆ is involved in the conversion of tryptophan to niacin, deficiency also may present with pellagralike findings.⁷⁰ Other clinical symptoms are outlined in the eTable.^80,81

Conditions that increase risk for vitamin B₆ deficiency are highlighted in the eTable and include malabsorptive disorders; psychiatric illness⁸²; and chronic disease, especially end-stage renal disease.⁸³ Vitamin B₆ deficiency associated with chronic alcohol use is due to both inadequate vitamin B₆ intake as well as reduced hepatic storage.⁷⁸ Medications such as isoniazid, hydralazine, and oral contraceptives may decrease vitamin B₆ levels (eTable).⁸²

Vitamin B₆ can be measured in the plasma as pyridoxal 5′-phosphate. Plasma concentrations of less than 20 nmol/L are suggestive of deficiency.⁸² Indirect tests include tryptophan and methionine loading.⁶ The treatment of vitamin B₆ deficiency is determined by symptom severity. Recommendations for oral supplementation range from 25 to 600 mg daily.⁸² Symptoms typically improve on 100 mg daily.⁶

Vitamins B₉ and B₁₂

Deficiencies of vitamins B₉ (folic acid, folate) and B₁₂ (cobalamin) have similar clinical presentations. Folate is essential in the metabolism of amino acids, purines, and pyrimidines.⁶ Cobalamin, found in animal products, is a cofactor for methionine synthase and methylmalonyl-CoA mutase.⁸⁴ Megaloblastic anemia is the main finding in folate or cobalamin deficiency. Neurologic findings only accompany cobalamin deficiency. Risk factors for folate deficiency include malabsorptive conditions,⁶ chronic alcohol use,⁸⁵ and antifolate medication use (eTable).⁶

Cobalamin absorption requires gastric acid and intrinsic factor binding in the duodenum. Deficiency may occur from strict diets, psychiatric illness, old age,⁸⁶ decreased gastric acid secretion,⁸⁷ abnormal intrinsic factor function, or intestinal infections.⁶

Generalized cutaneous hyperpigmentation may be the first manifestation of vitamins B₉ and B₁₂ deficiency.⁸⁸ Typically accentuated in acral creases and the oral cavity, pigmentation may mimic Addison disease. Hair depigmentation and linear streaking of the nails are reported.⁸⁴ The tongue becomes painful and red with atrophy of the filiform papillae (Hunter glossitis).⁷⁸ Linear lesions on the tongue and hard palate may serve as an early sign of cobalamin deficiency.⁸⁹

Folate deficiency is diagnosed by measuring the plasma folate level; coincidental cobalamin deficiency should be excluded. Deficiency is managed with oral supplementation (when possible) with 1 to 5 mg of folate daily.⁶ Cobalamin deficiency is based on low serum levels (<150 pg/mL is diagnostic).⁸⁶ Cobalamin deficiency may take years to develop, as vitamin B₁₂ exists in large body stores.⁶ Serum methylmalonic acid may be elevated in patients with clinical features but normal-low serum vitamin B₁₂ level.⁸⁶ Treatment of vitamin B₁₂ deficiency is with oral (2 mg once daily) or parenteral (1 mg every 4 weeks then maintained at once monthly) cyanocobalamin. For patients with neurologic symptoms, intramuscular injection should be given.⁸⁶ The underlying cause of deficiency must be elucidated and treated.

Vitamin C Deficiency

Vitamin C (ascorbic acid) is an essential cofactor for the hydroxylation of proline and lysine residues in collagen synthesis. Plant-based foods are the main dietary source of vitamin C, and deficiency presents clinically as scurvy. Cutaneous findings include follicular hyperkeratosis, perifollicular petechiae, and curled hair shafts (corkscrew hairs)(Figure 4). Ecchymoses of the lower extremities, forearms, and abdomen may be seen. Nodules representing intramuscular and subcutaneous hemorrhage can be present.⁹⁰ Woody edema may mimic cellulitis, while lower extremity hemorrhage may mimic vasculitis. Gingival hyperplasia, hemorrhage, and edema may occur,⁹⁰ along with linear splinter hemorrhages.⁹¹

Hoffman_June_2020_4.jpg

Hypovitaminosis C has been routinely demonstrated in hospitalized patients.⁹² Scurvy may occur in patients on strict diets,⁹³ chronic alcohol use,⁹⁴ psychiatric illness,⁹⁵ or gastrointestinal tract disease (eTable).^96-99 Those with low socioeconomic status⁷⁰ or dementia¹⁰⁰ as well as the elderly also are at risk.¹⁰¹ Scurvy has developed in patients with iron overload and those who are on hemodialysis⁴⁴ as well as in association with nilotinib use.¹⁰² Patients with chronic mucous membrane graft-vs-host disease may exhibit vitamin C deficiency.¹⁰³

Scurvy is a clinical diagnosis. Vitamin C levels normalize quickly with supplementation. Cutaneous biopsy will exhibit follicular hyperkeratosis, perifollicular hemorrhage, and fibrosis.⁹¹

Oral ascorbic acid supplementation should be initiated at 500 to 1000 mg daily in adults.¹⁰⁴ The cause of deficiency should be identified, and further supplementation should be decided based on patient risk factors. Lifestyle modifications, such as cessation of smoking and chronic alcohol use, is recommended. The diagnosis of scurvy should prompt workup for additional nutrient deficiencies.

Final Thoughts

Dermatologists play an important role in the early recognition of nutritional deficiencies, as cutaneous manifestations often are the first clue to diagnosis. Nutritional deficiencies are common yet underrecognized in the hospitalized patient and serve as an independent risk factor for patient morbidity and mortality.³ Awareness of the cutaneous manifestations of undernutrition as well as the risk factors for nutritional deficiency may expedite diagnosis and supplementation, thereby improving outcomes for hospitalized patients.

Many pediatric skin conditions can be safely monitored with minimal intervention, but certain skin conditions are emergent and require immediate attention and proper assessment of the neonate, infant, or child. The skin may provide the first presentation of a potentially fatal disease with serious sequelae. Cutaneous findings may indicate the need for further evaluation. Therefore, it is important to differentiate skin conditions with benign etiologies from those that require immediate diagnosis and treatment, as early intervention of some of these conditions can be lifesaving. Herein, we discuss pertinent pediatric dermatology emergencies that dermatologists should keep in mind so that these diagnoses are never missed.

Staphylococcal Scalded Skin Syndrome

Presentation
Staphylococcal scalded skin syndrome (SSSS), or Ritter disease, is a potentially fatal pediatric emergency, especially in newborns.¹ The mortality rate for SSSS in the United States is 3.6% to 11% in children.² It typically presents with a prodrome of tenderness, fever, and confluent erythematous patches on the folds of the skin such as the groin, axillae, nose, and ears, with eventual spread to the legs and trunk.^1,2 Within 24 to 48 hours of symptom onset, blistering and fluid accumulation will appear diffusely. Bullae are flaccid, and tangential and gentle pressure on involved unblistered skin may lead to shearing of the epithelium, which is a positive Nikolsky sign.^1,2

Causes
Staphylococcal scalded skin syndrome is caused by exfoliative toxins A and B, toxigenic strains of Staphylococcus aureus. Exfoliative toxins A and B are serine proteases that target and cleave desmoglein 1, which binds keratinocytes in the stratum granulosum.^1,3 Exfoliative toxins disrupt the adhesion of keratinocytes, resulting in bullae formation and subsequently diffuse sheetlike desquamation.^1,4,5 Although up to 30% of the human population are asymptomatically and permanently colonized with nasal S aureus,⁶ the exfoliative toxins are produced by only 5% of species.¹

[embed:render:related:node:217911]

In neonates, the immune and renal systems are underdeveloped; therefore, patients are susceptible to SSSS due to lack of neutralizing antibodies and decreased renal toxin excretion.⁴ Potential complications of SSSS are deeper soft-tissue infection, septicemia (blood-borne infection), and fluid and electrolyte imbalance.^1,4

Diagnosis and Treatment
The condition is diagnosed clinically based on the findings of tender erythroderma, bullae, and desquamation with a scalded appearance, especially in friction zones; periorificial crusting; positive Nikolsky sign; and lack of mucosal involvement (Figure 1).¹ Histopathology can aid in complicated clinical scenarios as well as culture from affected areas, including the upper respiratory tract, diaper region, and umbilicus.^1,4 Hospitalization is required for SSSS for intravenous antibiotics, fluids, and electrolyte repletion.

Robinson_HC_1.JPG

Robinson_HC_2.JPG

Impetigo

Presentation
Impetigo is the most common bacterial skin infection in children caused by S aureus or Streptococcus pyogenes.^7-9 It begins as erythematous papules transitioning to thin-walled vesicles that rapidly rupture and result in honey-crusted papules.^7,9,10 Individuals of any age can be affected by nonbullous impetigo, but it is the most common skin infection in children aged 2 to 5 years.⁷

[embed:render:related:node:212062]

Bullous impetigo primarily is seen in children, especially infants, and rarely can occur in teenagers or adults.⁷ It most commonly is caused by the exfoliative toxins of S aureus. Bullous impetigo presents as small vesicles that may converge into larger flaccid bullae or pustules.^7-10 Once the bullae rupture, an erythematous base with a collarette of scale remains without the formation of a honey-colored crust.⁸ Bullous impetigo usually affects moist intertriginous areas such as the axillae, neck, and diaper area^8,10 (Figure 3). Complications may result in cellulitis, septicemia, osteomyelitis, poststreptococcal glomerulonephritis associated with S pyogenes, and S aureus–induced SSSS.^7-9

Robinson_HC_3.JPG

Eczema Herpeticum

Presentation
Eczema herpeticum (EH), also known as Kaposi varicelliform eruption, is a disseminated herpes simplex virus infection of impaired skin, most commonly in patients with atopic dermatitis (AD).¹¹ Eczema herpeticum presents as a widespread eruption of erythematous monomorphic vesicles that progress to punched-out erosions with hemorrhagic crusting (Figure 4). Patients may have associated fever or lymphadenopathy.^12,13

Robinson_HC_4.JPG

Causes
The number of children hospitalized annually for EH in the United States is approximately 4 to 7 cases per million children. Less than 3% of pediatric AD patients are affected, with a particularly increased risk in patients with severe and earlier-onset AD.^12-15 Patients with AD have skin barrier defects, and decreased IFN-γ expression and cathelicidins predispose patients with AD to developing EH.^12,16,17

Diagnosis
Viral polymerase chain reaction for herpes simplex virus types 1 and 2 is the standard for confirmatory diagnosis. Herpes simplex virus cultures from cutaneous scrapings, direct fluorescent antibody testing, or Tzanck test revealing multinucleated giant cells also may help establish the diagnosis.^11,12,17

Management
Individuals with severe AD and other dermatologic conditions with cutaneous barrier compromise are at risk for developing EH, which is a medical emergency requiring hospitalization and prompt treatment with antiviral therapy such as acyclovir, often intravenously, as death can result if left untreated.^11,17 Topical or systemic antibiotic therapy should be initiated if there is suspicion for secondary bacterial superinfection. Patients should be evaluated for multiorgan involvement such as keratoconjunctivitis, meningitis, encephalitis, and systemic viremia due to increased mortality, especially in infants.^12,15,16

Langerhans Cell Histiocytosis

Presentation
Langerhans cell histiocytosis (LCH) has a variable clinical presentation and can involve a single or multiple organ systems, including the bones and skin. Cutaneous LCH can present as violaceous papules, nodules, or ulcerations and crusted erosions (Figure 5). The lymph nodes, liver, spleen, oral mucosa, and respiratory and central nervous systems also may be involved.

Robinson_HC_5.JPG

Langerhans cell histiocytosis affects individuals of any age group but more often is seen in pediatric patients. The incidence of LCH is approximately 4.6 cases per million children.¹⁸ The pathogenesis is secondary to pathologic Langerhans cells, characterized as a clonal myeloid malignancy and dysregulation of the immune system.^18,19

Diagnosis
A thorough physical examination is essential in patients with suspected LCH. Additionally, diagnosis of LCH is heavily based on histopathology of tissue from the involved organ system(s) with features of positive S-100 protein, CD1a, and CD207, and identification of Birbeck granules.²⁰ Imaging and laboratory studies also are indicated and can include a skeletal survey (to assess osteolytic and organ involvement), a complete hematologic panel, coagulation studies, and liver function tests.^18,21

Management
Management of LCH varies based on the organ system(s) involved along with the extent of the disease. Dermatology referral may be indicated in patients presenting with nonresolving cutaneous lesions as well as in severe cases. Single-organ and multisystem disease may require one treatment modality or a combination of chemotherapy, surgery, radiation, and/or immunotherapy.²¹

Infantile Hemangioma

Presentation
Infantile hemangioma (IH) is the most common benign tumor of infancy and usually is apparent a few weeks after birth. Lesions appear as bright red papules, nodules, or plaques. Deep or subcutaneous lesions present as raised, flesh-colored nodules with a blue hue and bruiselike appearance with or without a central patch of telangiectasia^22-24 (Figure 6). Although all IHs eventually resolve, residual skin changes such as scarring, atrophy, and fibrosis can persist.²⁴

Robinson_HC_6.JPG

The incidence of IH has been reported to occur in up to 4% to 5% of infants in the United States.^23,25 Infantile hemangiomas also have been found to be more common among white, preterm, and multiple-gestation infants.²⁵ The proposed pathogenesis of IHs includes angiogenic and vasogenic factors that cause rapid proliferation of blood vessels, likely driven by tissue hypoxia.^23,26,27

[embed:render:related:node:211551]

Diagnosis
Infantile hemangioma is diagnosed clinically; however, immunohistochemical staining showing positivity for glucose transporter 1 also is helpful.^26,27 Imaging modalities such as ultrasonography and magnetic resonance imaging also can be utilized to visualize the extent of lesions if necessary.²⁵

Management
Around 15% to 25% of IHs are considered complicated and require intervention.^25,27 Infantile hemangiomas can interfere with function depending on location or have potentially fatal complications. Based on the location and extent of involvement, these findings can include ulceration; hemorrhage; impairment of feeding, hearing, and/or vision; facial deformities; airway obstruction; hypothyroidism; and congestive heart failure.^25,28 Early treatment with topical or oral beta-blockers is imperative for potentially life-threatening IHs, which can be seen due to large size or dangerous location.^28,29 Because the rapid proliferative phase of IHs is thought to begin around 6 weeks of life, treatment should be initiated as early as possible. Initiation of beta-blocker therapy in the first few months of life can prevent functional impairment, ulceration, and permanent cosmetic changes. Additionally, surgery or pulsed dye laser treatment have been found to be effective for skin changes found after involution of IH.^25,29

Differential Diagnosis
The differential diagnosis for IH includes vascular malformations, which are present at birth and do not undergo rapid proliferation; sarcoma; and kaposiform hemangioendothelioma, which causes the Kasabach-Merritt phenomenon secondary to platelet trapping. Careful attention to the history of the skin lesion provides good support for diagnosis of IH in most cases.

IgA Vasculitis

Presentation
IgA vasculitis, or Henoch-Schönlein purpura, classically presents as a tetrad of palpable purpura, acute-onset arthritis or arthralgia, abdominal pain, and renal disease with proteinuria or hematuria.³⁰ Skin involvement is seen in almost all cases and is essential for diagnosis of IgA vasculitis. The initial dermatosis may be pruritic and present as an erythematous macular or urticarial wheal that evolves into petechiae, along with palpable purpura that is most frequently located on the legs or buttocks (Figure 7).^30-34

Robinson_HC_7.JPG

IgA vasculitis is an immune-mediated small vessel vasculitis with deposition of IgA in the small vessels. The underlying cause remains unknown, though infection, dietary allergens, drugs, vaccinations, and chemical triggers have been recognized in literature.^32,35,36 IgA vasculitis is largely a pediatric diagnosis, with 90% of affected individuals younger than 10 years worldwide.³⁷ In the pediatric population, the incidence has been reported to be 3 to 26.7 cases per 100,000 children.³²

Diagnosis
Diagnosis is based on the clinical presentation and histopathology.³⁰ On direct immunofluorescence, IgA deposition is seen in the vessel walls.³⁵ Laboratory testing is not diagnostic, but urinalysis is mandatory to identify involvement of renal vasculature. Imaging studies may be used in patients with abdominal symptoms, as an ultrasound can be used to visualize bowel structure and abnormalities such as intussusception.³³

[embed:render:related:node:211566]

Management
The majority of cases of IgA vasculitis recover spontaneously, with patients requiring hospital admission based on severity of symptoms.³⁰ The primary approach to management involves providing supportive care including hydration, adequate rest, and symptomatic pain relief of the joints and abdomen with oral analgesics. Systemic corticosteroids or steroid-sparing agents such as dapsone or colchicine can be used to treat cutaneous manifestations in addition to severe pain symptoms.^30,31 Patients with IgA vasculitis must be monitored for proteinuria or hematuria to assess the extent of renal involvement. Although much more common in adults, long-term renal impairment can result from childhood cases of IgA vasculitis.³⁴ 

Final Thoughts

Pediatric dermatology emergencies can be difficult to detect and accurately diagnose. Many of these diseases are potential emergencies that that may result in delayed treatment and considerable morbidity and mortality if missed. Clinicians should be aware that timely recognition and diagnosis, along with possible referral to pediatric dermatology, are essential to avoid complications.

Many pediatric skin conditions can be safely monitored with minimal intervention, but certain skin conditions are emergent and require immediate attention and proper assessment of the neonate, infant, or child. The skin may provide the first presentation of a potentially fatal disease with serious sequelae. Cutaneous findings may indicate the need for further evaluation. Therefore, it is important to differentiate skin conditions with benign etiologies from those that require immediate diagnosis and treatment, as early intervention of some of these conditions can be lifesaving. Herein, we discuss pertinent pediatric dermatology emergencies that dermatologists should keep in mind so that these diagnoses are never missed.

Staphylococcal Scalded Skin Syndrome

Presentation
Staphylococcal scalded skin syndrome (SSSS), or Ritter disease, is a potentially fatal pediatric emergency, especially in newborns.¹ The mortality rate for SSSS in the United States is 3.6% to 11% in children.² It typically presents with a prodrome of tenderness, fever, and confluent erythematous patches on the folds of the skin such as the groin, axillae, nose, and ears, with eventual spread to the legs and trunk.^1,2 Within 24 to 48 hours of symptom onset, blistering and fluid accumulation will appear diffusely. Bullae are flaccid, and tangential and gentle pressure on involved unblistered skin may lead to shearing of the epithelium, which is a positive Nikolsky sign.^1,2

Causes
Staphylococcal scalded skin syndrome is caused by exfoliative toxins A and B, toxigenic strains of Staphylococcus aureus. Exfoliative toxins A and B are serine proteases that target and cleave desmoglein 1, which binds keratinocytes in the stratum granulosum.^1,3 Exfoliative toxins disrupt the adhesion of keratinocytes, resulting in bullae formation and subsequently diffuse sheetlike desquamation.^1,4,5 Although up to 30% of the human population are asymptomatically and permanently colonized with nasal S aureus,⁶ the exfoliative toxins are produced by only 5% of species.¹

[embed:render:related:node:217911]

In neonates, the immune and renal systems are underdeveloped; therefore, patients are susceptible to SSSS due to lack of neutralizing antibodies and decreased renal toxin excretion.⁴ Potential complications of SSSS are deeper soft-tissue infection, septicemia (blood-borne infection), and fluid and electrolyte imbalance.^1,4

Diagnosis and Treatment
The condition is diagnosed clinically based on the findings of tender erythroderma, bullae, and desquamation with a scalded appearance, especially in friction zones; periorificial crusting; positive Nikolsky sign; and lack of mucosal involvement (Figure 1).¹ Histopathology can aid in complicated clinical scenarios as well as culture from affected areas, including the upper respiratory tract, diaper region, and umbilicus.^1,4 Hospitalization is required for SSSS for intravenous antibiotics, fluids, and electrolyte repletion.

Robinson_HC_1.JPG

Robinson_HC_2.JPG

Impetigo

Presentation
Impetigo is the most common bacterial skin infection in children caused by S aureus or Streptococcus pyogenes.^7-9 It begins as erythematous papules transitioning to thin-walled vesicles that rapidly rupture and result in honey-crusted papules.^7,9,10 Individuals of any age can be affected by nonbullous impetigo, but it is the most common skin infection in children aged 2 to 5 years.⁷

[embed:render:related:node:212062]

Bullous impetigo primarily is seen in children, especially infants, and rarely can occur in teenagers or adults.⁷ It most commonly is caused by the exfoliative toxins of S aureus. Bullous impetigo presents as small vesicles that may converge into larger flaccid bullae or pustules.^7-10 Once the bullae rupture, an erythematous base with a collarette of scale remains without the formation of a honey-colored crust.⁸ Bullous impetigo usually affects moist intertriginous areas such as the axillae, neck, and diaper area^8,10 (Figure 3). Complications may result in cellulitis, septicemia, osteomyelitis, poststreptococcal glomerulonephritis associated with S pyogenes, and S aureus–induced SSSS.^7-9

Robinson_HC_3.JPG

Eczema Herpeticum

Presentation
Eczema herpeticum (EH), also known as Kaposi varicelliform eruption, is a disseminated herpes simplex virus infection of impaired skin, most commonly in patients with atopic dermatitis (AD).¹¹ Eczema herpeticum presents as a widespread eruption of erythematous monomorphic vesicles that progress to punched-out erosions with hemorrhagic crusting (Figure 4). Patients may have associated fever or lymphadenopathy.^12,13

Robinson_HC_4.JPG

Causes
The number of children hospitalized annually for EH in the United States is approximately 4 to 7 cases per million children. Less than 3% of pediatric AD patients are affected, with a particularly increased risk in patients with severe and earlier-onset AD.^12-15 Patients with AD have skin barrier defects, and decreased IFN-γ expression and cathelicidins predispose patients with AD to developing EH.^12,16,17

Diagnosis
Viral polymerase chain reaction for herpes simplex virus types 1 and 2 is the standard for confirmatory diagnosis. Herpes simplex virus cultures from cutaneous scrapings, direct fluorescent antibody testing, or Tzanck test revealing multinucleated giant cells also may help establish the diagnosis.^11,12,17

Management
Individuals with severe AD and other dermatologic conditions with cutaneous barrier compromise are at risk for developing EH, which is a medical emergency requiring hospitalization and prompt treatment with antiviral therapy such as acyclovir, often intravenously, as death can result if left untreated.^11,17 Topical or systemic antibiotic therapy should be initiated if there is suspicion for secondary bacterial superinfection. Patients should be evaluated for multiorgan involvement such as keratoconjunctivitis, meningitis, encephalitis, and systemic viremia due to increased mortality, especially in infants.^12,15,16

Langerhans Cell Histiocytosis

Presentation
Langerhans cell histiocytosis (LCH) has a variable clinical presentation and can involve a single or multiple organ systems, including the bones and skin. Cutaneous LCH can present as violaceous papules, nodules, or ulcerations and crusted erosions (Figure 5). The lymph nodes, liver, spleen, oral mucosa, and respiratory and central nervous systems also may be involved.

Robinson_HC_5.JPG

Langerhans cell histiocytosis affects individuals of any age group but more often is seen in pediatric patients. The incidence of LCH is approximately 4.6 cases per million children.¹⁸ The pathogenesis is secondary to pathologic Langerhans cells, characterized as a clonal myeloid malignancy and dysregulation of the immune system.^18,19

Diagnosis
A thorough physical examination is essential in patients with suspected LCH. Additionally, diagnosis of LCH is heavily based on histopathology of tissue from the involved organ system(s) with features of positive S-100 protein, CD1a, and CD207, and identification of Birbeck granules.²⁰ Imaging and laboratory studies also are indicated and can include a skeletal survey (to assess osteolytic and organ involvement), a complete hematologic panel, coagulation studies, and liver function tests.^18,21

Management
Management of LCH varies based on the organ system(s) involved along with the extent of the disease. Dermatology referral may be indicated in patients presenting with nonresolving cutaneous lesions as well as in severe cases. Single-organ and multisystem disease may require one treatment modality or a combination of chemotherapy, surgery, radiation, and/or immunotherapy.²¹

Infantile Hemangioma

Presentation
Infantile hemangioma (IH) is the most common benign tumor of infancy and usually is apparent a few weeks after birth. Lesions appear as bright red papules, nodules, or plaques. Deep or subcutaneous lesions present as raised, flesh-colored nodules with a blue hue and bruiselike appearance with or without a central patch of telangiectasia^22-24 (Figure 6). Although all IHs eventually resolve, residual skin changes such as scarring, atrophy, and fibrosis can persist.²⁴

Robinson_HC_6.JPG

The incidence of IH has been reported to occur in up to 4% to 5% of infants in the United States.^23,25 Infantile hemangiomas also have been found to be more common among white, preterm, and multiple-gestation infants.²⁵ The proposed pathogenesis of IHs includes angiogenic and vasogenic factors that cause rapid proliferation of blood vessels, likely driven by tissue hypoxia.^23,26,27

[embed:render:related:node:211551]

Diagnosis
Infantile hemangioma is diagnosed clinically; however, immunohistochemical staining showing positivity for glucose transporter 1 also is helpful.^26,27 Imaging modalities such as ultrasonography and magnetic resonance imaging also can be utilized to visualize the extent of lesions if necessary.²⁵

Management
Around 15% to 25% of IHs are considered complicated and require intervention.^25,27 Infantile hemangiomas can interfere with function depending on location or have potentially fatal complications. Based on the location and extent of involvement, these findings can include ulceration; hemorrhage; impairment of feeding, hearing, and/or vision; facial deformities; airway obstruction; hypothyroidism; and congestive heart failure.^25,28 Early treatment with topical or oral beta-blockers is imperative for potentially life-threatening IHs, which can be seen due to large size or dangerous location.^28,29 Because the rapid proliferative phase of IHs is thought to begin around 6 weeks of life, treatment should be initiated as early as possible. Initiation of beta-blocker therapy in the first few months of life can prevent functional impairment, ulceration, and permanent cosmetic changes. Additionally, surgery or pulsed dye laser treatment have been found to be effective for skin changes found after involution of IH.^25,29

Differential Diagnosis
The differential diagnosis for IH includes vascular malformations, which are present at birth and do not undergo rapid proliferation; sarcoma; and kaposiform hemangioendothelioma, which causes the Kasabach-Merritt phenomenon secondary to platelet trapping. Careful attention to the history of the skin lesion provides good support for diagnosis of IH in most cases.

IgA Vasculitis

Presentation
IgA vasculitis, or Henoch-Schönlein purpura, classically presents as a tetrad of palpable purpura, acute-onset arthritis or arthralgia, abdominal pain, and renal disease with proteinuria or hematuria.³⁰ Skin involvement is seen in almost all cases and is essential for diagnosis of IgA vasculitis. The initial dermatosis may be pruritic and present as an erythematous macular or urticarial wheal that evolves into petechiae, along with palpable purpura that is most frequently located on the legs or buttocks (Figure 7).^30-34

Robinson_HC_7.JPG

IgA vasculitis is an immune-mediated small vessel vasculitis with deposition of IgA in the small vessels. The underlying cause remains unknown, though infection, dietary allergens, drugs, vaccinations, and chemical triggers have been recognized in literature.^32,35,36 IgA vasculitis is largely a pediatric diagnosis, with 90% of affected individuals younger than 10 years worldwide.³⁷ In the pediatric population, the incidence has been reported to be 3 to 26.7 cases per 100,000 children.³²

Diagnosis
Diagnosis is based on the clinical presentation and histopathology.³⁰ On direct immunofluorescence, IgA deposition is seen in the vessel walls.³⁵ Laboratory testing is not diagnostic, but urinalysis is mandatory to identify involvement of renal vasculature. Imaging studies may be used in patients with abdominal symptoms, as an ultrasound can be used to visualize bowel structure and abnormalities such as intussusception.³³

[embed:render:related:node:211566]

Management
The majority of cases of IgA vasculitis recover spontaneously, with patients requiring hospital admission based on severity of symptoms.³⁰ The primary approach to management involves providing supportive care including hydration, adequate rest, and symptomatic pain relief of the joints and abdomen with oral analgesics. Systemic corticosteroids or steroid-sparing agents such as dapsone or colchicine can be used to treat cutaneous manifestations in addition to severe pain symptoms.^30,31 Patients with IgA vasculitis must be monitored for proteinuria or hematuria to assess the extent of renal involvement. Although much more common in adults, long-term renal impairment can result from childhood cases of IgA vasculitis.³⁴ 

Final Thoughts

Pediatric dermatology emergencies can be difficult to detect and accurately diagnose. Many of these diseases are potential emergencies that that may result in delayed treatment and considerable morbidity and mortality if missed. Clinicians should be aware that timely recognition and diagnosis, along with possible referral to pediatric dermatology, are essential to avoid complications.

Many pediatric skin conditions can be safely monitored with minimal intervention, but certain skin conditions are emergent and require immediate attention and proper assessment of the neonate, infant, or child. The skin may provide the first presentation of a potentially fatal disease with serious sequelae. Cutaneous findings may indicate the need for further evaluation. Therefore, it is important to differentiate skin conditions with benign etiologies from those that require immediate diagnosis and treatment, as early intervention of some of these conditions can be lifesaving. Herein, we discuss pertinent pediatric dermatology emergencies that dermatologists should keep in mind so that these diagnoses are never missed.

Staphylococcal Scalded Skin Syndrome

Presentation
Staphylococcal scalded skin syndrome (SSSS), or Ritter disease, is a potentially fatal pediatric emergency, especially in newborns.¹ The mortality rate for SSSS in the United States is 3.6% to 11% in children.² It typically presents with a prodrome of tenderness, fever, and confluent erythematous patches on the folds of the skin such as the groin, axillae, nose, and ears, with eventual spread to the legs and trunk.^1,2 Within 24 to 48 hours of symptom onset, blistering and fluid accumulation will appear diffusely. Bullae are flaccid, and tangential and gentle pressure on involved unblistered skin may lead to shearing of the epithelium, which is a positive Nikolsky sign.^1,2

Causes
Staphylococcal scalded skin syndrome is caused by exfoliative toxins A and B, toxigenic strains of Staphylococcus aureus. Exfoliative toxins A and B are serine proteases that target and cleave desmoglein 1, which binds keratinocytes in the stratum granulosum.^1,3 Exfoliative toxins disrupt the adhesion of keratinocytes, resulting in bullae formation and subsequently diffuse sheetlike desquamation.^1,4,5 Although up to 30% of the human population are asymptomatically and permanently colonized with nasal S aureus,⁶ the exfoliative toxins are produced by only 5% of species.¹

[embed:render:related:node:217911]

In neonates, the immune and renal systems are underdeveloped; therefore, patients are susceptible to SSSS due to lack of neutralizing antibodies and decreased renal toxin excretion.⁴ Potential complications of SSSS are deeper soft-tissue infection, septicemia (blood-borne infection), and fluid and electrolyte imbalance.^1,4

Diagnosis and Treatment
The condition is diagnosed clinically based on the findings of tender erythroderma, bullae, and desquamation with a scalded appearance, especially in friction zones; periorificial crusting; positive Nikolsky sign; and lack of mucosal involvement (Figure 1).¹ Histopathology can aid in complicated clinical scenarios as well as culture from affected areas, including the upper respiratory tract, diaper region, and umbilicus.^1,4 Hospitalization is required for SSSS for intravenous antibiotics, fluids, and electrolyte repletion.

Robinson_HC_1.JPG

Robinson_HC_2.JPG

Impetigo

Presentation
Impetigo is the most common bacterial skin infection in children caused by S aureus or Streptococcus pyogenes.^7-9 It begins as erythematous papules transitioning to thin-walled vesicles that rapidly rupture and result in honey-crusted papules.^7,9,10 Individuals of any age can be affected by nonbullous impetigo, but it is the most common skin infection in children aged 2 to 5 years.⁷

[embed:render:related:node:212062]

Bullous impetigo primarily is seen in children, especially infants, and rarely can occur in teenagers or adults.⁷ It most commonly is caused by the exfoliative toxins of S aureus. Bullous impetigo presents as small vesicles that may converge into larger flaccid bullae or pustules.^7-10 Once the bullae rupture, an erythematous base with a collarette of scale remains without the formation of a honey-colored crust.⁸ Bullous impetigo usually affects moist intertriginous areas such as the axillae, neck, and diaper area^8,10 (Figure 3). Complications may result in cellulitis, septicemia, osteomyelitis, poststreptococcal glomerulonephritis associated with S pyogenes, and S aureus–induced SSSS.^7-9

Robinson_HC_3.JPG

Eczema Herpeticum

Presentation
Eczema herpeticum (EH), also known as Kaposi varicelliform eruption, is a disseminated herpes simplex virus infection of impaired skin, most commonly in patients with atopic dermatitis (AD).¹¹ Eczema herpeticum presents as a widespread eruption of erythematous monomorphic vesicles that progress to punched-out erosions with hemorrhagic crusting (Figure 4). Patients may have associated fever or lymphadenopathy.^12,13

Robinson_HC_4.JPG

Causes
The number of children hospitalized annually for EH in the United States is approximately 4 to 7 cases per million children. Less than 3% of pediatric AD patients are affected, with a particularly increased risk in patients with severe and earlier-onset AD.^12-15 Patients with AD have skin barrier defects, and decreased IFN-γ expression and cathelicidins predispose patients with AD to developing EH.^12,16,17

Diagnosis
Viral polymerase chain reaction for herpes simplex virus types 1 and 2 is the standard for confirmatory diagnosis. Herpes simplex virus cultures from cutaneous scrapings, direct fluorescent antibody testing, or Tzanck test revealing multinucleated giant cells also may help establish the diagnosis.^11,12,17

Management
Individuals with severe AD and other dermatologic conditions with cutaneous barrier compromise are at risk for developing EH, which is a medical emergency requiring hospitalization and prompt treatment with antiviral therapy such as acyclovir, often intravenously, as death can result if left untreated.^11,17 Topical or systemic antibiotic therapy should be initiated if there is suspicion for secondary bacterial superinfection. Patients should be evaluated for multiorgan involvement such as keratoconjunctivitis, meningitis, encephalitis, and systemic viremia due to increased mortality, especially in infants.^12,15,16

Langerhans Cell Histiocytosis

Presentation
Langerhans cell histiocytosis (LCH) has a variable clinical presentation and can involve a single or multiple organ systems, including the bones and skin. Cutaneous LCH can present as violaceous papules, nodules, or ulcerations and crusted erosions (Figure 5). The lymph nodes, liver, spleen, oral mucosa, and respiratory and central nervous systems also may be involved.

Robinson_HC_5.JPG

Langerhans cell histiocytosis affects individuals of any age group but more often is seen in pediatric patients. The incidence of LCH is approximately 4.6 cases per million children.¹⁸ The pathogenesis is secondary to pathologic Langerhans cells, characterized as a clonal myeloid malignancy and dysregulation of the immune system.^18,19

Diagnosis
A thorough physical examination is essential in patients with suspected LCH. Additionally, diagnosis of LCH is heavily based on histopathology of tissue from the involved organ system(s) with features of positive S-100 protein, CD1a, and CD207, and identification of Birbeck granules.²⁰ Imaging and laboratory studies also are indicated and can include a skeletal survey (to assess osteolytic and organ involvement), a complete hematologic panel, coagulation studies, and liver function tests.^18,21

Management
Management of LCH varies based on the organ system(s) involved along with the extent of the disease. Dermatology referral may be indicated in patients presenting with nonresolving cutaneous lesions as well as in severe cases. Single-organ and multisystem disease may require one treatment modality or a combination of chemotherapy, surgery, radiation, and/or immunotherapy.²¹

Infantile Hemangioma

Presentation
Infantile hemangioma (IH) is the most common benign tumor of infancy and usually is apparent a few weeks after birth. Lesions appear as bright red papules, nodules, or plaques. Deep or subcutaneous lesions present as raised, flesh-colored nodules with a blue hue and bruiselike appearance with or without a central patch of telangiectasia^22-24 (Figure 6). Although all IHs eventually resolve, residual skin changes such as scarring, atrophy, and fibrosis can persist.²⁴

Robinson_HC_6.JPG

The incidence of IH has been reported to occur in up to 4% to 5% of infants in the United States.^23,25 Infantile hemangiomas also have been found to be more common among white, preterm, and multiple-gestation infants.²⁵ The proposed pathogenesis of IHs includes angiogenic and vasogenic factors that cause rapid proliferation of blood vessels, likely driven by tissue hypoxia.^23,26,27

[embed:render:related:node:211551]

Diagnosis
Infantile hemangioma is diagnosed clinically; however, immunohistochemical staining showing positivity for glucose transporter 1 also is helpful.^26,27 Imaging modalities such as ultrasonography and magnetic resonance imaging also can be utilized to visualize the extent of lesions if necessary.²⁵

Management
Around 15% to 25% of IHs are considered complicated and require intervention.^25,27 Infantile hemangiomas can interfere with function depending on location or have potentially fatal complications. Based on the location and extent of involvement, these findings can include ulceration; hemorrhage; impairment of feeding, hearing, and/or vision; facial deformities; airway obstruction; hypothyroidism; and congestive heart failure.^25,28 Early treatment with topical or oral beta-blockers is imperative for potentially life-threatening IHs, which can be seen due to large size or dangerous location.^28,29 Because the rapid proliferative phase of IHs is thought to begin around 6 weeks of life, treatment should be initiated as early as possible. Initiation of beta-blocker therapy in the first few months of life can prevent functional impairment, ulceration, and permanent cosmetic changes. Additionally, surgery or pulsed dye laser treatment have been found to be effective for skin changes found after involution of IH.^25,29

Differential Diagnosis
The differential diagnosis for IH includes vascular malformations, which are present at birth and do not undergo rapid proliferation; sarcoma; and kaposiform hemangioendothelioma, which causes the Kasabach-Merritt phenomenon secondary to platelet trapping. Careful attention to the history of the skin lesion provides good support for diagnosis of IH in most cases.

IgA Vasculitis

Presentation
IgA vasculitis, or Henoch-Schönlein purpura, classically presents as a tetrad of palpable purpura, acute-onset arthritis or arthralgia, abdominal pain, and renal disease with proteinuria or hematuria.³⁰ Skin involvement is seen in almost all cases and is essential for diagnosis of IgA vasculitis. The initial dermatosis may be pruritic and present as an erythematous macular or urticarial wheal that evolves into petechiae, along with palpable purpura that is most frequently located on the legs or buttocks (Figure 7).^30-34

Robinson_HC_7.JPG

IgA vasculitis is an immune-mediated small vessel vasculitis with deposition of IgA in the small vessels. The underlying cause remains unknown, though infection, dietary allergens, drugs, vaccinations, and chemical triggers have been recognized in literature.^32,35,36 IgA vasculitis is largely a pediatric diagnosis, with 90% of affected individuals younger than 10 years worldwide.³⁷ In the pediatric population, the incidence has been reported to be 3 to 26.7 cases per 100,000 children.³²

Diagnosis
Diagnosis is based on the clinical presentation and histopathology.³⁰ On direct immunofluorescence, IgA deposition is seen in the vessel walls.³⁵ Laboratory testing is not diagnostic, but urinalysis is mandatory to identify involvement of renal vasculature. Imaging studies may be used in patients with abdominal symptoms, as an ultrasound can be used to visualize bowel structure and abnormalities such as intussusception.³³

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Management
The majority of cases of IgA vasculitis recover spontaneously, with patients requiring hospital admission based on severity of symptoms.³⁰ The primary approach to management involves providing supportive care including hydration, adequate rest, and symptomatic pain relief of the joints and abdomen with oral analgesics. Systemic corticosteroids or steroid-sparing agents such as dapsone or colchicine can be used to treat cutaneous manifestations in addition to severe pain symptoms.^30,31 Patients with IgA vasculitis must be monitored for proteinuria or hematuria to assess the extent of renal involvement. Although much more common in adults, long-term renal impairment can result from childhood cases of IgA vasculitis.³⁴ 

Final Thoughts

Pediatric dermatology emergencies can be difficult to detect and accurately diagnose. Many of these diseases are potential emergencies that that may result in delayed treatment and considerable morbidity and mortality if missed. Clinicians should be aware that timely recognition and diagnosis, along with possible referral to pediatric dermatology, are essential to avoid complications.

[embed:render:podcast_episode_embedded:node:215612]

Leukemia is a malignant, life-threatening neoplasm affecting the hematopoietic system. Extramedullary manifestations can occur in various organs, including skin.¹ Skin findings in leukemia patients are common and varied, including pallor secondary to anemia, petechiae or ecchymoses due to thrombocytopenia, and skin manifestations of neutropenia and chemotherapy.² When patients with leukemia develop skin lesions without leukemic infiltration, the resulting nonspecific cutaneous manifestations are known as leukemids.³ Specific cutaneous manifestations of leukemia resulting from direct invasion of leukemic cells into the epidermis, dermis, or subcutis are referred to as leukemia cutis (LC).^2,3

[embed:render:related:node:198141]

Acute myeloid leukemia (AML) is the most common type of leukemia associated with LC, but LC also is seen in other leukemias with various frequencies.¹ The lesions of LC can present anywhere on skin, though it has been reported that LC has a tendency to occur at sites of prior ongoing inflammation,^2,4 most commonly the extremities, trunk, and face.^2,5,6 LC lesions have a range of morphological findings and most commonly present as nodules, papules, and plaques.^1,7

Most reports of LC in the literature are case reports or case series with small numbers of subjects.^3,6,8 A study of LC patients (N=75) in Korea by Kang et al⁷ has been the only one to analyze clinical characteristics of LC since 2000.

[embed:render:related:node:176219]

The aim of this study was to further contribute to the knowledge of clinical characteristics of LC. Clinical patterns of 46 patients were analyzed to further characterize the presentation of LC and to compare our results with those in the literature.

Methods

We conducted a single-institution retrospective review of medical records of patients with LC diagnosed in the Department of Dermatology at Wake Forest School of Medicine (Winston-Salem, North Carolina) over a 17-year period (2001-2017). The study protocol was approved by the institutional review board of Wake Forest University School of Medicine (IRB No. 00054474). Patients had a leukemia diagnosis established by bone marrow biopsy. Patients were included in this analysis if they had ongoing active leukemia and a skin biopsy consistent with LC. Patients of all sexes and ages were included in the cohort. Patients were excluded if they presented only with nonspecific cutaneous lesions associated with leukemia (leukemids). After removing duplicate records from a total of 60 patients initially identified, 46 unique patients were included in this study.

Results

Demographics
Fifty-six percent (26/46) of patients were male. The average age at diagnosis of leukemia was 58 years (range, 8.5 months–84 years). Eighty-five percent of patients were white (39/46), 11% were black (5/46), 2% were Hispanic (1/46), and 2% were of unknown ethnicity (1/46).

[embed:render:related:node:100367]

Eighty percent (37/46) of patients with LC had AML; 3 of these patients had a prior diagnosis of chronic myeloid leukemia (CML) and 2 had myelodysplastic syndrome (MDS) that did not develop LC until after they had transitioned to AML. Other subtypes of leukemia in this patient population included acute lymphoblastic leukemia (ALL)(n=2), plasma cell leukemia (PCL)(n=2), undifferentiated leukemia (n=2), chronic lymphocytic leukemia (CLL)(n=1), myelodysplastic syndrome (n=1), and Burkitt-type leukemia (n=1).

Distribution and Morphology of LC Lesions
The clinical appearance of LC was widely variable in morphology and anatomic location (Table 1 and Figure). Eighty-four percent of LC occurrences involved more than one lesion (n=32); 14% were a solitary lesion (n=6). For the 2 patients who had 2 separate episodes of LC, the initial presentation of LC was multiple lesions; recurrent LC at relapse presented as a solitary lesion in both cases. Most LC lesions (77% [67/87]) occurred on the trunk or extremities; 23% (20/87) of LC lesions occurred on less common sites, such as the groin, face, hands, feet, and mucosa. Papules (38% [22/58]) and nodules (31% [18/58]) were the most common morphology; macules, plaques, and ulcers were observed less frequently. Clinical descriptions of LC lesions varied widely, with the most common descriptive characteristics being erythematous (57% [20/35]), violaceous (31% [11/35]), and asymptomatic (84% [32/38]). Rare descriptors included flesh colored, hyperpigmented, tender, pruritic, edema, crusting, and confluent erythematous.

Haidari_CT104006326_Table1.JPG

Haidari_CT104006326_Fig_ABCDE.JPG

Haidari_CT104006326_Table2.JPG

Haidari_CT104006326_eTable.JPG

Discussion

Cutaneous manifestations are not uncommon in leukemia patients and can have a number of causes, including paraneoplastic cutaneous manifestations, such as pyoderma gangrenosum and Sweet syndrome; infection; cutaneous toxicities from antineoplastic agents; and LC.² Leukemia cutis can be confused with other skin lesions in leukemia patients; diagnosis requires biopsy.^2,9

[embed:render:related:node:100170]

We analyzed clinical characteristics and prognosis of 46 patients with LC over a 17-year period. To the best of our knowledge, this is the largest study of LC patients published in the United States. A similar study by Kang et al⁷ analyzed 75 patients in Korea; however, the incidence of LC among different types of leukemia in the Korean population cannot be applied to Western countries. We did compare the clinical characteristics of our cohort of patients to those reported by Kang et al⁷ and other studies including a smaller number of patients.

In this study, the male to female ratio was 1.3 to 1 compared to the 2:1 ratio reported by Kang et al.⁷ The mean age of leukemia diagnosis among our patients was 58 years, which is notably older than the mean age previously reported.⁷ In this cohort, 4 patients (8.7%) were 34 years or younger, including 1 infant aged 8.5 months; 24 (52.2%) were aged 35 to 64 years; and 18 (39.1%) were 65 years and older.

Consistent with other studies,^2,5,7 the most common type of leukemia in patients who developed LC was AML (80%). Among AML patients, the mean age at AML diagnosis (59.8 years) was notably younger than the reported US average age of patients who had a diagnosis of AML (68 years).¹⁰ Gender breakdown was slightly different than US statistics: 63% of AML patients in our group were male, whereas AML is only slightly more common among men in the United States.¹⁰

Clinically, skin lesions observed most commonly were (in decreasing order) papules, nodules, macules, plaques, and ulcers. Papules (38%) were the most common lesion overall in our study, which differed from the Kang et al⁷ report in which nodules were the most common. Nodules (31%) were the second most common LC morphology among our patients. Among AML patients, papules were seen in 56% of patients (18/32); nodules were seen in 44% (14/32). The extremities (when combined together) were the most common location of LC lesions (46% [arms, 24%; legs, 22%]); the trunk was the second most common body region (31%). Our study did not find a difference among most common LC anatomic sites compared to other studies.^5,7 Less common sites in our cohort included the head, scalp/ears, neck, hands, mucosa, and feet. All body sites were represented, including ocular and oral mucosa and groin, a finding that underscores the importance of complete and comprehensive skin examinations in this patient population. The terms erythematous and violaceous were used to describe the color of most lesions (88%), which commonly presented as multiple lesions (84%) and often were asymptomatic (84%).

It has been reported that, first, in most cases of LC, the condition develops in patients who have already been given a diagnosis of leukemia and, second, simultaneous manifestation of systemic leukemia and LC is less common.^11,12 Leukemia cutis also can precede peripheral or bone marrow leukemia (known as aleukemic LC).^1,13 Two AML patients (4.3% [2/46]) in this study met criteria for aleukemic LC because they had LC at the same time as negative bone marrow biopsy, which is consistent with a prior report that aleukemic LC can affect as many as 7% of patients.¹ Our results differed slightly from prior studies in that most of our patients had LC as one of the presenting manifestations of their leukemia.^3,7

Regardless of leukemia type, patients were likely to die within 1 year of LC diagnosis, on average, which is consistent with prior reports.^7,11,12 However, the time between diagnosis of LC and death varied greatly among our patients (range, 12 days to 4.1 years). From 2007 to 2013, the 5-year relative survival rate overall for leukemia patients in the US population (by type) was 86.2% (CLL), 71.0% (ALL), 68.0% (CML), and 27.4% (AML).¹⁴ Compared to these national statistics, the relative survival rate in LC is poor, with patients who have AML surviving, on average, less than 8 months from time of leukemia diagnosis, whereas ALL and CLL patients survive less than 6 months.

[embed:render:related:node:82097]

When LC is a late presentation of B-cell CLL or when it presents as myeloid leukemia, blastic transformation (Richter syndrome), or T-cell CLL, it is occasionally associated with poor prognosis, though LC does not affect survival.^15-17 In a study of the association of LC with survival in AML, 5-year survival among 62 AML patients with LC was 8.6%, shorter than 28.3% among the 186 matched patients with AML without LC.¹⁸ Similarly, the estimated 5-year survival for all patients with AML, according to Surveillance, Epidemiology, and End Results Program data (2007-2013), was 27.4%.¹⁴ Based on those results, LC might be a good prognostic indicator in patients with AML.

Conclusion

This study characterized the clinical presentation of LC, which is highly variable in appearance, symptoms, distribution, and stage of leukemia at presentation. In our study cohort, LC most commonly presented as asymptomatic erythematous or violaceous papules or nodules in older male AML patients at leukemia diagnosis. Given such wide variability, dermatologists and oncologists need to keep LC in the differential diagnosis for any new skin lesion and to have a low threshold for performing skin biopsy. Complete and thorough skin examinations should be performed on leukemia patients throughout the course of their disease to identify LC early so that treatment can be implemented in a timely fashion at initial diagnosis, first sign of relapse, or change in disease state.

[embed:render:podcast_episode_embedded:node:215612]

Leukemia is a malignant, life-threatening neoplasm affecting the hematopoietic system. Extramedullary manifestations can occur in various organs, including skin.¹ Skin findings in leukemia patients are common and varied, including pallor secondary to anemia, petechiae or ecchymoses due to thrombocytopenia, and skin manifestations of neutropenia and chemotherapy.² When patients with leukemia develop skin lesions without leukemic infiltration, the resulting nonspecific cutaneous manifestations are known as leukemids.³ Specific cutaneous manifestations of leukemia resulting from direct invasion of leukemic cells into the epidermis, dermis, or subcutis are referred to as leukemia cutis (LC).^2,3

[embed:render:related:node:198141]

Acute myeloid leukemia (AML) is the most common type of leukemia associated with LC, but LC also is seen in other leukemias with various frequencies.¹ The lesions of LC can present anywhere on skin, though it has been reported that LC has a tendency to occur at sites of prior ongoing inflammation,^2,4 most commonly the extremities, trunk, and face.^2,5,6 LC lesions have a range of morphological findings and most commonly present as nodules, papules, and plaques.^1,7

Most reports of LC in the literature are case reports or case series with small numbers of subjects.^3,6,8 A study of LC patients (N=75) in Korea by Kang et al⁷ has been the only one to analyze clinical characteristics of LC since 2000.

[embed:render:related:node:176219]

The aim of this study was to further contribute to the knowledge of clinical characteristics of LC. Clinical patterns of 46 patients were analyzed to further characterize the presentation of LC and to compare our results with those in the literature.

Methods

We conducted a single-institution retrospective review of medical records of patients with LC diagnosed in the Department of Dermatology at Wake Forest School of Medicine (Winston-Salem, North Carolina) over a 17-year period (2001-2017). The study protocol was approved by the institutional review board of Wake Forest University School of Medicine (IRB No. 00054474). Patients had a leukemia diagnosis established by bone marrow biopsy. Patients were included in this analysis if they had ongoing active leukemia and a skin biopsy consistent with LC. Patients of all sexes and ages were included in the cohort. Patients were excluded if they presented only with nonspecific cutaneous lesions associated with leukemia (leukemids). After removing duplicate records from a total of 60 patients initially identified, 46 unique patients were included in this study.

Results

Demographics
Fifty-six percent (26/46) of patients were male. The average age at diagnosis of leukemia was 58 years (range, 8.5 months–84 years). Eighty-five percent of patients were white (39/46), 11% were black (5/46), 2% were Hispanic (1/46), and 2% were of unknown ethnicity (1/46).

[embed:render:related:node:100367]

Eighty percent (37/46) of patients with LC had AML; 3 of these patients had a prior diagnosis of chronic myeloid leukemia (CML) and 2 had myelodysplastic syndrome (MDS) that did not develop LC until after they had transitioned to AML. Other subtypes of leukemia in this patient population included acute lymphoblastic leukemia (ALL)(n=2), plasma cell leukemia (PCL)(n=2), undifferentiated leukemia (n=2), chronic lymphocytic leukemia (CLL)(n=1), myelodysplastic syndrome (n=1), and Burkitt-type leukemia (n=1).

Distribution and Morphology of LC Lesions
The clinical appearance of LC was widely variable in morphology and anatomic location (Table 1 and Figure). Eighty-four percent of LC occurrences involved more than one lesion (n=32); 14% were a solitary lesion (n=6). For the 2 patients who had 2 separate episodes of LC, the initial presentation of LC was multiple lesions; recurrent LC at relapse presented as a solitary lesion in both cases. Most LC lesions (77% [67/87]) occurred on the trunk or extremities; 23% (20/87) of LC lesions occurred on less common sites, such as the groin, face, hands, feet, and mucosa. Papules (38% [22/58]) and nodules (31% [18/58]) were the most common morphology; macules, plaques, and ulcers were observed less frequently. Clinical descriptions of LC lesions varied widely, with the most common descriptive characteristics being erythematous (57% [20/35]), violaceous (31% [11/35]), and asymptomatic (84% [32/38]). Rare descriptors included flesh colored, hyperpigmented, tender, pruritic, edema, crusting, and confluent erythematous.

Haidari_CT104006326_Table1.JPG

Haidari_CT104006326_Fig_ABCDE.JPG

Haidari_CT104006326_Table2.JPG

Haidari_CT104006326_eTable.JPG

Discussion

Cutaneous manifestations are not uncommon in leukemia patients and can have a number of causes, including paraneoplastic cutaneous manifestations, such as pyoderma gangrenosum and Sweet syndrome; infection; cutaneous toxicities from antineoplastic agents; and LC.² Leukemia cutis can be confused with other skin lesions in leukemia patients; diagnosis requires biopsy.^2,9

[embed:render:related:node:100170]

We analyzed clinical characteristics and prognosis of 46 patients with LC over a 17-year period. To the best of our knowledge, this is the largest study of LC patients published in the United States. A similar study by Kang et al⁷ analyzed 75 patients in Korea; however, the incidence of LC among different types of leukemia in the Korean population cannot be applied to Western countries. We did compare the clinical characteristics of our cohort of patients to those reported by Kang et al⁷ and other studies including a smaller number of patients.

In this study, the male to female ratio was 1.3 to 1 compared to the 2:1 ratio reported by Kang et al.⁷ The mean age of leukemia diagnosis among our patients was 58 years, which is notably older than the mean age previously reported.⁷ In this cohort, 4 patients (8.7%) were 34 years or younger, including 1 infant aged 8.5 months; 24 (52.2%) were aged 35 to 64 years; and 18 (39.1%) were 65 years and older.

Consistent with other studies,^2,5,7 the most common type of leukemia in patients who developed LC was AML (80%). Among AML patients, the mean age at AML diagnosis (59.8 years) was notably younger than the reported US average age of patients who had a diagnosis of AML (68 years).¹⁰ Gender breakdown was slightly different than US statistics: 63% of AML patients in our group were male, whereas AML is only slightly more common among men in the United States.¹⁰

Clinically, skin lesions observed most commonly were (in decreasing order) papules, nodules, macules, plaques, and ulcers. Papules (38%) were the most common lesion overall in our study, which differed from the Kang et al⁷ report in which nodules were the most common. Nodules (31%) were the second most common LC morphology among our patients. Among AML patients, papules were seen in 56% of patients (18/32); nodules were seen in 44% (14/32). The extremities (when combined together) were the most common location of LC lesions (46% [arms, 24%; legs, 22%]); the trunk was the second most common body region (31%). Our study did not find a difference among most common LC anatomic sites compared to other studies.^5,7 Less common sites in our cohort included the head, scalp/ears, neck, hands, mucosa, and feet. All body sites were represented, including ocular and oral mucosa and groin, a finding that underscores the importance of complete and comprehensive skin examinations in this patient population. The terms erythematous and violaceous were used to describe the color of most lesions (88%), which commonly presented as multiple lesions (84%) and often were asymptomatic (84%).

It has been reported that, first, in most cases of LC, the condition develops in patients who have already been given a diagnosis of leukemia and, second, simultaneous manifestation of systemic leukemia and LC is less common.^11,12 Leukemia cutis also can precede peripheral or bone marrow leukemia (known as aleukemic LC).^1,13 Two AML patients (4.3% [2/46]) in this study met criteria for aleukemic LC because they had LC at the same time as negative bone marrow biopsy, which is consistent with a prior report that aleukemic LC can affect as many as 7% of patients.¹ Our results differed slightly from prior studies in that most of our patients had LC as one of the presenting manifestations of their leukemia.^3,7

Regardless of leukemia type, patients were likely to die within 1 year of LC diagnosis, on average, which is consistent with prior reports.^7,11,12 However, the time between diagnosis of LC and death varied greatly among our patients (range, 12 days to 4.1 years). From 2007 to 2013, the 5-year relative survival rate overall for leukemia patients in the US population (by type) was 86.2% (CLL), 71.0% (ALL), 68.0% (CML), and 27.4% (AML).¹⁴ Compared to these national statistics, the relative survival rate in LC is poor, with patients who have AML surviving, on average, less than 8 months from time of leukemia diagnosis, whereas ALL and CLL patients survive less than 6 months.

[embed:render:related:node:82097]

When LC is a late presentation of B-cell CLL or when it presents as myeloid leukemia, blastic transformation (Richter syndrome), or T-cell CLL, it is occasionally associated with poor prognosis, though LC does not affect survival.^15-17 In a study of the association of LC with survival in AML, 5-year survival among 62 AML patients with LC was 8.6%, shorter than 28.3% among the 186 matched patients with AML without LC.¹⁸ Similarly, the estimated 5-year survival for all patients with AML, according to Surveillance, Epidemiology, and End Results Program data (2007-2013), was 27.4%.¹⁴ Based on those results, LC might be a good prognostic indicator in patients with AML.

Conclusion

This study characterized the clinical presentation of LC, which is highly variable in appearance, symptoms, distribution, and stage of leukemia at presentation. In our study cohort, LC most commonly presented as asymptomatic erythematous or violaceous papules or nodules in older male AML patients at leukemia diagnosis. Given such wide variability, dermatologists and oncologists need to keep LC in the differential diagnosis for any new skin lesion and to have a low threshold for performing skin biopsy. Complete and thorough skin examinations should be performed on leukemia patients throughout the course of their disease to identify LC early so that treatment can be implemented in a timely fashion at initial diagnosis, first sign of relapse, or change in disease state.

[embed:render:podcast_episode_embedded:node:215612]

Leukemia is a malignant, life-threatening neoplasm affecting the hematopoietic system. Extramedullary manifestations can occur in various organs, including skin.¹ Skin findings in leukemia patients are common and varied, including pallor secondary to anemia, petechiae or ecchymoses due to thrombocytopenia, and skin manifestations of neutropenia and chemotherapy.² When patients with leukemia develop skin lesions without leukemic infiltration, the resulting nonspecific cutaneous manifestations are known as leukemids.³ Specific cutaneous manifestations of leukemia resulting from direct invasion of leukemic cells into the epidermis, dermis, or subcutis are referred to as leukemia cutis (LC).^2,3

[embed:render:related:node:198141]

Acute myeloid leukemia (AML) is the most common type of leukemia associated with LC, but LC also is seen in other leukemias with various frequencies.¹ The lesions of LC can present anywhere on skin, though it has been reported that LC has a tendency to occur at sites of prior ongoing inflammation,^2,4 most commonly the extremities, trunk, and face.^2,5,6 LC lesions have a range of morphological findings and most commonly present as nodules, papules, and plaques.^1,7

Most reports of LC in the literature are case reports or case series with small numbers of subjects.^3,6,8 A study of LC patients (N=75) in Korea by Kang et al⁷ has been the only one to analyze clinical characteristics of LC since 2000.

[embed:render:related:node:176219]

The aim of this study was to further contribute to the knowledge of clinical characteristics of LC. Clinical patterns of 46 patients were analyzed to further characterize the presentation of LC and to compare our results with those in the literature.

Methods

We conducted a single-institution retrospective review of medical records of patients with LC diagnosed in the Department of Dermatology at Wake Forest School of Medicine (Winston-Salem, North Carolina) over a 17-year period (2001-2017). The study protocol was approved by the institutional review board of Wake Forest University School of Medicine (IRB No. 00054474). Patients had a leukemia diagnosis established by bone marrow biopsy. Patients were included in this analysis if they had ongoing active leukemia and a skin biopsy consistent with LC. Patients of all sexes and ages were included in the cohort. Patients were excluded if they presented only with nonspecific cutaneous lesions associated with leukemia (leukemids). After removing duplicate records from a total of 60 patients initially identified, 46 unique patients were included in this study.

Results

Demographics
Fifty-six percent (26/46) of patients were male. The average age at diagnosis of leukemia was 58 years (range, 8.5 months–84 years). Eighty-five percent of patients were white (39/46), 11% were black (5/46), 2% were Hispanic (1/46), and 2% were of unknown ethnicity (1/46).

[embed:render:related:node:100367]

Eighty percent (37/46) of patients with LC had AML; 3 of these patients had a prior diagnosis of chronic myeloid leukemia (CML) and 2 had myelodysplastic syndrome (MDS) that did not develop LC until after they had transitioned to AML. Other subtypes of leukemia in this patient population included acute lymphoblastic leukemia (ALL)(n=2), plasma cell leukemia (PCL)(n=2), undifferentiated leukemia (n=2), chronic lymphocytic leukemia (CLL)(n=1), myelodysplastic syndrome (n=1), and Burkitt-type leukemia (n=1).

Distribution and Morphology of LC Lesions
The clinical appearance of LC was widely variable in morphology and anatomic location (Table 1 and Figure). Eighty-four percent of LC occurrences involved more than one lesion (n=32); 14% were a solitary lesion (n=6). For the 2 patients who had 2 separate episodes of LC, the initial presentation of LC was multiple lesions; recurrent LC at relapse presented as a solitary lesion in both cases. Most LC lesions (77% [67/87]) occurred on the trunk or extremities; 23% (20/87) of LC lesions occurred on less common sites, such as the groin, face, hands, feet, and mucosa. Papules (38% [22/58]) and nodules (31% [18/58]) were the most common morphology; macules, plaques, and ulcers were observed less frequently. Clinical descriptions of LC lesions varied widely, with the most common descriptive characteristics being erythematous (57% [20/35]), violaceous (31% [11/35]), and asymptomatic (84% [32/38]). Rare descriptors included flesh colored, hyperpigmented, tender, pruritic, edema, crusting, and confluent erythematous.

Haidari_CT104006326_Table1.JPG

Haidari_CT104006326_Fig_ABCDE.JPG

Haidari_CT104006326_Table2.JPG

Haidari_CT104006326_eTable.JPG

Discussion

Cutaneous manifestations are not uncommon in leukemia patients and can have a number of causes, including paraneoplastic cutaneous manifestations, such as pyoderma gangrenosum and Sweet syndrome; infection; cutaneous toxicities from antineoplastic agents; and LC.² Leukemia cutis can be confused with other skin lesions in leukemia patients; diagnosis requires biopsy.^2,9

[embed:render:related:node:100170]

We analyzed clinical characteristics and prognosis of 46 patients with LC over a 17-year period. To the best of our knowledge, this is the largest study of LC patients published in the United States. A similar study by Kang et al⁷ analyzed 75 patients in Korea; however, the incidence of LC among different types of leukemia in the Korean population cannot be applied to Western countries. We did compare the clinical characteristics of our cohort of patients to those reported by Kang et al⁷ and other studies including a smaller number of patients.

In this study, the male to female ratio was 1.3 to 1 compared to the 2:1 ratio reported by Kang et al.⁷ The mean age of leukemia diagnosis among our patients was 58 years, which is notably older than the mean age previously reported.⁷ In this cohort, 4 patients (8.7%) were 34 years or younger, including 1 infant aged 8.5 months; 24 (52.2%) were aged 35 to 64 years; and 18 (39.1%) were 65 years and older.

Consistent with other studies,^2,5,7 the most common type of leukemia in patients who developed LC was AML (80%). Among AML patients, the mean age at AML diagnosis (59.8 years) was notably younger than the reported US average age of patients who had a diagnosis of AML (68 years).¹⁰ Gender breakdown was slightly different than US statistics: 63% of AML patients in our group were male, whereas AML is only slightly more common among men in the United States.¹⁰

Clinically, skin lesions observed most commonly were (in decreasing order) papules, nodules, macules, plaques, and ulcers. Papules (38%) were the most common lesion overall in our study, which differed from the Kang et al⁷ report in which nodules were the most common. Nodules (31%) were the second most common LC morphology among our patients. Among AML patients, papules were seen in 56% of patients (18/32); nodules were seen in 44% (14/32). The extremities (when combined together) were the most common location of LC lesions (46% [arms, 24%; legs, 22%]); the trunk was the second most common body region (31%). Our study did not find a difference among most common LC anatomic sites compared to other studies.^5,7 Less common sites in our cohort included the head, scalp/ears, neck, hands, mucosa, and feet. All body sites were represented, including ocular and oral mucosa and groin, a finding that underscores the importance of complete and comprehensive skin examinations in this patient population. The terms erythematous and violaceous were used to describe the color of most lesions (88%), which commonly presented as multiple lesions (84%) and often were asymptomatic (84%).

It has been reported that, first, in most cases of LC, the condition develops in patients who have already been given a diagnosis of leukemia and, second, simultaneous manifestation of systemic leukemia and LC is less common.^11,12 Leukemia cutis also can precede peripheral or bone marrow leukemia (known as aleukemic LC).^1,13 Two AML patients (4.3% [2/46]) in this study met criteria for aleukemic LC because they had LC at the same time as negative bone marrow biopsy, which is consistent with a prior report that aleukemic LC can affect as many as 7% of patients.¹ Our results differed slightly from prior studies in that most of our patients had LC as one of the presenting manifestations of their leukemia.^3,7

Regardless of leukemia type, patients were likely to die within 1 year of LC diagnosis, on average, which is consistent with prior reports.^7,11,12 However, the time between diagnosis of LC and death varied greatly among our patients (range, 12 days to 4.1 years). From 2007 to 2013, the 5-year relative survival rate overall for leukemia patients in the US population (by type) was 86.2% (CLL), 71.0% (ALL), 68.0% (CML), and 27.4% (AML).¹⁴ Compared to these national statistics, the relative survival rate in LC is poor, with patients who have AML surviving, on average, less than 8 months from time of leukemia diagnosis, whereas ALL and CLL patients survive less than 6 months.

[embed:render:related:node:82097]

When LC is a late presentation of B-cell CLL or when it presents as myeloid leukemia, blastic transformation (Richter syndrome), or T-cell CLL, it is occasionally associated with poor prognosis, though LC does not affect survival.^15-17 In a study of the association of LC with survival in AML, 5-year survival among 62 AML patients with LC was 8.6%, shorter than 28.3% among the 186 matched patients with AML without LC.¹⁸ Similarly, the estimated 5-year survival for all patients with AML, according to Surveillance, Epidemiology, and End Results Program data (2007-2013), was 27.4%.¹⁴ Based on those results, LC might be a good prognostic indicator in patients with AML.

Conclusion

This study characterized the clinical presentation of LC, which is highly variable in appearance, symptoms, distribution, and stage of leukemia at presentation. In our study cohort, LC most commonly presented as asymptomatic erythematous or violaceous papules or nodules in older male AML patients at leukemia diagnosis. Given such wide variability, dermatologists and oncologists need to keep LC in the differential diagnosis for any new skin lesion and to have a low threshold for performing skin biopsy. Complete and thorough skin examinations should be performed on leukemia patients throughout the course of their disease to identify LC early so that treatment can be implemented in a timely fashion at initial diagnosis, first sign of relapse, or change in disease state.

Hidradenitis suppurativa (HS) is a common chronic inflammatory skin disease characterized by purulent subcutaneous nodules, papules, abscesses, and fistula tracts that lead to scarring and fibrosis. Lesions develop primarily in the axilla, groin, and other intertriginous and hair-bearing areas.

[embed:render:related:node:206167]

The natural history of the disease is characterized by periods of disease flare, followed by periods of disease quiescence. Patients might have weeks or months of low disease activity but frequently develop multiple exacerbating episodes over the course of weeks or months. The condition primarily presents in adolescent and peripubescent years, continuing throughout adulthood. Some evidence suggests a bimodal disease distribution, with a second peak of incidence in middle-aged adults. Women and men are affected equally; however, the disease can be phenotypically different in men and women.

Patients frequently present in emergency and inpatient settings for evaluation because of the pain and severity of HS flares as well as associated systemic symptoms. Inpatient and emergency department (ED) care are unique opportunities for dermatologic hospitalist and dermatologic consultative services to educate other physicians about the condition and initiate aggressive treatments that are frequently necessary to control HS flares. This article aims to address best methods for treating HS in these settings.

Pathophysiology

Although the exact pathophysiology of the condition is unknown, HS is thought to begin with follicular occlusion with downstream inflammation mediating neutrophilic activity and scarring. Hyperplasia of the infundibular epithelium is observed on histology, and the resulting occlusion, contained keratin, and follicular rupture initiate robust downstream inflammation.^1,2 Follicular occlusion might be initially androgen mediated³ or might occur in combination with friction⁴ and genetic or acquired factors involving Notch signaling. Although HS characteristically presents in areas of high apocrine density, apocrine glands are not thought to be the primary mediator of disease activity.⁵ IL-17, IL-23, tumor necrosis factor α, and IL-1β are implicated in the pathogenesis of HS, but it is unknown if these cytokines are the driving pathologic factor in HS or if they are merely secondary sequelae.⁶

[embed:render:related:node:200161]

Demographics and Prevalence in Hospitalized Patients

Although increasing treatment availability has brought more attention to HS, true prevalence is unknown. A prevalence of 1% has been reported in many European countries.⁷ Global prevalence has been more difficult to determine, with variable data suggesting a prevalence of 0.03% to 8%, depending on the population included.⁸ Most patients studied in a US-based claims database were aged 30 to 64 years, and the overall prevalence was 0.05%.⁹ Despite prevalence similar to psoriasis, utilization of high-cost emergency and inpatient admissions is notably higher among patients with HS. Recent claims data suggest that HS patients utilize the ED at a rate 3 times higher than psoriasis patients and are admitted as inpatients at a rate 5 times higher.¹⁰ Similar data suggest an associated increased cost of care for patients with HS vs other conditions, such as psoriasis, due to frequent ED and inpatient stays.¹¹ Although HS frequently presents in the inpatient and emergency settings, there is little literature on best methods for managing patients in these settings.

Pearls for Inpatient and Emergency Evaluation and Management

Initial Evaluation
When dermatologic consultative services are asked to evaluate patients with HS, preliminary evaluation should reflect the acuity of the patient. Vital signs and toxicity should be reviewed to ensure that there is no evidence of severe infection necessitating critical or acute care.

History
History-taking should reflect assessment of the patient’s baseline disease, including date of initial onset; exacerbating factors, such as friction, smoking, pregnancy, and menses; and the current history of the patient’s flare. A history of antibiotics, immunosuppression, topical therapy, antiandrogen therapy, and vitamin A analog therapy also should be reviewed. If an initial diagnosis is made in the ED or inpatient setting, a family and personal history should focus on specific risk factors and disease associations, including inflammatory bowel disease,¹² pilonidal cysts,¹³ polycystic ovary syndrome,¹⁴ and metabolic syndrome.¹⁵

Physical Examination
As with all dermatologic consultations, a full-body skin examination, with special attention to the axilla, inframammary skin, groin, buttocks, and perineum, should be undertaken. In addition to these common areas of disease progression, examination should focus on atypical sites for disease manifestation, including the posterior auricular scalp, skin folds in the pannus and back, and the beard area in men. Evaluation of axillary and gluteal hair should note features of folliculitis and hair removal, which can exacerbate HS. Examination also should include an investigation of cutaneous manifestations of comorbid conditions, including acanthosis nigricans, contiguous or metastatic cutaneous Crohn disease, erythema nodosum, and pilonidal cysts. Caution should be exercised when diagnosing pilonidal cysts, as isolated or evolving HS in the gluteal cleft often is misdiagnosed as a pilonidal cyst.

[embed:render:related:node:189412]

Laboratory Evaluation
Testing often is misleading in patients with HS, especially in the acute setting, because the condition is a chronic inflammatory process. The C-reactive protein level as well as the absolute white blood cell and neutrophil counts often are elevated, even in the absence of acute infection.¹⁶ In fact, although patients often are treated with intravenous antibiotics by inpatient and emergency teams in the setting of these 3 laboratory abnormalities, these findings often reflect disease activity, not frank infection. Fever, especially low-grade fever, also can reflect ongoing disease activity. Thrombocytosis and anemia also are anecdotally common, though these findings have not been reported specifically in the literature.

Bacterial Cultures
The role of lesional and perilesional bacterial cultures is controversial in HS. Prior studies have demonstrated that biofilm formation may be associated with the chronic inflammation seen in HS.¹⁷ However, most data to date suggest that infection is not the primary driver of HS disease flares, as demonstrated by the frequency of sterile cultures and the variable response of the disease to penicillin and related antibiotics.¹⁸

Imaging
Ultrasonography and magnetic resonance imaging can be conducted if there is concern about deeper abscesses that are not apparent on examination. When interpreted by nondermatologic practitioners, however, the findings of these modalities can result in unnecessary surgical intervention, given the concern for development of infectious abscess.¹⁹

Diagnosis
Many patients with HS experience a notable delay in time to diagnosis, living with symptoms for 7 years on average prior to being given a name for their condition.²⁰ Often, patients seek ED care at initial presentation because lesions can present quickly and are associated with remarkable pain. Inpatient dermatologic evaluation can provide patients with definitive diagnosis, appropriate counseling that provides an overview of the natural history of the disease, lifestyle recommendations, and expedited connection to outpatient longitudinal care.

Diagnosis is made clinically by assessment for typical lesions, such as painful or tender papules, nodules, or abscesses in the axillae, inframammary region, groin, thighs, and perineal and perianal regions. Cordlike scarring often is seen in the absence of active inflammatory lesions.²¹ Double-headed open comedones and prominent follicular occlusion are seen in some phenotypes but are not required for diagnosis.²²

Multiple scoring modalities are in use²³; the Hurley staging system, initially developed for surgical staging, has become a commonly used method in the clinical setting²⁴:

• Hurley stage I: isolated nodules or abscesses;

• Hurley stage II: widely separate lesions and sinus tracts or scarring are suggestive; and

• Hurley stage III: multiple lesions with near-diffuse involvement and formation of sinus tracts and scarring.

Other scoring modalities, such as the Hidradenitis Suppurativa Clinical Response (HiSCR), are more commonly used in the clinical trial setting and quantitatively capture lesion count improvement while the patient is being treated.²⁵

Treatment
Evaluation in the ED might necessitate recommendations for inpatient admission. Dermatologic consultation can be helpful in providing ED physicians with context for interpretation of laboratory results and clinical findings. Specifically, dermatologic evaluation can help differentiate presentations consistent with a primary infection from a more common presentation of HS flaring and associated bacterial colonization. Indications for inpatient admission are severe pain; concern for systemic infection, including high fever or sepsis; and need for surgical intervention. Patients with severe disease who do not have a longitudinal care plan or who lack the ability to care for lesions at home also are candidates for inpatient admission, where they can receive more intensive nursing and wound care as well as outpatient logistical management.

[embed:render:related:node:178600]

Acute care should be aimed at treatments that work quickly and aggressively and have both anti-inflammatory and antimicrobial effects. Severe flares require aggressive initial treatment to ensure more long-term remission. Adalimumab, maintained at 40 mg/wk after a loading dose, is the mainstay of evidence-based treatment for moderate to severe HS in patients 12 years or older; however, this treatment might not be easy to initiate in the inpatient setting because of its cost and availability and the fact that it is not as fast acting as other therapies.²⁶ For patients with severe disease flares, prednisone,²⁷ infliximab,²⁸ or cyclosporine²⁹ can be used in combination with antimicrobial therapy in the inpatient setting to quickly control active flaring. Intravenous antimicrobial therapy might be necessary in severe disease and should include coverage of gram-positive³⁰ and anaerobic organisms.³¹

Although management of acute flares is critical, especially for hospitalized patients, initiating longitudinal treatment modalities while the patient is an inpatient will help prevent future readmissions, facilitate better outcomes, and enable longer periods of disease-free progression. Specific treatments, stratified by disease severity, are listed in the Table.

Charrow_CT104005276_Table.JPG

[embed:render:related:node:176148]

Lastly, appropriate postdischarge maintenance therapy also can be initiated during the inpatient stay, including maintenance antibiotic therapy, spironolactone³² for female patients, and acitretin³³ for comedonal-predominant patients.

Final Thoughts

Hidradenitis suppurativa is a common dermatologic condition that frequently presents in emergency and inpatient settings, given its association with painful and acutely indurated lesions that often appear concerning for infection. Elevated inflammatory markers and fever are common in HS and are not necessarily suggestive of infection. As such, while antibiotics may be part of acute management of HS, care also should address the inflammatory component of the disease. Longitudinal outpatient care coordination with a dermatologist and primary care physician is imperative for limiting ED and inpatient care utilization.

Hidradenitis suppurativa (HS) is a common chronic inflammatory skin disease characterized by purulent subcutaneous nodules, papules, abscesses, and fistula tracts that lead to scarring and fibrosis. Lesions develop primarily in the axilla, groin, and other intertriginous and hair-bearing areas.

[embed:render:related:node:206167]

The natural history of the disease is characterized by periods of disease flare, followed by periods of disease quiescence. Patients might have weeks or months of low disease activity but frequently develop multiple exacerbating episodes over the course of weeks or months. The condition primarily presents in adolescent and peripubescent years, continuing throughout adulthood. Some evidence suggests a bimodal disease distribution, with a second peak of incidence in middle-aged adults. Women and men are affected equally; however, the disease can be phenotypically different in men and women.

Patients frequently present in emergency and inpatient settings for evaluation because of the pain and severity of HS flares as well as associated systemic symptoms. Inpatient and emergency department (ED) care are unique opportunities for dermatologic hospitalist and dermatologic consultative services to educate other physicians about the condition and initiate aggressive treatments that are frequently necessary to control HS flares. This article aims to address best methods for treating HS in these settings.

Pathophysiology

Although the exact pathophysiology of the condition is unknown, HS is thought to begin with follicular occlusion with downstream inflammation mediating neutrophilic activity and scarring. Hyperplasia of the infundibular epithelium is observed on histology, and the resulting occlusion, contained keratin, and follicular rupture initiate robust downstream inflammation.^1,2 Follicular occlusion might be initially androgen mediated³ or might occur in combination with friction⁴ and genetic or acquired factors involving Notch signaling. Although HS characteristically presents in areas of high apocrine density, apocrine glands are not thought to be the primary mediator of disease activity.⁵ IL-17, IL-23, tumor necrosis factor α, and IL-1β are implicated in the pathogenesis of HS, but it is unknown if these cytokines are the driving pathologic factor in HS or if they are merely secondary sequelae.⁶

[embed:render:related:node:200161]

Demographics and Prevalence in Hospitalized Patients

Although increasing treatment availability has brought more attention to HS, true prevalence is unknown. A prevalence of 1% has been reported in many European countries.⁷ Global prevalence has been more difficult to determine, with variable data suggesting a prevalence of 0.03% to 8%, depending on the population included.⁸ Most patients studied in a US-based claims database were aged 30 to 64 years, and the overall prevalence was 0.05%.⁹ Despite prevalence similar to psoriasis, utilization of high-cost emergency and inpatient admissions is notably higher among patients with HS. Recent claims data suggest that HS patients utilize the ED at a rate 3 times higher than psoriasis patients and are admitted as inpatients at a rate 5 times higher.¹⁰ Similar data suggest an associated increased cost of care for patients with HS vs other conditions, such as psoriasis, due to frequent ED and inpatient stays.¹¹ Although HS frequently presents in the inpatient and emergency settings, there is little literature on best methods for managing patients in these settings.

Pearls for Inpatient and Emergency Evaluation and Management

Initial Evaluation
When dermatologic consultative services are asked to evaluate patients with HS, preliminary evaluation should reflect the acuity of the patient. Vital signs and toxicity should be reviewed to ensure that there is no evidence of severe infection necessitating critical or acute care.

History
History-taking should reflect assessment of the patient’s baseline disease, including date of initial onset; exacerbating factors, such as friction, smoking, pregnancy, and menses; and the current history of the patient’s flare. A history of antibiotics, immunosuppression, topical therapy, antiandrogen therapy, and vitamin A analog therapy also should be reviewed. If an initial diagnosis is made in the ED or inpatient setting, a family and personal history should focus on specific risk factors and disease associations, including inflammatory bowel disease,¹² pilonidal cysts,¹³ polycystic ovary syndrome,¹⁴ and metabolic syndrome.¹⁵

Physical Examination
As with all dermatologic consultations, a full-body skin examination, with special attention to the axilla, inframammary skin, groin, buttocks, and perineum, should be undertaken. In addition to these common areas of disease progression, examination should focus on atypical sites for disease manifestation, including the posterior auricular scalp, skin folds in the pannus and back, and the beard area in men. Evaluation of axillary and gluteal hair should note features of folliculitis and hair removal, which can exacerbate HS. Examination also should include an investigation of cutaneous manifestations of comorbid conditions, including acanthosis nigricans, contiguous or metastatic cutaneous Crohn disease, erythema nodosum, and pilonidal cysts. Caution should be exercised when diagnosing pilonidal cysts, as isolated or evolving HS in the gluteal cleft often is misdiagnosed as a pilonidal cyst.

[embed:render:related:node:189412]

Laboratory Evaluation
Testing often is misleading in patients with HS, especially in the acute setting, because the condition is a chronic inflammatory process. The C-reactive protein level as well as the absolute white blood cell and neutrophil counts often are elevated, even in the absence of acute infection.¹⁶ In fact, although patients often are treated with intravenous antibiotics by inpatient and emergency teams in the setting of these 3 laboratory abnormalities, these findings often reflect disease activity, not frank infection. Fever, especially low-grade fever, also can reflect ongoing disease activity. Thrombocytosis and anemia also are anecdotally common, though these findings have not been reported specifically in the literature.

Bacterial Cultures
The role of lesional and perilesional bacterial cultures is controversial in HS. Prior studies have demonstrated that biofilm formation may be associated with the chronic inflammation seen in HS.¹⁷ However, most data to date suggest that infection is not the primary driver of HS disease flares, as demonstrated by the frequency of sterile cultures and the variable response of the disease to penicillin and related antibiotics.¹⁸

Imaging
Ultrasonography and magnetic resonance imaging can be conducted if there is concern about deeper abscesses that are not apparent on examination. When interpreted by nondermatologic practitioners, however, the findings of these modalities can result in unnecessary surgical intervention, given the concern for development of infectious abscess.¹⁹

Diagnosis
Many patients with HS experience a notable delay in time to diagnosis, living with symptoms for 7 years on average prior to being given a name for their condition.²⁰ Often, patients seek ED care at initial presentation because lesions can present quickly and are associated with remarkable pain. Inpatient dermatologic evaluation can provide patients with definitive diagnosis, appropriate counseling that provides an overview of the natural history of the disease, lifestyle recommendations, and expedited connection to outpatient longitudinal care.

Diagnosis is made clinically by assessment for typical lesions, such as painful or tender papules, nodules, or abscesses in the axillae, inframammary region, groin, thighs, and perineal and perianal regions. Cordlike scarring often is seen in the absence of active inflammatory lesions.²¹ Double-headed open comedones and prominent follicular occlusion are seen in some phenotypes but are not required for diagnosis.²²

Multiple scoring modalities are in use²³; the Hurley staging system, initially developed for surgical staging, has become a commonly used method in the clinical setting²⁴:

• Hurley stage I: isolated nodules or abscesses;

• Hurley stage II: widely separate lesions and sinus tracts or scarring are suggestive; and

• Hurley stage III: multiple lesions with near-diffuse involvement and formation of sinus tracts and scarring.

Other scoring modalities, such as the Hidradenitis Suppurativa Clinical Response (HiSCR), are more commonly used in the clinical trial setting and quantitatively capture lesion count improvement while the patient is being treated.²⁵

Treatment
Evaluation in the ED might necessitate recommendations for inpatient admission. Dermatologic consultation can be helpful in providing ED physicians with context for interpretation of laboratory results and clinical findings. Specifically, dermatologic evaluation can help differentiate presentations consistent with a primary infection from a more common presentation of HS flaring and associated bacterial colonization. Indications for inpatient admission are severe pain; concern for systemic infection, including high fever or sepsis; and need for surgical intervention. Patients with severe disease who do not have a longitudinal care plan or who lack the ability to care for lesions at home also are candidates for inpatient admission, where they can receive more intensive nursing and wound care as well as outpatient logistical management.

[embed:render:related:node:178600]

Acute care should be aimed at treatments that work quickly and aggressively and have both anti-inflammatory and antimicrobial effects. Severe flares require aggressive initial treatment to ensure more long-term remission. Adalimumab, maintained at 40 mg/wk after a loading dose, is the mainstay of evidence-based treatment for moderate to severe HS in patients 12 years or older; however, this treatment might not be easy to initiate in the inpatient setting because of its cost and availability and the fact that it is not as fast acting as other therapies.²⁶ For patients with severe disease flares, prednisone,²⁷ infliximab,²⁸ or cyclosporine²⁹ can be used in combination with antimicrobial therapy in the inpatient setting to quickly control active flaring. Intravenous antimicrobial therapy might be necessary in severe disease and should include coverage of gram-positive³⁰ and anaerobic organisms.³¹

Although management of acute flares is critical, especially for hospitalized patients, initiating longitudinal treatment modalities while the patient is an inpatient will help prevent future readmissions, facilitate better outcomes, and enable longer periods of disease-free progression. Specific treatments, stratified by disease severity, are listed in the Table.

Charrow_CT104005276_Table.JPG

[embed:render:related:node:176148]

Lastly, appropriate postdischarge maintenance therapy also can be initiated during the inpatient stay, including maintenance antibiotic therapy, spironolactone³² for female patients, and acitretin³³ for comedonal-predominant patients.

Final Thoughts

Hidradenitis suppurativa is a common dermatologic condition that frequently presents in emergency and inpatient settings, given its association with painful and acutely indurated lesions that often appear concerning for infection. Elevated inflammatory markers and fever are common in HS and are not necessarily suggestive of infection. As such, while antibiotics may be part of acute management of HS, care also should address the inflammatory component of the disease. Longitudinal outpatient care coordination with a dermatologist and primary care physician is imperative for limiting ED and inpatient care utilization.

Hidradenitis suppurativa (HS) is a common chronic inflammatory skin disease characterized by purulent subcutaneous nodules, papules, abscesses, and fistula tracts that lead to scarring and fibrosis. Lesions develop primarily in the axilla, groin, and other intertriginous and hair-bearing areas.

[embed:render:related:node:206167]

The natural history of the disease is characterized by periods of disease flare, followed by periods of disease quiescence. Patients might have weeks or months of low disease activity but frequently develop multiple exacerbating episodes over the course of weeks or months. The condition primarily presents in adolescent and peripubescent years, continuing throughout adulthood. Some evidence suggests a bimodal disease distribution, with a second peak of incidence in middle-aged adults. Women and men are affected equally; however, the disease can be phenotypically different in men and women.

Patients frequently present in emergency and inpatient settings for evaluation because of the pain and severity of HS flares as well as associated systemic symptoms. Inpatient and emergency department (ED) care are unique opportunities for dermatologic hospitalist and dermatologic consultative services to educate other physicians about the condition and initiate aggressive treatments that are frequently necessary to control HS flares. This article aims to address best methods for treating HS in these settings.

Pathophysiology

Although the exact pathophysiology of the condition is unknown, HS is thought to begin with follicular occlusion with downstream inflammation mediating neutrophilic activity and scarring. Hyperplasia of the infundibular epithelium is observed on histology, and the resulting occlusion, contained keratin, and follicular rupture initiate robust downstream inflammation.^1,2 Follicular occlusion might be initially androgen mediated³ or might occur in combination with friction⁴ and genetic or acquired factors involving Notch signaling. Although HS characteristically presents in areas of high apocrine density, apocrine glands are not thought to be the primary mediator of disease activity.⁵ IL-17, IL-23, tumor necrosis factor α, and IL-1β are implicated in the pathogenesis of HS, but it is unknown if these cytokines are the driving pathologic factor in HS or if they are merely secondary sequelae.⁶

[embed:render:related:node:200161]

Demographics and Prevalence in Hospitalized Patients

Although increasing treatment availability has brought more attention to HS, true prevalence is unknown. A prevalence of 1% has been reported in many European countries.⁷ Global prevalence has been more difficult to determine, with variable data suggesting a prevalence of 0.03% to 8%, depending on the population included.⁸ Most patients studied in a US-based claims database were aged 30 to 64 years, and the overall prevalence was 0.05%.⁹ Despite prevalence similar to psoriasis, utilization of high-cost emergency and inpatient admissions is notably higher among patients with HS. Recent claims data suggest that HS patients utilize the ED at a rate 3 times higher than psoriasis patients and are admitted as inpatients at a rate 5 times higher.¹⁰ Similar data suggest an associated increased cost of care for patients with HS vs other conditions, such as psoriasis, due to frequent ED and inpatient stays.¹¹ Although HS frequently presents in the inpatient and emergency settings, there is little literature on best methods for managing patients in these settings.

Pearls for Inpatient and Emergency Evaluation and Management

Initial Evaluation
When dermatologic consultative services are asked to evaluate patients with HS, preliminary evaluation should reflect the acuity of the patient. Vital signs and toxicity should be reviewed to ensure that there is no evidence of severe infection necessitating critical or acute care.

History
History-taking should reflect assessment of the patient’s baseline disease, including date of initial onset; exacerbating factors, such as friction, smoking, pregnancy, and menses; and the current history of the patient’s flare. A history of antibiotics, immunosuppression, topical therapy, antiandrogen therapy, and vitamin A analog therapy also should be reviewed. If an initial diagnosis is made in the ED or inpatient setting, a family and personal history should focus on specific risk factors and disease associations, including inflammatory bowel disease,¹² pilonidal cysts,¹³ polycystic ovary syndrome,¹⁴ and metabolic syndrome.¹⁵

Physical Examination
As with all dermatologic consultations, a full-body skin examination, with special attention to the axilla, inframammary skin, groin, buttocks, and perineum, should be undertaken. In addition to these common areas of disease progression, examination should focus on atypical sites for disease manifestation, including the posterior auricular scalp, skin folds in the pannus and back, and the beard area in men. Evaluation of axillary and gluteal hair should note features of folliculitis and hair removal, which can exacerbate HS. Examination also should include an investigation of cutaneous manifestations of comorbid conditions, including acanthosis nigricans, contiguous or metastatic cutaneous Crohn disease, erythema nodosum, and pilonidal cysts. Caution should be exercised when diagnosing pilonidal cysts, as isolated or evolving HS in the gluteal cleft often is misdiagnosed as a pilonidal cyst.

[embed:render:related:node:189412]

Laboratory Evaluation
Testing often is misleading in patients with HS, especially in the acute setting, because the condition is a chronic inflammatory process. The C-reactive protein level as well as the absolute white blood cell and neutrophil counts often are elevated, even in the absence of acute infection.¹⁶ In fact, although patients often are treated with intravenous antibiotics by inpatient and emergency teams in the setting of these 3 laboratory abnormalities, these findings often reflect disease activity, not frank infection. Fever, especially low-grade fever, also can reflect ongoing disease activity. Thrombocytosis and anemia also are anecdotally common, though these findings have not been reported specifically in the literature.

Bacterial Cultures
The role of lesional and perilesional bacterial cultures is controversial in HS. Prior studies have demonstrated that biofilm formation may be associated with the chronic inflammation seen in HS.¹⁷ However, most data to date suggest that infection is not the primary driver of HS disease flares, as demonstrated by the frequency of sterile cultures and the variable response of the disease to penicillin and related antibiotics.¹⁸

Imaging
Ultrasonography and magnetic resonance imaging can be conducted if there is concern about deeper abscesses that are not apparent on examination. When interpreted by nondermatologic practitioners, however, the findings of these modalities can result in unnecessary surgical intervention, given the concern for development of infectious abscess.¹⁹

Diagnosis
Many patients with HS experience a notable delay in time to diagnosis, living with symptoms for 7 years on average prior to being given a name for their condition.²⁰ Often, patients seek ED care at initial presentation because lesions can present quickly and are associated with remarkable pain. Inpatient dermatologic evaluation can provide patients with definitive diagnosis, appropriate counseling that provides an overview of the natural history of the disease, lifestyle recommendations, and expedited connection to outpatient longitudinal care.

Diagnosis is made clinically by assessment for typical lesions, such as painful or tender papules, nodules, or abscesses in the axillae, inframammary region, groin, thighs, and perineal and perianal regions. Cordlike scarring often is seen in the absence of active inflammatory lesions.²¹ Double-headed open comedones and prominent follicular occlusion are seen in some phenotypes but are not required for diagnosis.²²

Multiple scoring modalities are in use²³; the Hurley staging system, initially developed for surgical staging, has become a commonly used method in the clinical setting²⁴:

• Hurley stage I: isolated nodules or abscesses;

• Hurley stage II: widely separate lesions and sinus tracts or scarring are suggestive; and

• Hurley stage III: multiple lesions with near-diffuse involvement and formation of sinus tracts and scarring.

Other scoring modalities, such as the Hidradenitis Suppurativa Clinical Response (HiSCR), are more commonly used in the clinical trial setting and quantitatively capture lesion count improvement while the patient is being treated.²⁵

Treatment
Evaluation in the ED might necessitate recommendations for inpatient admission. Dermatologic consultation can be helpful in providing ED physicians with context for interpretation of laboratory results and clinical findings. Specifically, dermatologic evaluation can help differentiate presentations consistent with a primary infection from a more common presentation of HS flaring and associated bacterial colonization. Indications for inpatient admission are severe pain; concern for systemic infection, including high fever or sepsis; and need for surgical intervention. Patients with severe disease who do not have a longitudinal care plan or who lack the ability to care for lesions at home also are candidates for inpatient admission, where they can receive more intensive nursing and wound care as well as outpatient logistical management.

[embed:render:related:node:178600]

Acute care should be aimed at treatments that work quickly and aggressively and have both anti-inflammatory and antimicrobial effects. Severe flares require aggressive initial treatment to ensure more long-term remission. Adalimumab, maintained at 40 mg/wk after a loading dose, is the mainstay of evidence-based treatment for moderate to severe HS in patients 12 years or older; however, this treatment might not be easy to initiate in the inpatient setting because of its cost and availability and the fact that it is not as fast acting as other therapies.²⁶ For patients with severe disease flares, prednisone,²⁷ infliximab,²⁸ or cyclosporine²⁹ can be used in combination with antimicrobial therapy in the inpatient setting to quickly control active flaring. Intravenous antimicrobial therapy might be necessary in severe disease and should include coverage of gram-positive³⁰ and anaerobic organisms.³¹

Although management of acute flares is critical, especially for hospitalized patients, initiating longitudinal treatment modalities while the patient is an inpatient will help prevent future readmissions, facilitate better outcomes, and enable longer periods of disease-free progression. Specific treatments, stratified by disease severity, are listed in the Table.

Charrow_CT104005276_Table.JPG

[embed:render:related:node:176148]

Lastly, appropriate postdischarge maintenance therapy also can be initiated during the inpatient stay, including maintenance antibiotic therapy, spironolactone³² for female patients, and acitretin³³ for comedonal-predominant patients.

Final Thoughts

Hidradenitis suppurativa is a common dermatologic condition that frequently presents in emergency and inpatient settings, given its association with painful and acutely indurated lesions that often appear concerning for infection. Elevated inflammatory markers and fever are common in HS and are not necessarily suggestive of infection. As such, while antibiotics may be part of acute management of HS, care also should address the inflammatory component of the disease. Longitudinal outpatient care coordination with a dermatologist and primary care physician is imperative for limiting ED and inpatient care utilization.

Consultative dermatologists, or dermatology hospitalists (DHs), perform a critical role in the care of inpatients with skin disease, providing efficient diagnosis and management of patients with complex skin conditions as well as education of patients and trainees in the hospital setting.¹ In 2013, 27% of the US population was seen by a physician for a skin disease.² In 2014, there were nearly 650,000 hospital admissions principally for skin disease.³ Input by dermatologists facilitates accurate diagnosis and management of inpatients with skin disease,⁴ including a substantial number of cutaneous malignancies diagnosed in the inpatient setting.⁵ Several studies have highlighted the generally low level of diagnostic concordance between referring services and dermatology consultants,^4,6 with dermatology consultants frequently noting diagnoses not considered by referring services,⁷ reinforcing the importance of having access to dermatologists in the hospital setting.

[embed:render:related:node:211043]

The care of skin disease in the inpatient setting has become increasingly complex. The Society for Dermatology Hospitalists (SDH) was created in 2009 to address this complexity, with the goal to “strive to develop the highest standards of clinical care of hospitalized patients with skin disease.”⁸ A recent survey found that 50% of DHs spend between 41 to 52 weeks per year on service.⁹ Despite this degree of commitment, there are considerable barriers that prevent the majority of dermatologists from efficiently providing inpatient consultative care. The inpatient and outpatient provision of dermatology care varies greatly, including the variety of ethical situations encountered and the diversity of skin conditions treated.^10-12 Additionally, the transition between inpatient and outpatient care can be challenging for providers.¹³

[embed:render:related:node:200161]

The goal of this study was to evaluate the overall job satisfaction of DHs and further describe potential barriers to inpatient dermatology consultations.

Methods

An anonymous 31-question electronic survey was sent via email to all current members of the SDH from November 20 to December 10, 2018. The study was reviewed and determined to be exempt from federal human subjects regulations by the University of Washington Human Subjects Division (Seattle, Washington)(STUDY00005832).

Results

At the time of survey distribution, the SDH had 145 members, including attending-level dermatologists and resident members. Thirty-seven self-identified DHs (46% [17/37] women; 54% [20/37] men) completed the survey. The majority of respondents were junior faculty, with 46% (17/37) assistant professors, 5% (2/37) acting instructors, 32% (12/37) associate professors, and 16% (6/37) professors. All regions of the United States were represented.

Time Dedicated to Providing Inpatient Dermatology Consultations
The majority of those surveyed were satisfied or very satisfied (68% [25/37]) with the amount of time allotted for inpatient dermatology consultations, while 14% (5/37) were unsatisfied or very unsatisfied. Of those surveyed, 46% (17/37) reported that 21% to 50% of their time is dedicated to inpatient dermatology consultations. The majority (57% [21/37]) reported that their outpatient clinic efforts are reduced when providing dermatology inpatient consultations.

Regarding travel to the inpatient practice site, 60% (22/37) rated their travel time/effort as very easy, with 38% (14/37) reporting that the sites at which they provide inpatient dermatology consultations and their main outpatient clinics are the same physical location; 38% (14/37) reported travel times of less than 15 minutes between clinical practice sites.

Eighty-nine percent (33/37) of respondents said they are able to spend more time teaching trainees when providing inpatient dermatology consultations compared to their time spent in clinic. Similarly, 70% (26/37) said they are able to spend more time learning about patients and their conditions when providing inpatient dermatology consultations. Respondents also reported additional time expenditures because of inpatient dermatology consultations, primarily additional teaching requirements (49% [18/37]), additional electronic medical record training (35% [13/37]), and credentialing requirements (24% [9/37]).

Infrastructure for Providing Inpatient Dermatology Consultations
For many respondents (30% [11/37]), only 2 faculty dermatologists regularly provide inpatient dermatology consultations at their institutions. Four respondents reported having at least 5 faculty dermatologists who regularly provide inpatient dermatology consultations; excluding these, the average number of DHs was 2.42 faculty per institution.

Most respondents (57% [21/37]) reported their institutions support inpatient dermatology services by providing salary support for residents to cover services. Other methods of support included dedicated office spaces (30% [11/37]), free hospital parking while providing inpatient consultations (24% [9/37]), and administrative support (11% [4/37]).

Consultation Composition
Respondents indicated that requests for DH consultations most often come from medical services, including medical intensive care, internal medicine, and family medicine (95% [35/37]); the emergency department (95% [35/37]); surgical services (92% [34/37]); and hematology/oncology (89% [33/37]). Fewer DHs reported receiving consultation requests from pediatrics (70% [26/37]).

[embed:render:related:node:189412]

Many respondents (49% [18/37]) reported consulting for patients with skin disorders that they considered to be life-threatening or potentially life-threatening either very frequently (daily) or frequently (several times weekly), with only 16% (6/37) responding that they see such patients about once per month.

Compensation for Inpatient Dermatology Consultation
The most commonly reported compensation models for DHs were fixed salary plus productivity or performance incentives and fixed salary only models (49% [18/37] and 32% [12/37], respectively), with relative value unit (RVU) models and other models less frequently reported (16% [6/37] and 3% [1/37], respectively). Only 46% (17/37) of respondents were satisfied or very satisfied with their institutions’ compensation models; the remainder (54% [20/37]) were either neutral, unsatisfied, or very unsatisfied regarding their institutions’ compensation models. Overall compensation satisfaction was higher, with 60% (22/37) of DHs reporting they were satisfied or very satisfied with their salaries and 41% (15/37) reporting they were either neutral or not satisfied. The majority (60% [2/37]) of respondents felt that fixed salary plus productivity or performance incentives models would be the ideal compensation model for DHs.

[embed:render:related:node:178600]

Of the DHs whose compensations models were RVU based (6/37 [16%]), 67% (4/6) said they receive incentive pay upon meeting their RVU targets. No respondents reported that they were expected to generate an equivalent number of RVUs when performing inpatient consultations as compared to an outpatient session. Only 32% (12/37) of respondents reported keeping the revenue/RVUs generated by inpatient dermatology consultations; most (57% [21/37]) noted that their dermatology divisions/departments keep the revenue/RVUs, followed by university hospitals (27% [10/37]), schools of medicine (11% [4/37]), and departments of medicine (3% [1/37]). The remainder of respondents (22% [8/37]) were unsure who keeps the revenue/RVUs generated by inpatient dermatology consultations.

Most respondents (70% [26/37]) reported that the revenue (or RVU equivalent) generated by inpatient dermatology consultations does not fully support their salary for the time spent as consultants. Rather, these DHs noted sources of additional financial support, primarily the DHs themselves (69% [18/26]), followed by dermatology divisions/departments (50% [13/26]), departments of medicine (23% [6/26]), university hospitals (23% [6/26]), and schools of medicine (12% [3/26]).

Job Fulfillment Among DHs
Most respondents said they choose to provide inpatient dermatology consultations due to their interest in complex medical dermatology and their desire to work with other medical teams and specialties (92% [34/37] and 76% [28/37], respectively). Seventy percent (26/37) said they choose to provide inpatient consultations to be able to teach medical students and residents as well as to take advantage of the added opportunities to practice in a variety of settings beyond their outpatient clinics (57% [21/37]). Only 3% (1/37) of respondents reported that they provide inpatient dermatology consultations because they are “required to do so.”

Most DHs (84% [31/37]) said they feel their institutions as well as their dermatology divisions/departments value having access to inpatient dermatology services, though some did not feel this way (16% [6/37] neutral or strongly disagree). Nearly all respondents (97% [36/37]) felt they provide a critical service when performing inpatient dermatology consultations. All respondents (100%) said they found providing inpatient dermatology consultations fulfilling, and 65% (24/37) said they prefer providing inpatient dermatology consultations to spending time in clinic. Of the DHs who were surveyed, 68% (25/37) said they were satisfied with the balance of outpatient and inpatient services in their clinical practice and 30% (11/37) said they were not.

Comment

Factors such as patient care, hospital infrastructure, and procedural support have all been cited by DHs as crucial aspects of their contributions to the care of hospitalized patients.¹⁴ Of those surveyed in the present study, 97% felt they provide a critical service within their division/department and 84% felt their divisions/departments value the services that they provide. Nearly half of DHs surveyed said they regularly consult for patients with life-threatening or potentially life-threatening skin disorders several times weekly, and most receive consultation requests from multiple departments, reinforcing the critical role that dermatologists still play in the hospital setting.

Dermatology is primarily an outpatient specialty, and our study highlighted several important challenges for providers performing inpatient dermatology consultations. A major issue is time expenditures, including additional teaching requirements, additional electronic medical record training, and credentialing requirements. Travel time to inpatient hospital sites does not appear to be one of these hindering factors; nearly 60% of respondents rated their travel time/effort as very easy, with approximately 75% of respondents’ consultation locations being either at the same physical location as their main outpatient clinic or less than 15 minutes away. Maintaining easy travel between outpatient and inpatient settings is important to the success of the DH.

Our data suggest that compensation of DHs is a potential limitation to providing inpatient dermatology care. Our survey reinforced that providers who do inpatient dermatology consultations generally do not generate the revenue necessary to cover these efforts. More than 40% of DH respondents said they either feel neutral about or unsatisfied with their overall salary, and more than half said they feel similarly regarding their institutions’ compensation models. Most respondents said that a fixed salary model plus productivity or performance incentives is the ideal compensation model for those providing inpatient dermatology consultations, though only half said they actually are compensated according to this model. This discrepancy highlights the disconnect between the current accepted compensation models and the DH’s ideal model and provides direction for dermatology chairs and division heads as to what compensation model is preferable to support the success of DHs at their institutions.

Despite the barriers and compensation constraints we identified, DHs report high job satisfaction, which we hypothesize could combat burnout. In our study, all DHs surveyed say they find providing inpatient dermatology consultations fulfilling, and most were satisfied with the amount of time allotted for consultations. Some of the possible reasons why DHs may find their work fulfilling include increased time for teaching trainees and learning about patients and their conditions while consulting, as well as a preference for providing inpatient dermatology consultations to spending time in clinic. Most DHs said they choose to provide inpatient dermatology consultation rather than do so as a requirement, primarily due to their interest in complex medical dermatology and their desire to work with other medical teams/specialties; thankfully, only a small percentage said they provide these consultations because they are required to do so.

[embed:render:related:node:176148]

This study was conducted to analyze job satisfaction among DHs who provided inpatient dermatology consultations and determine common barriers and obstacles to their job satisfaction. Limitations to our study included the small sample size and the possibly limited representation of the intended population, as only the members of the SDH were surveyed, potentially excluding providers who regularly perform inpatient dermatology consultations but are not members of the SDH. Further limitations included recall bias and the qualitative nature of the survey instrument.

Final Thoughts

There was near-unanimous agreement among the DHs we surveyed regarding the importance of the role they play in their divisions/departments, but there are clear barriers to provision of inpatient dermatology consultation, specifically relating to extraneous time expenditures and compensation. Despite these barriers, the majority of respondents said they are very satisfied with the role they play in the inpatient setting and feel that their contributions are valued by the institutions where they work. Protecting these benefits of providing dermatology hospital consultations will be critical for maintaining this high job satisfaction and balancing out the barriers to providing these consultations. Protecting the time required to provide consultations is paramount so DHs continue to gain fulfillment from teaching trainees, caring for complex patients, and maintaining their place as valuable colleagues in the hospital setting.


Acknowledgment
The authors thank the members of the SDH for their participation in this survey.

Consultative dermatologists, or dermatology hospitalists (DHs), perform a critical role in the care of inpatients with skin disease, providing efficient diagnosis and management of patients with complex skin conditions as well as education of patients and trainees in the hospital setting.¹ In 2013, 27% of the US population was seen by a physician for a skin disease.² In 2014, there were nearly 650,000 hospital admissions principally for skin disease.³ Input by dermatologists facilitates accurate diagnosis and management of inpatients with skin disease,⁴ including a substantial number of cutaneous malignancies diagnosed in the inpatient setting.⁵ Several studies have highlighted the generally low level of diagnostic concordance between referring services and dermatology consultants,^4,6 with dermatology consultants frequently noting diagnoses not considered by referring services,⁷ reinforcing the importance of having access to dermatologists in the hospital setting.

[embed:render:related:node:211043]

The care of skin disease in the inpatient setting has become increasingly complex. The Society for Dermatology Hospitalists (SDH) was created in 2009 to address this complexity, with the goal to “strive to develop the highest standards of clinical care of hospitalized patients with skin disease.”⁸ A recent survey found that 50% of DHs spend between 41 to 52 weeks per year on service.⁹ Despite this degree of commitment, there are considerable barriers that prevent the majority of dermatologists from efficiently providing inpatient consultative care. The inpatient and outpatient provision of dermatology care varies greatly, including the variety of ethical situations encountered and the diversity of skin conditions treated.^10-12 Additionally, the transition between inpatient and outpatient care can be challenging for providers.¹³

[embed:render:related:node:200161]

The goal of this study was to evaluate the overall job satisfaction of DHs and further describe potential barriers to inpatient dermatology consultations.

Methods

An anonymous 31-question electronic survey was sent via email to all current members of the SDH from November 20 to December 10, 2018. The study was reviewed and determined to be exempt from federal human subjects regulations by the University of Washington Human Subjects Division (Seattle, Washington)(STUDY00005832).

Results

At the time of survey distribution, the SDH had 145 members, including attending-level dermatologists and resident members. Thirty-seven self-identified DHs (46% [17/37] women; 54% [20/37] men) completed the survey. The majority of respondents were junior faculty, with 46% (17/37) assistant professors, 5% (2/37) acting instructors, 32% (12/37) associate professors, and 16% (6/37) professors. All regions of the United States were represented.

Time Dedicated to Providing Inpatient Dermatology Consultations
The majority of those surveyed were satisfied or very satisfied (68% [25/37]) with the amount of time allotted for inpatient dermatology consultations, while 14% (5/37) were unsatisfied or very unsatisfied. Of those surveyed, 46% (17/37) reported that 21% to 50% of their time is dedicated to inpatient dermatology consultations. The majority (57% [21/37]) reported that their outpatient clinic efforts are reduced when providing dermatology inpatient consultations.

Regarding travel to the inpatient practice site, 60% (22/37) rated their travel time/effort as very easy, with 38% (14/37) reporting that the sites at which they provide inpatient dermatology consultations and their main outpatient clinics are the same physical location; 38% (14/37) reported travel times of less than 15 minutes between clinical practice sites.

Eighty-nine percent (33/37) of respondents said they are able to spend more time teaching trainees when providing inpatient dermatology consultations compared to their time spent in clinic. Similarly, 70% (26/37) said they are able to spend more time learning about patients and their conditions when providing inpatient dermatology consultations. Respondents also reported additional time expenditures because of inpatient dermatology consultations, primarily additional teaching requirements (49% [18/37]), additional electronic medical record training (35% [13/37]), and credentialing requirements (24% [9/37]).

Infrastructure for Providing Inpatient Dermatology Consultations
For many respondents (30% [11/37]), only 2 faculty dermatologists regularly provide inpatient dermatology consultations at their institutions. Four respondents reported having at least 5 faculty dermatologists who regularly provide inpatient dermatology consultations; excluding these, the average number of DHs was 2.42 faculty per institution.

Most respondents (57% [21/37]) reported their institutions support inpatient dermatology services by providing salary support for residents to cover services. Other methods of support included dedicated office spaces (30% [11/37]), free hospital parking while providing inpatient consultations (24% [9/37]), and administrative support (11% [4/37]).

Consultation Composition
Respondents indicated that requests for DH consultations most often come from medical services, including medical intensive care, internal medicine, and family medicine (95% [35/37]); the emergency department (95% [35/37]); surgical services (92% [34/37]); and hematology/oncology (89% [33/37]). Fewer DHs reported receiving consultation requests from pediatrics (70% [26/37]).

[embed:render:related:node:189412]

Many respondents (49% [18/37]) reported consulting for patients with skin disorders that they considered to be life-threatening or potentially life-threatening either very frequently (daily) or frequently (several times weekly), with only 16% (6/37) responding that they see such patients about once per month.

Compensation for Inpatient Dermatology Consultation
The most commonly reported compensation models for DHs were fixed salary plus productivity or performance incentives and fixed salary only models (49% [18/37] and 32% [12/37], respectively), with relative value unit (RVU) models and other models less frequently reported (16% [6/37] and 3% [1/37], respectively). Only 46% (17/37) of respondents were satisfied or very satisfied with their institutions’ compensation models; the remainder (54% [20/37]) were either neutral, unsatisfied, or very unsatisfied regarding their institutions’ compensation models. Overall compensation satisfaction was higher, with 60% (22/37) of DHs reporting they were satisfied or very satisfied with their salaries and 41% (15/37) reporting they were either neutral or not satisfied. The majority (60% [2/37]) of respondents felt that fixed salary plus productivity or performance incentives models would be the ideal compensation model for DHs.

[embed:render:related:node:178600]

Of the DHs whose compensations models were RVU based (6/37 [16%]), 67% (4/6) said they receive incentive pay upon meeting their RVU targets. No respondents reported that they were expected to generate an equivalent number of RVUs when performing inpatient consultations as compared to an outpatient session. Only 32% (12/37) of respondents reported keeping the revenue/RVUs generated by inpatient dermatology consultations; most (57% [21/37]) noted that their dermatology divisions/departments keep the revenue/RVUs, followed by university hospitals (27% [10/37]), schools of medicine (11% [4/37]), and departments of medicine (3% [1/37]). The remainder of respondents (22% [8/37]) were unsure who keeps the revenue/RVUs generated by inpatient dermatology consultations.

Most respondents (70% [26/37]) reported that the revenue (or RVU equivalent) generated by inpatient dermatology consultations does not fully support their salary for the time spent as consultants. Rather, these DHs noted sources of additional financial support, primarily the DHs themselves (69% [18/26]), followed by dermatology divisions/departments (50% [13/26]), departments of medicine (23% [6/26]), university hospitals (23% [6/26]), and schools of medicine (12% [3/26]).

Job Fulfillment Among DHs
Most respondents said they choose to provide inpatient dermatology consultations due to their interest in complex medical dermatology and their desire to work with other medical teams and specialties (92% [34/37] and 76% [28/37], respectively). Seventy percent (26/37) said they choose to provide inpatient consultations to be able to teach medical students and residents as well as to take advantage of the added opportunities to practice in a variety of settings beyond their outpatient clinics (57% [21/37]). Only 3% (1/37) of respondents reported that they provide inpatient dermatology consultations because they are “required to do so.”

Most DHs (84% [31/37]) said they feel their institutions as well as their dermatology divisions/departments value having access to inpatient dermatology services, though some did not feel this way (16% [6/37] neutral or strongly disagree). Nearly all respondents (97% [36/37]) felt they provide a critical service when performing inpatient dermatology consultations. All respondents (100%) said they found providing inpatient dermatology consultations fulfilling, and 65% (24/37) said they prefer providing inpatient dermatology consultations to spending time in clinic. Of the DHs who were surveyed, 68% (25/37) said they were satisfied with the balance of outpatient and inpatient services in their clinical practice and 30% (11/37) said they were not.

Comment

Factors such as patient care, hospital infrastructure, and procedural support have all been cited by DHs as crucial aspects of their contributions to the care of hospitalized patients.¹⁴ Of those surveyed in the present study, 97% felt they provide a critical service within their division/department and 84% felt their divisions/departments value the services that they provide. Nearly half of DHs surveyed said they regularly consult for patients with life-threatening or potentially life-threatening skin disorders several times weekly, and most receive consultation requests from multiple departments, reinforcing the critical role that dermatologists still play in the hospital setting.

Dermatology is primarily an outpatient specialty, and our study highlighted several important challenges for providers performing inpatient dermatology consultations. A major issue is time expenditures, including additional teaching requirements, additional electronic medical record training, and credentialing requirements. Travel time to inpatient hospital sites does not appear to be one of these hindering factors; nearly 60% of respondents rated their travel time/effort as very easy, with approximately 75% of respondents’ consultation locations being either at the same physical location as their main outpatient clinic or less than 15 minutes away. Maintaining easy travel between outpatient and inpatient settings is important to the success of the DH.

Our data suggest that compensation of DHs is a potential limitation to providing inpatient dermatology care. Our survey reinforced that providers who do inpatient dermatology consultations generally do not generate the revenue necessary to cover these efforts. More than 40% of DH respondents said they either feel neutral about or unsatisfied with their overall salary, and more than half said they feel similarly regarding their institutions’ compensation models. Most respondents said that a fixed salary model plus productivity or performance incentives is the ideal compensation model for those providing inpatient dermatology consultations, though only half said they actually are compensated according to this model. This discrepancy highlights the disconnect between the current accepted compensation models and the DH’s ideal model and provides direction for dermatology chairs and division heads as to what compensation model is preferable to support the success of DHs at their institutions.

Despite the barriers and compensation constraints we identified, DHs report high job satisfaction, which we hypothesize could combat burnout. In our study, all DHs surveyed say they find providing inpatient dermatology consultations fulfilling, and most were satisfied with the amount of time allotted for consultations. Some of the possible reasons why DHs may find their work fulfilling include increased time for teaching trainees and learning about patients and their conditions while consulting, as well as a preference for providing inpatient dermatology consultations to spending time in clinic. Most DHs said they choose to provide inpatient dermatology consultation rather than do so as a requirement, primarily due to their interest in complex medical dermatology and their desire to work with other medical teams/specialties; thankfully, only a small percentage said they provide these consultations because they are required to do so.

[embed:render:related:node:176148]

This study was conducted to analyze job satisfaction among DHs who provided inpatient dermatology consultations and determine common barriers and obstacles to their job satisfaction. Limitations to our study included the small sample size and the possibly limited representation of the intended population, as only the members of the SDH were surveyed, potentially excluding providers who regularly perform inpatient dermatology consultations but are not members of the SDH. Further limitations included recall bias and the qualitative nature of the survey instrument.

Final Thoughts

There was near-unanimous agreement among the DHs we surveyed regarding the importance of the role they play in their divisions/departments, but there are clear barriers to provision of inpatient dermatology consultation, specifically relating to extraneous time expenditures and compensation. Despite these barriers, the majority of respondents said they are very satisfied with the role they play in the inpatient setting and feel that their contributions are valued by the institutions where they work. Protecting these benefits of providing dermatology hospital consultations will be critical for maintaining this high job satisfaction and balancing out the barriers to providing these consultations. Protecting the time required to provide consultations is paramount so DHs continue to gain fulfillment from teaching trainees, caring for complex patients, and maintaining their place as valuable colleagues in the hospital setting.


Acknowledgment
The authors thank the members of the SDH for their participation in this survey.

Consultative dermatologists, or dermatology hospitalists (DHs), perform a critical role in the care of inpatients with skin disease, providing efficient diagnosis and management of patients with complex skin conditions as well as education of patients and trainees in the hospital setting.¹ In 2013, 27% of the US population was seen by a physician for a skin disease.² In 2014, there were nearly 650,000 hospital admissions principally for skin disease.³ Input by dermatologists facilitates accurate diagnosis and management of inpatients with skin disease,⁴ including a substantial number of cutaneous malignancies diagnosed in the inpatient setting.⁵ Several studies have highlighted the generally low level of diagnostic concordance between referring services and dermatology consultants,^4,6 with dermatology consultants frequently noting diagnoses not considered by referring services,⁷ reinforcing the importance of having access to dermatologists in the hospital setting.

[embed:render:related:node:211043]

The care of skin disease in the inpatient setting has become increasingly complex. The Society for Dermatology Hospitalists (SDH) was created in 2009 to address this complexity, with the goal to “strive to develop the highest standards of clinical care of hospitalized patients with skin disease.”⁸ A recent survey found that 50% of DHs spend between 41 to 52 weeks per year on service.⁹ Despite this degree of commitment, there are considerable barriers that prevent the majority of dermatologists from efficiently providing inpatient consultative care. The inpatient and outpatient provision of dermatology care varies greatly, including the variety of ethical situations encountered and the diversity of skin conditions treated.^10-12 Additionally, the transition between inpatient and outpatient care can be challenging for providers.¹³

[embed:render:related:node:200161]

The goal of this study was to evaluate the overall job satisfaction of DHs and further describe potential barriers to inpatient dermatology consultations.

Methods

An anonymous 31-question electronic survey was sent via email to all current members of the SDH from November 20 to December 10, 2018. The study was reviewed and determined to be exempt from federal human subjects regulations by the University of Washington Human Subjects Division (Seattle, Washington)(STUDY00005832).

Results

At the time of survey distribution, the SDH had 145 members, including attending-level dermatologists and resident members. Thirty-seven self-identified DHs (46% [17/37] women; 54% [20/37] men) completed the survey. The majority of respondents were junior faculty, with 46% (17/37) assistant professors, 5% (2/37) acting instructors, 32% (12/37) associate professors, and 16% (6/37) professors. All regions of the United States were represented.

Time Dedicated to Providing Inpatient Dermatology Consultations
The majority of those surveyed were satisfied or very satisfied (68% [25/37]) with the amount of time allotted for inpatient dermatology consultations, while 14% (5/37) were unsatisfied or very unsatisfied. Of those surveyed, 46% (17/37) reported that 21% to 50% of their time is dedicated to inpatient dermatology consultations. The majority (57% [21/37]) reported that their outpatient clinic efforts are reduced when providing dermatology inpatient consultations.

Regarding travel to the inpatient practice site, 60% (22/37) rated their travel time/effort as very easy, with 38% (14/37) reporting that the sites at which they provide inpatient dermatology consultations and their main outpatient clinics are the same physical location; 38% (14/37) reported travel times of less than 15 minutes between clinical practice sites.

Eighty-nine percent (33/37) of respondents said they are able to spend more time teaching trainees when providing inpatient dermatology consultations compared to their time spent in clinic. Similarly, 70% (26/37) said they are able to spend more time learning about patients and their conditions when providing inpatient dermatology consultations. Respondents also reported additional time expenditures because of inpatient dermatology consultations, primarily additional teaching requirements (49% [18/37]), additional electronic medical record training (35% [13/37]), and credentialing requirements (24% [9/37]).

Infrastructure for Providing Inpatient Dermatology Consultations
For many respondents (30% [11/37]), only 2 faculty dermatologists regularly provide inpatient dermatology consultations at their institutions. Four respondents reported having at least 5 faculty dermatologists who regularly provide inpatient dermatology consultations; excluding these, the average number of DHs was 2.42 faculty per institution.

Most respondents (57% [21/37]) reported their institutions support inpatient dermatology services by providing salary support for residents to cover services. Other methods of support included dedicated office spaces (30% [11/37]), free hospital parking while providing inpatient consultations (24% [9/37]), and administrative support (11% [4/37]).

Consultation Composition
Respondents indicated that requests for DH consultations most often come from medical services, including medical intensive care, internal medicine, and family medicine (95% [35/37]); the emergency department (95% [35/37]); surgical services (92% [34/37]); and hematology/oncology (89% [33/37]). Fewer DHs reported receiving consultation requests from pediatrics (70% [26/37]).

[embed:render:related:node:189412]

Many respondents (49% [18/37]) reported consulting for patients with skin disorders that they considered to be life-threatening or potentially life-threatening either very frequently (daily) or frequently (several times weekly), with only 16% (6/37) responding that they see such patients about once per month.

Compensation for Inpatient Dermatology Consultation
The most commonly reported compensation models for DHs were fixed salary plus productivity or performance incentives and fixed salary only models (49% [18/37] and 32% [12/37], respectively), with relative value unit (RVU) models and other models less frequently reported (16% [6/37] and 3% [1/37], respectively). Only 46% (17/37) of respondents were satisfied or very satisfied with their institutions’ compensation models; the remainder (54% [20/37]) were either neutral, unsatisfied, or very unsatisfied regarding their institutions’ compensation models. Overall compensation satisfaction was higher, with 60% (22/37) of DHs reporting they were satisfied or very satisfied with their salaries and 41% (15/37) reporting they were either neutral or not satisfied. The majority (60% [2/37]) of respondents felt that fixed salary plus productivity or performance incentives models would be the ideal compensation model for DHs.

[embed:render:related:node:178600]

Of the DHs whose compensations models were RVU based (6/37 [16%]), 67% (4/6) said they receive incentive pay upon meeting their RVU targets. No respondents reported that they were expected to generate an equivalent number of RVUs when performing inpatient consultations as compared to an outpatient session. Only 32% (12/37) of respondents reported keeping the revenue/RVUs generated by inpatient dermatology consultations; most (57% [21/37]) noted that their dermatology divisions/departments keep the revenue/RVUs, followed by university hospitals (27% [10/37]), schools of medicine (11% [4/37]), and departments of medicine (3% [1/37]). The remainder of respondents (22% [8/37]) were unsure who keeps the revenue/RVUs generated by inpatient dermatology consultations.

Most respondents (70% [26/37]) reported that the revenue (or RVU equivalent) generated by inpatient dermatology consultations does not fully support their salary for the time spent as consultants. Rather, these DHs noted sources of additional financial support, primarily the DHs themselves (69% [18/26]), followed by dermatology divisions/departments (50% [13/26]), departments of medicine (23% [6/26]), university hospitals (23% [6/26]), and schools of medicine (12% [3/26]).

Job Fulfillment Among DHs
Most respondents said they choose to provide inpatient dermatology consultations due to their interest in complex medical dermatology and their desire to work with other medical teams and specialties (92% [34/37] and 76% [28/37], respectively). Seventy percent (26/37) said they choose to provide inpatient consultations to be able to teach medical students and residents as well as to take advantage of the added opportunities to practice in a variety of settings beyond their outpatient clinics (57% [21/37]). Only 3% (1/37) of respondents reported that they provide inpatient dermatology consultations because they are “required to do so.”

Most DHs (84% [31/37]) said they feel their institutions as well as their dermatology divisions/departments value having access to inpatient dermatology services, though some did not feel this way (16% [6/37] neutral or strongly disagree). Nearly all respondents (97% [36/37]) felt they provide a critical service when performing inpatient dermatology consultations. All respondents (100%) said they found providing inpatient dermatology consultations fulfilling, and 65% (24/37) said they prefer providing inpatient dermatology consultations to spending time in clinic. Of the DHs who were surveyed, 68% (25/37) said they were satisfied with the balance of outpatient and inpatient services in their clinical practice and 30% (11/37) said they were not.

Comment

Factors such as patient care, hospital infrastructure, and procedural support have all been cited by DHs as crucial aspects of their contributions to the care of hospitalized patients.¹⁴ Of those surveyed in the present study, 97% felt they provide a critical service within their division/department and 84% felt their divisions/departments value the services that they provide. Nearly half of DHs surveyed said they regularly consult for patients with life-threatening or potentially life-threatening skin disorders several times weekly, and most receive consultation requests from multiple departments, reinforcing the critical role that dermatologists still play in the hospital setting.

Dermatology is primarily an outpatient specialty, and our study highlighted several important challenges for providers performing inpatient dermatology consultations. A major issue is time expenditures, including additional teaching requirements, additional electronic medical record training, and credentialing requirements. Travel time to inpatient hospital sites does not appear to be one of these hindering factors; nearly 60% of respondents rated their travel time/effort as very easy, with approximately 75% of respondents’ consultation locations being either at the same physical location as their main outpatient clinic or less than 15 minutes away. Maintaining easy travel between outpatient and inpatient settings is important to the success of the DH.

Our data suggest that compensation of DHs is a potential limitation to providing inpatient dermatology care. Our survey reinforced that providers who do inpatient dermatology consultations generally do not generate the revenue necessary to cover these efforts. More than 40% of DH respondents said they either feel neutral about or unsatisfied with their overall salary, and more than half said they feel similarly regarding their institutions’ compensation models. Most respondents said that a fixed salary model plus productivity or performance incentives is the ideal compensation model for those providing inpatient dermatology consultations, though only half said they actually are compensated according to this model. This discrepancy highlights the disconnect between the current accepted compensation models and the DH’s ideal model and provides direction for dermatology chairs and division heads as to what compensation model is preferable to support the success of DHs at their institutions.

Despite the barriers and compensation constraints we identified, DHs report high job satisfaction, which we hypothesize could combat burnout. In our study, all DHs surveyed say they find providing inpatient dermatology consultations fulfilling, and most were satisfied with the amount of time allotted for consultations. Some of the possible reasons why DHs may find their work fulfilling include increased time for teaching trainees and learning about patients and their conditions while consulting, as well as a preference for providing inpatient dermatology consultations to spending time in clinic. Most DHs said they choose to provide inpatient dermatology consultation rather than do so as a requirement, primarily due to their interest in complex medical dermatology and their desire to work with other medical teams/specialties; thankfully, only a small percentage said they provide these consultations because they are required to do so.

[embed:render:related:node:176148]

This study was conducted to analyze job satisfaction among DHs who provided inpatient dermatology consultations and determine common barriers and obstacles to their job satisfaction. Limitations to our study included the small sample size and the possibly limited representation of the intended population, as only the members of the SDH were surveyed, potentially excluding providers who regularly perform inpatient dermatology consultations but are not members of the SDH. Further limitations included recall bias and the qualitative nature of the survey instrument.

Final Thoughts

There was near-unanimous agreement among the DHs we surveyed regarding the importance of the role they play in their divisions/departments, but there are clear barriers to provision of inpatient dermatology consultation, specifically relating to extraneous time expenditures and compensation. Despite these barriers, the majority of respondents said they are very satisfied with the role they play in the inpatient setting and feel that their contributions are valued by the institutions where they work. Protecting these benefits of providing dermatology hospital consultations will be critical for maintaining this high job satisfaction and balancing out the barriers to providing these consultations. Protecting the time required to provide consultations is paramount so DHs continue to gain fulfillment from teaching trainees, caring for complex patients, and maintaining their place as valuable colleagues in the hospital setting.


Acknowledgment
The authors thank the members of the SDH for their participation in this survey.

[embed:render:podcast_episode_embedded:node:202401]

It has been estimated that 2 million serious adverse drug reactions (ADRs) occur annually in the United States, resulting in 100,000 deaths.¹ Although the acute morbidity and mortality of these ADRs are readily apparent, postdischarge sequalae are critical aspects of a patient’s care. Herein, we present an approach to outpatient dermatologic follow-up of 3 ADRs: acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). For these ADRs, the first step is prompt diagnosis and discontinuation of any potentially causative medications.

[embed:render:related:node:198731]

ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS

Ninety percent of the time, AGEP is caused by medications, most commonly antibiotics, and less often it is caused by viruses.^2-4 It presents as a cutaneous eruption with nonfollicular sterile pustules, fever, and leukocytosis, usually within 5 days after starting a causative medication.⁵ After stopping the medication, cutaneous findings generally improve within 1 week, and leukocytosis often resolves within 1 week.³

Notable Sequelae

Although AGEP typically is considered benign,² there have been reports of severe sequelae including death from a systemic inflammatory response and complications such as bacterial superinfection and sepsis.^6,7 Visceral involvement can be seen in up to 20% of AGEP patients, with systemic symptoms similar  to those seen in DRESS syndrome. Mortality has been reported in up to 5% of cases, mainly in patients with comorbidities and notable mucosal involvement.⁸ More severe disease can be seen in patients with known dermatologic disease, as AGEP can provoke an isomorphic phenomenon.⁹ Laboratory alterations typically seen in AGEP include neutrophilia, eosinophilia, and elevated liver enzymes.²

Follow-up Recommendations

Patients should be informed of the expected timeline for resolution and should be counseled on the possibility of rare systemic symptoms. Laboratory abnormalities should be monitored every 2 to 4 weeks until normalized.

DRESS SYNDROME

DRESS syndrome is characterized by a morbilliform eruption that can be accompanied by fever; eosinophilia; purpura; facial edema; lymphadenopathy; and liver, renal, or other organ dysfunction. DRESS syndrome most often presents within 8 weeks of exposure to a causative drug.^10,11 The most common causative agents are anticonvulsants, antimicrobials, and allopurinol.¹² Treatment includes topical corticosteroids and systemic corticosteroids for internal organ involvement.¹⁰

Short-term Sequelae

Several potential sequelae may occur within 6 months of resolution of DRESS syndrome, resulting from both the ADR itself and/or systemic corticosteroids that often are required for treatment.¹³ Complications secondary to herpesviruses have been reported.¹⁴ Cases of cytomegalovirus-induced gastric ulcers can lead to gastrointestinal tract bleeds.¹⁵

[embed:render:related:node:189925]

Infections including Cryptococcus species and herpes zoster also have been reported.¹⁶ Patients, particularly those treated with systemic corticosteroids, should be monitored with close follow-up for infectious complications and treatment-related adverse effects.¹³

Long-term Sequelae

Endocrine
Thyroid gland abnormalities secondary to DRESS syndrome include Graves disease and Hashimoto disease as well as variations in biomarkers including elevated free thyroxine and low and elevated thyroid-stimulating hormone levels.^16,17 Type 1 diabetes mellitus also has been seen after DRESS syndrome, developing within the first 10 months after onset with unknown pathogenesis.¹⁸

[embed:render:related:node:189412]

Autoimmune
Other reported sequelae of DRESS syndrome include elevated antinuclear antibodies with possible development into systemic lupus erythematosus, autoimmune hemolytic anemia, vitiligo, and rheumatoid arthritis.^11,16 Symptoms may be exacerbated in patients with preexisting autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, and patients with preexisting renal disease are at an increased risk for requiring lifelong hemodialysis after DRESS syndrome.¹⁶

Other
Studies have demonstrated that pneumonia, thrombosis, and alopecia can be complications of DRESS syndrome.^11,16 Psychiatric disturbances including fear of taking new medications, anxiety, and depression also have been reported.¹⁹ Children with DRESS syndrome may develop vitiligo, alopecia, sclerodermatous lesions, photophobia, uveitis, and Vogt-Koyanagi-Harada disease.¹⁷

Follow-up Recommendations

It is important to inform patients of both the potential short-term and long-term sequelae of DRESS syndrome, including those associated with treatment. A thorough review of systems should be performed at each visit, along with laboratory evaluation including a complete blood cell count with differential and liver function testing every 1 to 2 weeks after discharge until normalized, with monthly monitoring of glucose, thyroid-stimulating hormone, and free thyroxine levels for 3 months after discharge.

STEVENS-JOHNSON SYNDROME/TOXIC EPIDERMAL NECROLYSIS

Stevens-Johnson syndrome/toxic epidermal necrolysis are severe ADRs that present with dusky violaceous macules. Inciting medications include nonsteroidal anti-inflammatory drugs, allopurinol, antibiotics, and anticonvulsants, and symptoms begin 1 to 3 weeks after medication exposure.¹² Initially, the lesions often begin on the trunk and can progress to full-body erythema and exfoliation with a necrotic epidermis and mucosal involvement.^12,20

Notable Sequelae

Cutaneous
Chronic eczema can present at any time and can vary in severity in SJS/TEN patients.²¹ Xerosis and pruritus can be treated with emollients.¹¹ Dyschromia is common. Hypertrophic and keloidal scarring can result from surgical debridement and are best prevented with the use of nonadherent dressings.²² Nail changes such as anonychia, dystrophy, longitudinal ridges, and pterygium also are seen, and topical steroids can be helpful. Other reported dermatologic sequelae include dyschromia and eruption of ectopic sebaceous glands.^21,22

Ocular
Ocular sequelae include dry eyes, photophobia, symblepharon, corneal scarring, corneal neovascularization, corneal xerosis, trichiasis, reduced visual acuity, blindness, and subconjunctival fibrosis. The most common sequelae are bilateral conjunctivitis and corneal ulcerations.^22,23 Early and regular ophthalmologic follow-up is recommended, as SJS/TEN-induced blindness can result from delayed therapy, destroying corneal stem cells.²¹ Amniotic membrane transplantation replaces the damaged corneal membrane, which may reduce corneal inflammation.²⁴

Chronic dry eye syndrome can recur for years after SJS/TEN resolves and progresses over time.²² Frequent use of nonpreserved artificial tears and salivary gland transplantation can be helpful.²⁴ Unfortunately, ocular disease may develop months after discharge; therefore, it is recommended that dermatologists ask all SJS/TEN patients about ocular symptoms in follow-up visits. If ocular involvement was present initially, patients should be followed by ophthalmology for at least 1 year after discharge.²³

Genitourinary
Genitourinary sequelae in SJS/TEN include adhesions, particularly in the female urethra and vaginal opening; vaginal adenosis; vulvovaginal endometriosis; and persistent genital ulcerations most commonly reported in females.²² Prompt inpatient gynecologic or urologic consultation is critical to reduce these potentially permanent outcomes. Topical corticosteroid therapy is recommended in the acute phase.²²

[embed:render:related:node:178600]

Psychologic
Posttraumatic stress disorder may occur in patients with SJS/TEN. One study showed that 23% (7/30) of patients had posttraumatic stress disorder 6 months after hospitalization for SJS/TEN. The investigators recommended routine psychiatric assessment in the acute disease period and for at least 1 year after discharge.²⁵

Pulmonary, Gastrointestinal, and Renal
Interstitial pneumonia and obliterative bronchitis/bronchiolitis can be caused by SJS/TEN. Interstitial pneumonia tends to occur during the acute course, while obliterative airway disease manifests after resolution of SJS/TEN.^21,22 Abnormal pulmonary function testing can be seen in more than half of SJS/TEN patients 2 months after the ADR.²² Gastrointestinal sequelae include esophageal strictures, intestinal ulceration, and cholestasis.²² Renal sequelae include acute kidney injury and glomerulonephritis, which may be secondary to the volume loss seen in SJS/TEN but may be irreversible.²¹

Special Populations
A correlation with infertility in women has been documented in patients with SJS/TEN; thus, follow-up with obstetrics and gynecology is recommended in women of child-bearing potential. The most considerable risk in pregnant women with SJS/TEN is premature birth, and mucosal necrosis of SJS/TEN can impair vaginal delivery.²⁶ Antiretrovirals can be a cause of SJS/TEN in the human immunodeficiency virus–positive population.²⁷ In those cases, it is best to discontinue the medication and find an alternative.

Risk factors for children can be different and can include viral and febrile illnesses as well as mycoplasma infection.²⁸ Children also can be at an increased risk for poor ocular outcomes, such as permanent deficiency in visual acuity and blindness.²⁹

Follow-up Recommendations

Patients should be counseled regarding sequelae and the multisystem nature of SJS/TEN. Inpatient referrals should be given as needed. It is important to watch for ocular symptoms for 1 year after SJS/TEN resolution. When ocular involvement is present, follow-up with ophthalmology is recommended within 1 month of discharge and then at the discretion of the ophthalmologist. Pulmonary function should be monitored for 1 year after SJS/TEN, starting 1 month after discharge and then at the discretion of the pulmonologist. Patients also should be screened for psychologic sequelae for at least 1 year after discharge.

FINAL THOUGHTS

Adverse drug reactions are notable causes of inpatient hospitalization and may lead to considerable sequelae. These ADRs range in severity from more common and benign maculopapular exanthems to severe multiorgan ADRs such as DRESS syndrome and SJS/TEN.

In AGEP, it is important to monitor patients with preexisting dermatologic diseases and to screen for visceral involvement. DRESS syndrome has the potential to cause immune dysregulation and variable long-term adverse sequelae, both from the disease itself and from corticosteroid therapy. Mucocutaneous sequelae of SJS/TEN can potentially affect a patient’s cutaneous, ocular, genitourinary, mental, pulmonary, gastrointestinal, and renal health.

The baseline recommendations provided here warrant more frequent monitoring if the findings and symptoms are severe. In all of these cases, if a causative medication is identified, it should be added to the patient’s allergy list and the patient should be counseled extensively to avoid this medication and other medications in the same class. If a single agent cannot be identified, referrals for patch testing may be of some utility, particularly in AGEP and DRESS syndrome.^30,31

[embed:render:podcast_episode_embedded:node:202401]

It has been estimated that 2 million serious adverse drug reactions (ADRs) occur annually in the United States, resulting in 100,000 deaths.¹ Although the acute morbidity and mortality of these ADRs are readily apparent, postdischarge sequalae are critical aspects of a patient’s care. Herein, we present an approach to outpatient dermatologic follow-up of 3 ADRs: acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). For these ADRs, the first step is prompt diagnosis and discontinuation of any potentially causative medications.

[embed:render:related:node:198731]

ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS

Ninety percent of the time, AGEP is caused by medications, most commonly antibiotics, and less often it is caused by viruses.^2-4 It presents as a cutaneous eruption with nonfollicular sterile pustules, fever, and leukocytosis, usually within 5 days after starting a causative medication.⁵ After stopping the medication, cutaneous findings generally improve within 1 week, and leukocytosis often resolves within 1 week.³

Notable Sequelae

Although AGEP typically is considered benign,² there have been reports of severe sequelae including death from a systemic inflammatory response and complications such as bacterial superinfection and sepsis.^6,7 Visceral involvement can be seen in up to 20% of AGEP patients, with systemic symptoms similar  to those seen in DRESS syndrome. Mortality has been reported in up to 5% of cases, mainly in patients with comorbidities and notable mucosal involvement.⁸ More severe disease can be seen in patients with known dermatologic disease, as AGEP can provoke an isomorphic phenomenon.⁹ Laboratory alterations typically seen in AGEP include neutrophilia, eosinophilia, and elevated liver enzymes.²

Follow-up Recommendations

Patients should be informed of the expected timeline for resolution and should be counseled on the possibility of rare systemic symptoms. Laboratory abnormalities should be monitored every 2 to 4 weeks until normalized.

DRESS SYNDROME

DRESS syndrome is characterized by a morbilliform eruption that can be accompanied by fever; eosinophilia; purpura; facial edema; lymphadenopathy; and liver, renal, or other organ dysfunction. DRESS syndrome most often presents within 8 weeks of exposure to a causative drug.^10,11 The most common causative agents are anticonvulsants, antimicrobials, and allopurinol.¹² Treatment includes topical corticosteroids and systemic corticosteroids for internal organ involvement.¹⁰

Short-term Sequelae

Several potential sequelae may occur within 6 months of resolution of DRESS syndrome, resulting from both the ADR itself and/or systemic corticosteroids that often are required for treatment.¹³ Complications secondary to herpesviruses have been reported.¹⁴ Cases of cytomegalovirus-induced gastric ulcers can lead to gastrointestinal tract bleeds.¹⁵

[embed:render:related:node:189925]

Infections including Cryptococcus species and herpes zoster also have been reported.¹⁶ Patients, particularly those treated with systemic corticosteroids, should be monitored with close follow-up for infectious complications and treatment-related adverse effects.¹³

Long-term Sequelae

Endocrine
Thyroid gland abnormalities secondary to DRESS syndrome include Graves disease and Hashimoto disease as well as variations in biomarkers including elevated free thyroxine and low and elevated thyroid-stimulating hormone levels.^16,17 Type 1 diabetes mellitus also has been seen after DRESS syndrome, developing within the first 10 months after onset with unknown pathogenesis.¹⁸

[embed:render:related:node:189412]

Autoimmune
Other reported sequelae of DRESS syndrome include elevated antinuclear antibodies with possible development into systemic lupus erythematosus, autoimmune hemolytic anemia, vitiligo, and rheumatoid arthritis.^11,16 Symptoms may be exacerbated in patients with preexisting autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, and patients with preexisting renal disease are at an increased risk for requiring lifelong hemodialysis after DRESS syndrome.¹⁶

Other
Studies have demonstrated that pneumonia, thrombosis, and alopecia can be complications of DRESS syndrome.^11,16 Psychiatric disturbances including fear of taking new medications, anxiety, and depression also have been reported.¹⁹ Children with DRESS syndrome may develop vitiligo, alopecia, sclerodermatous lesions, photophobia, uveitis, and Vogt-Koyanagi-Harada disease.¹⁷

Follow-up Recommendations

It is important to inform patients of both the potential short-term and long-term sequelae of DRESS syndrome, including those associated with treatment. A thorough review of systems should be performed at each visit, along with laboratory evaluation including a complete blood cell count with differential and liver function testing every 1 to 2 weeks after discharge until normalized, with monthly monitoring of glucose, thyroid-stimulating hormone, and free thyroxine levels for 3 months after discharge.

STEVENS-JOHNSON SYNDROME/TOXIC EPIDERMAL NECROLYSIS

Stevens-Johnson syndrome/toxic epidermal necrolysis are severe ADRs that present with dusky violaceous macules. Inciting medications include nonsteroidal anti-inflammatory drugs, allopurinol, antibiotics, and anticonvulsants, and symptoms begin 1 to 3 weeks after medication exposure.¹² Initially, the lesions often begin on the trunk and can progress to full-body erythema and exfoliation with a necrotic epidermis and mucosal involvement.^12,20

Notable Sequelae

Cutaneous
Chronic eczema can present at any time and can vary in severity in SJS/TEN patients.²¹ Xerosis and pruritus can be treated with emollients.¹¹ Dyschromia is common. Hypertrophic and keloidal scarring can result from surgical debridement and are best prevented with the use of nonadherent dressings.²² Nail changes such as anonychia, dystrophy, longitudinal ridges, and pterygium also are seen, and topical steroids can be helpful. Other reported dermatologic sequelae include dyschromia and eruption of ectopic sebaceous glands.^21,22

Ocular
Ocular sequelae include dry eyes, photophobia, symblepharon, corneal scarring, corneal neovascularization, corneal xerosis, trichiasis, reduced visual acuity, blindness, and subconjunctival fibrosis. The most common sequelae are bilateral conjunctivitis and corneal ulcerations.^22,23 Early and regular ophthalmologic follow-up is recommended, as SJS/TEN-induced blindness can result from delayed therapy, destroying corneal stem cells.²¹ Amniotic membrane transplantation replaces the damaged corneal membrane, which may reduce corneal inflammation.²⁴

Chronic dry eye syndrome can recur for years after SJS/TEN resolves and progresses over time.²² Frequent use of nonpreserved artificial tears and salivary gland transplantation can be helpful.²⁴ Unfortunately, ocular disease may develop months after discharge; therefore, it is recommended that dermatologists ask all SJS/TEN patients about ocular symptoms in follow-up visits. If ocular involvement was present initially, patients should be followed by ophthalmology for at least 1 year after discharge.²³

Genitourinary
Genitourinary sequelae in SJS/TEN include adhesions, particularly in the female urethra and vaginal opening; vaginal adenosis; vulvovaginal endometriosis; and persistent genital ulcerations most commonly reported in females.²² Prompt inpatient gynecologic or urologic consultation is critical to reduce these potentially permanent outcomes. Topical corticosteroid therapy is recommended in the acute phase.²²

[embed:render:related:node:178600]

Psychologic
Posttraumatic stress disorder may occur in patients with SJS/TEN. One study showed that 23% (7/30) of patients had posttraumatic stress disorder 6 months after hospitalization for SJS/TEN. The investigators recommended routine psychiatric assessment in the acute disease period and for at least 1 year after discharge.²⁵

Pulmonary, Gastrointestinal, and Renal
Interstitial pneumonia and obliterative bronchitis/bronchiolitis can be caused by SJS/TEN. Interstitial pneumonia tends to occur during the acute course, while obliterative airway disease manifests after resolution of SJS/TEN.^21,22 Abnormal pulmonary function testing can be seen in more than half of SJS/TEN patients 2 months after the ADR.²² Gastrointestinal sequelae include esophageal strictures, intestinal ulceration, and cholestasis.²² Renal sequelae include acute kidney injury and glomerulonephritis, which may be secondary to the volume loss seen in SJS/TEN but may be irreversible.²¹

Special Populations
A correlation with infertility in women has been documented in patients with SJS/TEN; thus, follow-up with obstetrics and gynecology is recommended in women of child-bearing potential. The most considerable risk in pregnant women with SJS/TEN is premature birth, and mucosal necrosis of SJS/TEN can impair vaginal delivery.²⁶ Antiretrovirals can be a cause of SJS/TEN in the human immunodeficiency virus–positive population.²⁷ In those cases, it is best to discontinue the medication and find an alternative.

Risk factors for children can be different and can include viral and febrile illnesses as well as mycoplasma infection.²⁸ Children also can be at an increased risk for poor ocular outcomes, such as permanent deficiency in visual acuity and blindness.²⁹

Follow-up Recommendations

Patients should be counseled regarding sequelae and the multisystem nature of SJS/TEN. Inpatient referrals should be given as needed. It is important to watch for ocular symptoms for 1 year after SJS/TEN resolution. When ocular involvement is present, follow-up with ophthalmology is recommended within 1 month of discharge and then at the discretion of the ophthalmologist. Pulmonary function should be monitored for 1 year after SJS/TEN, starting 1 month after discharge and then at the discretion of the pulmonologist. Patients also should be screened for psychologic sequelae for at least 1 year after discharge.

FINAL THOUGHTS

Adverse drug reactions are notable causes of inpatient hospitalization and may lead to considerable sequelae. These ADRs range in severity from more common and benign maculopapular exanthems to severe multiorgan ADRs such as DRESS syndrome and SJS/TEN.

In AGEP, it is important to monitor patients with preexisting dermatologic diseases and to screen for visceral involvement. DRESS syndrome has the potential to cause immune dysregulation and variable long-term adverse sequelae, both from the disease itself and from corticosteroid therapy. Mucocutaneous sequelae of SJS/TEN can potentially affect a patient’s cutaneous, ocular, genitourinary, mental, pulmonary, gastrointestinal, and renal health.

The baseline recommendations provided here warrant more frequent monitoring if the findings and symptoms are severe. In all of these cases, if a causative medication is identified, it should be added to the patient’s allergy list and the patient should be counseled extensively to avoid this medication and other medications in the same class. If a single agent cannot be identified, referrals for patch testing may be of some utility, particularly in AGEP and DRESS syndrome.^30,31

[embed:render:podcast_episode_embedded:node:202401]

It has been estimated that 2 million serious adverse drug reactions (ADRs) occur annually in the United States, resulting in 100,000 deaths.¹ Although the acute morbidity and mortality of these ADRs are readily apparent, postdischarge sequalae are critical aspects of a patient’s care. Herein, we present an approach to outpatient dermatologic follow-up of 3 ADRs: acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). For these ADRs, the first step is prompt diagnosis and discontinuation of any potentially causative medications.

[embed:render:related:node:198731]

ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS

Ninety percent of the time, AGEP is caused by medications, most commonly antibiotics, and less often it is caused by viruses.^2-4 It presents as a cutaneous eruption with nonfollicular sterile pustules, fever, and leukocytosis, usually within 5 days after starting a causative medication.⁵ After stopping the medication, cutaneous findings generally improve within 1 week, and leukocytosis often resolves within 1 week.³

Notable Sequelae

Although AGEP typically is considered benign,² there have been reports of severe sequelae including death from a systemic inflammatory response and complications such as bacterial superinfection and sepsis.^6,7 Visceral involvement can be seen in up to 20% of AGEP patients, with systemic symptoms similar  to those seen in DRESS syndrome. Mortality has been reported in up to 5% of cases, mainly in patients with comorbidities and notable mucosal involvement.⁸ More severe disease can be seen in patients with known dermatologic disease, as AGEP can provoke an isomorphic phenomenon.⁹ Laboratory alterations typically seen in AGEP include neutrophilia, eosinophilia, and elevated liver enzymes.²

Follow-up Recommendations

Patients should be informed of the expected timeline for resolution and should be counseled on the possibility of rare systemic symptoms. Laboratory abnormalities should be monitored every 2 to 4 weeks until normalized.

DRESS SYNDROME

DRESS syndrome is characterized by a morbilliform eruption that can be accompanied by fever; eosinophilia; purpura; facial edema; lymphadenopathy; and liver, renal, or other organ dysfunction. DRESS syndrome most often presents within 8 weeks of exposure to a causative drug.^10,11 The most common causative agents are anticonvulsants, antimicrobials, and allopurinol.¹² Treatment includes topical corticosteroids and systemic corticosteroids for internal organ involvement.¹⁰

Short-term Sequelae

Several potential sequelae may occur within 6 months of resolution of DRESS syndrome, resulting from both the ADR itself and/or systemic corticosteroids that often are required for treatment.¹³ Complications secondary to herpesviruses have been reported.¹⁴ Cases of cytomegalovirus-induced gastric ulcers can lead to gastrointestinal tract bleeds.¹⁵

[embed:render:related:node:189925]

Infections including Cryptococcus species and herpes zoster also have been reported.¹⁶ Patients, particularly those treated with systemic corticosteroids, should be monitored with close follow-up for infectious complications and treatment-related adverse effects.¹³

Long-term Sequelae

Endocrine
Thyroid gland abnormalities secondary to DRESS syndrome include Graves disease and Hashimoto disease as well as variations in biomarkers including elevated free thyroxine and low and elevated thyroid-stimulating hormone levels.^16,17 Type 1 diabetes mellitus also has been seen after DRESS syndrome, developing within the first 10 months after onset with unknown pathogenesis.¹⁸

[embed:render:related:node:189412]

Autoimmune
Other reported sequelae of DRESS syndrome include elevated antinuclear antibodies with possible development into systemic lupus erythematosus, autoimmune hemolytic anemia, vitiligo, and rheumatoid arthritis.^11,16 Symptoms may be exacerbated in patients with preexisting autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, and patients with preexisting renal disease are at an increased risk for requiring lifelong hemodialysis after DRESS syndrome.¹⁶

Other
Studies have demonstrated that pneumonia, thrombosis, and alopecia can be complications of DRESS syndrome.^11,16 Psychiatric disturbances including fear of taking new medications, anxiety, and depression also have been reported.¹⁹ Children with DRESS syndrome may develop vitiligo, alopecia, sclerodermatous lesions, photophobia, uveitis, and Vogt-Koyanagi-Harada disease.¹⁷

Follow-up Recommendations

It is important to inform patients of both the potential short-term and long-term sequelae of DRESS syndrome, including those associated with treatment. A thorough review of systems should be performed at each visit, along with laboratory evaluation including a complete blood cell count with differential and liver function testing every 1 to 2 weeks after discharge until normalized, with monthly monitoring of glucose, thyroid-stimulating hormone, and free thyroxine levels for 3 months after discharge.

STEVENS-JOHNSON SYNDROME/TOXIC EPIDERMAL NECROLYSIS

Stevens-Johnson syndrome/toxic epidermal necrolysis are severe ADRs that present with dusky violaceous macules. Inciting medications include nonsteroidal anti-inflammatory drugs, allopurinol, antibiotics, and anticonvulsants, and symptoms begin 1 to 3 weeks after medication exposure.¹² Initially, the lesions often begin on the trunk and can progress to full-body erythema and exfoliation with a necrotic epidermis and mucosal involvement.^12,20

Notable Sequelae

Cutaneous
Chronic eczema can present at any time and can vary in severity in SJS/TEN patients.²¹ Xerosis and pruritus can be treated with emollients.¹¹ Dyschromia is common. Hypertrophic and keloidal scarring can result from surgical debridement and are best prevented with the use of nonadherent dressings.²² Nail changes such as anonychia, dystrophy, longitudinal ridges, and pterygium also are seen, and topical steroids can be helpful. Other reported dermatologic sequelae include dyschromia and eruption of ectopic sebaceous glands.^21,22

Ocular
Ocular sequelae include dry eyes, photophobia, symblepharon, corneal scarring, corneal neovascularization, corneal xerosis, trichiasis, reduced visual acuity, blindness, and subconjunctival fibrosis. The most common sequelae are bilateral conjunctivitis and corneal ulcerations.^22,23 Early and regular ophthalmologic follow-up is recommended, as SJS/TEN-induced blindness can result from delayed therapy, destroying corneal stem cells.²¹ Amniotic membrane transplantation replaces the damaged corneal membrane, which may reduce corneal inflammation.²⁴

Chronic dry eye syndrome can recur for years after SJS/TEN resolves and progresses over time.²² Frequent use of nonpreserved artificial tears and salivary gland transplantation can be helpful.²⁴ Unfortunately, ocular disease may develop months after discharge; therefore, it is recommended that dermatologists ask all SJS/TEN patients about ocular symptoms in follow-up visits. If ocular involvement was present initially, patients should be followed by ophthalmology for at least 1 year after discharge.²³

Genitourinary
Genitourinary sequelae in SJS/TEN include adhesions, particularly in the female urethra and vaginal opening; vaginal adenosis; vulvovaginal endometriosis; and persistent genital ulcerations most commonly reported in females.²² Prompt inpatient gynecologic or urologic consultation is critical to reduce these potentially permanent outcomes. Topical corticosteroid therapy is recommended in the acute phase.²²

[embed:render:related:node:178600]

Psychologic
Posttraumatic stress disorder may occur in patients with SJS/TEN. One study showed that 23% (7/30) of patients had posttraumatic stress disorder 6 months after hospitalization for SJS/TEN. The investigators recommended routine psychiatric assessment in the acute disease period and for at least 1 year after discharge.²⁵

Pulmonary, Gastrointestinal, and Renal
Interstitial pneumonia and obliterative bronchitis/bronchiolitis can be caused by SJS/TEN. Interstitial pneumonia tends to occur during the acute course, while obliterative airway disease manifests after resolution of SJS/TEN.^21,22 Abnormal pulmonary function testing can be seen in more than half of SJS/TEN patients 2 months after the ADR.²² Gastrointestinal sequelae include esophageal strictures, intestinal ulceration, and cholestasis.²² Renal sequelae include acute kidney injury and glomerulonephritis, which may be secondary to the volume loss seen in SJS/TEN but may be irreversible.²¹

Special Populations
A correlation with infertility in women has been documented in patients with SJS/TEN; thus, follow-up with obstetrics and gynecology is recommended in women of child-bearing potential. The most considerable risk in pregnant women with SJS/TEN is premature birth, and mucosal necrosis of SJS/TEN can impair vaginal delivery.²⁶ Antiretrovirals can be a cause of SJS/TEN in the human immunodeficiency virus–positive population.²⁷ In those cases, it is best to discontinue the medication and find an alternative.

Risk factors for children can be different and can include viral and febrile illnesses as well as mycoplasma infection.²⁸ Children also can be at an increased risk for poor ocular outcomes, such as permanent deficiency in visual acuity and blindness.²⁹

Follow-up Recommendations

Patients should be counseled regarding sequelae and the multisystem nature of SJS/TEN. Inpatient referrals should be given as needed. It is important to watch for ocular symptoms for 1 year after SJS/TEN resolution. When ocular involvement is present, follow-up with ophthalmology is recommended within 1 month of discharge and then at the discretion of the ophthalmologist. Pulmonary function should be monitored for 1 year after SJS/TEN, starting 1 month after discharge and then at the discretion of the pulmonologist. Patients also should be screened for psychologic sequelae for at least 1 year after discharge.

FINAL THOUGHTS

Adverse drug reactions are notable causes of inpatient hospitalization and may lead to considerable sequelae. These ADRs range in severity from more common and benign maculopapular exanthems to severe multiorgan ADRs such as DRESS syndrome and SJS/TEN.

In AGEP, it is important to monitor patients with preexisting dermatologic diseases and to screen for visceral involvement. DRESS syndrome has the potential to cause immune dysregulation and variable long-term adverse sequelae, both from the disease itself and from corticosteroid therapy. Mucocutaneous sequelae of SJS/TEN can potentially affect a patient’s cutaneous, ocular, genitourinary, mental, pulmonary, gastrointestinal, and renal health.

The baseline recommendations provided here warrant more frequent monitoring if the findings and symptoms are severe. In all of these cases, if a causative medication is identified, it should be added to the patient’s allergy list and the patient should be counseled extensively to avoid this medication and other medications in the same class. If a single agent cannot be identified, referrals for patch testing may be of some utility, particularly in AGEP and DRESS syndrome.^30,31

[embed:render:podcast_episode_embedded:node:201513]

Calciphylaxis, also known as calcific uremic arteriolopathy, is a painful skin condition classically seen in patients with end-stage renal disease (ESRD), particularly those on chronic dialysis.^1,2 It also has increasingly been reported in patients with normal renal function and calcium and phosphate homeostasis.^3,4 Effective diagnosis and management of calciphylaxis remains challenging for physicians.^2,5 The condition is characterized by tissue ischemia caused by calcification of cutaneous arteriolar vessels. As a result, calciphylaxis is associated with high mortality rates, ranging from 60% to 80%.^5,6 Excruciating pain and nonhealing ulcers often lead to recurrent hospitalizations and infectious complications,⁷ and poor nutritional status, chronic pain, depression, and insomnia can further complicate recovery and lead to poor quality of life.⁸

We provide an update on calciphylaxis etiopathogenesis, diagnosis, and management. We also highlight some challenges faced in managing this potentially fatal condition.

Epidemiology

Calciphylaxis is considered a rare dermatosis with an estimated annual incidence of 1% to 4% in ESRD patients on dialysis. Recent data suggest that incidence of calciphylaxis is rising,^5,7,9 which may stem from an increased use of calcium-based phosphate binders, an actual rise in disease incidence, and/or increased recognition of the disease.⁵ It is difficult to estimate the exact disease burden of calciphylaxis because the diagnostic criteria are not well defined, often leading to missed or delayed diagnosis.^3,10 Furthermore, there is no centralized registry for calciphylaxis cases.³

[embed:render:related:node:67241]

Etiology and Pathogenesis

Calciphylaxis is thought to have a multifactorial etiology with the exact cause or trigger unknown.⁷ A long list of risk factors and triggers is associated with the condition (Table 1). Calciphylaxis primarily affects small arteries (40–600 μm in diameter) that become calcified due to an imbalance between inhibitors and promoters of calcification.^2,11 Fetuin-A and matrix Gla protein inhibit vascular calcification and are downregulated in calciphylaxis.^12,13 Dysfunctional calcium, phosphate, and parathyroid hormone regulatory pathways provide an increased substrate for the process of calcification, which causes endothelial damage and microthrombosis, resulting in tissue ischemia and infarction.^14,15 Notably, there is growing interest in the role of vitamin K in the pathogenesis of calciphylaxis. Vitamin K inhibits vascular calcification, possibly by increasing the circulating levels of carboxylated matrix Gla protein.¹⁶

CT102006395_t1.JPG

Clinical Features

Calciphylaxis is most commonly seen on the legs, abdomen, and buttocks.² Patients with ESRD commonly develop proximal lesions affecting adipose-rich sites and have a poor prognosis. Distal lesions are more common in patients with nonuremic calciphylaxis, and mortality rates are lower in this population.²

Early lesions present as painful skin nodules or indurated plaques that often are rock-hard or firm to palpation with overlying mottling or a livedoid pattern (Figure, A). Early lesions progress from livedo reticularis to livedo racemosa and then to retiform purpura (Figure, B). Purpuric lesions later evolve into black eschars (Figure, C), then to necrotic, ulcerated, malodorous plaques or nodules in later stages of the disease (Figure, D). Lesions also may develop a gangrenous sclerotic appearance.^2,5

ct102006395_f1.png

Although most patients with calciphylaxis have ESRD, nonuremic patients also can develop the disease. Those with calciphylaxis who do not have renal dysfunction frequently have other risk factors for the disease and often report another notable health problem in the weeks or months prior to presentation.⁴ More than half of patients with calciphylaxis become bedridden or require use of a wheelchair.¹⁷ Pain is characteristically severe throughout the course of the disease; it may even precede the appearance of the skin lesions.¹⁸ Because the pain is associated with ischemia, it tends to be relatively refractory to treatment with opioids. Rare extracutaneous vascular calcifications may lead to visual impairment, gastrointestinal tract bleeding, and myopathy.^5,9,19,20

Diagnosis

Considering the high morbidity and mortality associated with calciphylaxis, it is important to provide accurate and timely diagnosis; however, there currently are no validated diagnostic criteria for calciphylaxis. Careful correlation of clinical and histologic findings is required. Calciphylaxis biopsies have demonstrated medial calcification and proliferation of the intima of small- to medium-sized arteries.²¹ Lobular and septal panniculitis and extravascular soft-tissue calcification, particularly stippled calcification of the eccrine sweat glands, also has been seen.^2,22 Special calcium stains (eg, von Kossa, Alizarin red) increase the sensitivity of biopsy by highlighting subtle areas of intravascular and extravascular calcification.^5,23 Sufficient sampling of subcutaneous tissue and specimen evaluation by an experienced dermatopathologist are necessary to ensure proper interpretation of the histologic findings.

Despite these measures, skin biopsies may be nondiagnostic or falsely negative; therefore, when there is high clinical suspicion, it may be appropriate to move forward with a presumptive diagnosis of calciphylaxis even if the histologic findings are nondiagnostic.^1,9,24 It also is worth noting that localized progression and ulceration may occur following skin biopsy, such that biopsy may even be contraindicated in certain cases (eg, penile calciphylaxis).

[embed:render:related:node:66981]

Standard laboratory workup for calciphylaxis includes evaluation for associated risk factors as well as exclusion of other conditions in the differential diagnosis (Table 2). Blood tests to evaluate for risk factors include liver and renal function tests, a complete metabolic panel, parathyroid hormone level, and serum albumin level.⁵ Elevated calcium and phosphate levels may signal disturbed calcium and phosphate homeostasis but are neither sensitive nor specific for the diagnosis.²⁵ Complete blood cell count, blood cultures, thorough hypercoagulability workup (including but not limited to antiphospholipid antibodies, proteins C and S, factor V Leiden, antithrombin III, homocysteine, methylenetetrahydrofolate reductase mutation, and cryoglobulins), rheumatoid factor, antineutrophil cytoplasmic antibodies, and antinuclear antibody testing may be relevant to help identify contributing factors or mimickers of calciphylaxis.⁵ Various imaging modalities also have been used to evaluate for the presence of soft-tissue calcification in areas of suspected calciphylaxis, including radiography, mammography, computed tomography, ultrasonography, nuclear bone scintigraphy, and spectroscopy.^2,26,27 Unfortunately, there currently is no standardized reproducible imaging modality for reliable diagnosis of calciphylaxis. Ultimately, histologic and radiographic findings should always be interpreted in the context of relevant clinical findings.^2,9

CT102006395_t2.JPG

Prevention

Reduction of the net calcium phosphorus product may help reduce the risk of calciphylaxis in ESRD patients, which can be accomplished by using non–calcium-phosphate binders, adequate dialysis, and restricting use of vitamin D and vitamin K antagonists.^2,5 There are limited data regarding the benefits of using bisphosphonates and cinacalcet in ESRD patients on dialysis to prevent calciphylaxis.^28,29

Management

Management of calciphylaxis is multifactorial. Besides dermatology and nephrology, specialists in pain management, wound care, plastic surgery, and nutrition are critical partners in management.^1,5,9,30 Nephrologists can help optimize calcium and phosphate balance and ensure adequate dialysis. Pain specialists can aid in creating aggressive multiagent pain regimens that target the neuropathic/ischemic and physical aspects of calciphylaxis pain. When appropriate, nutrition specialists can help establish high-protein, low-phosphorus diets, and wound specialists can provide access to advanced wound dressings and adjunctive hyperbaric oxygen therapy. Plastic surgeons can provide conservative debridement procedures in a subset of patients, usually those with distal stable disease.

The limited understanding of the etiopathogenesis of calciphylaxis and the lack of data on its management are reflected in the limited treatment options for the disease (Table 3).^2,5,9 There are no formal algorithms for the treatment of calciphylaxis. Therapeutic trials are scarce, and most of the current treatment recommendations are based on small retrospective reports or case series. Sodium thiosulfate has been the most widely used treatment option since 2004, when its use in calciphylaxis was first reported.³¹ Sodium thiosulfate chelates calcium and is thought to have antioxidant and vasodilatory properties.³² There are a few promising clinical trials and large-scale studies (Table 4) that aim to evaluate the efficacy of existing treatments (eg, sodium thiosulfate) as well as novel treatment options such as lanthanum carbonate, SNF472 (hexasodium phytate), and vitamin K.^33-36

[embed:render:related:node:66994]

CT102006395_t3.JPG

CT102006395_t4.JPG

Prognosis

Calciphylaxis is a potentially fatal condition with a poor prognosis and a median survival rate of approximately 1 year following the appearance of skin lesions.^37-39 Patients with proximal lesions and those on peritoneal dialysis (as opposed to hemodialysis) have a worse prognosis.⁴⁰ Mortality rates are estimated to be 30% at 6 months, 50% at 12 months, and 80% at 2 years, with sepsis secondary to infection of cutaneous ulcers being the leading cause of death.^37-39 The impact of calciphylaxis on patient quality of life and activities of daily living is severe.^8,17

Future Directions

Multi-institution cohort studies and collaborative registries are needed to provide updated information related to the epidemiology, diagnosis, treatment, morbidity, and mortality associated with calciphylaxis and to help formulate evidence-based diagnostic criteria. Radiographic and histologic studies, as well as other tools for early and accurate diagnosis of calciphylaxis, should be studied for feasibility, accuracy, and reproducibility. The incidence of nonuremic calciphylaxis points toward pathogenic pathways besides those based on the bone-mineral axis. Basic science research directed at improving understanding of the pathophysiology of calciphylaxis would be helpful in devising new treatment strategies targeting these pathways. Establishment of a collaborative, multi-institutional calciphylaxis working group would enable experts to formulate therapeutic guidelines based on current evidence. Such a group could facilitate initiation of large prospective studies to establish the efficacy of existing and new treatment modalities for calciphylaxis. A working group within the Society for Dermatology Hospitalists has been tasked with addressing these issues and is currently establishing a multicenter calciphylaxis database.

[embed:render:podcast_episode_embedded:node:201513]

Calciphylaxis, also known as calcific uremic arteriolopathy, is a painful skin condition classically seen in patients with end-stage renal disease (ESRD), particularly those on chronic dialysis.^1,2 It also has increasingly been reported in patients with normal renal function and calcium and phosphate homeostasis.^3,4 Effective diagnosis and management of calciphylaxis remains challenging for physicians.^2,5 The condition is characterized by tissue ischemia caused by calcification of cutaneous arteriolar vessels. As a result, calciphylaxis is associated with high mortality rates, ranging from 60% to 80%.^5,6 Excruciating pain and nonhealing ulcers often lead to recurrent hospitalizations and infectious complications,⁷ and poor nutritional status, chronic pain, depression, and insomnia can further complicate recovery and lead to poor quality of life.⁸

We provide an update on calciphylaxis etiopathogenesis, diagnosis, and management. We also highlight some challenges faced in managing this potentially fatal condition.

Epidemiology

Calciphylaxis is considered a rare dermatosis with an estimated annual incidence of 1% to 4% in ESRD patients on dialysis. Recent data suggest that incidence of calciphylaxis is rising,^5,7,9 which may stem from an increased use of calcium-based phosphate binders, an actual rise in disease incidence, and/or increased recognition of the disease.⁵ It is difficult to estimate the exact disease burden of calciphylaxis because the diagnostic criteria are not well defined, often leading to missed or delayed diagnosis.^3,10 Furthermore, there is no centralized registry for calciphylaxis cases.³

[embed:render:related:node:67241]

Etiology and Pathogenesis

Calciphylaxis is thought to have a multifactorial etiology with the exact cause or trigger unknown.⁷ A long list of risk factors and triggers is associated with the condition (Table 1). Calciphylaxis primarily affects small arteries (40–600 μm in diameter) that become calcified due to an imbalance between inhibitors and promoters of calcification.^2,11 Fetuin-A and matrix Gla protein inhibit vascular calcification and are downregulated in calciphylaxis.^12,13 Dysfunctional calcium, phosphate, and parathyroid hormone regulatory pathways provide an increased substrate for the process of calcification, which causes endothelial damage and microthrombosis, resulting in tissue ischemia and infarction.^14,15 Notably, there is growing interest in the role of vitamin K in the pathogenesis of calciphylaxis. Vitamin K inhibits vascular calcification, possibly by increasing the circulating levels of carboxylated matrix Gla protein.¹⁶

CT102006395_t1.JPG

Clinical Features

Calciphylaxis is most commonly seen on the legs, abdomen, and buttocks.² Patients with ESRD commonly develop proximal lesions affecting adipose-rich sites and have a poor prognosis. Distal lesions are more common in patients with nonuremic calciphylaxis, and mortality rates are lower in this population.²

Early lesions present as painful skin nodules or indurated plaques that often are rock-hard or firm to palpation with overlying mottling or a livedoid pattern (Figure, A). Early lesions progress from livedo reticularis to livedo racemosa and then to retiform purpura (Figure, B). Purpuric lesions later evolve into black eschars (Figure, C), then to necrotic, ulcerated, malodorous plaques or nodules in later stages of the disease (Figure, D). Lesions also may develop a gangrenous sclerotic appearance.^2,5

ct102006395_f1.png

Although most patients with calciphylaxis have ESRD, nonuremic patients also can develop the disease. Those with calciphylaxis who do not have renal dysfunction frequently have other risk factors for the disease and often report another notable health problem in the weeks or months prior to presentation.⁴ More than half of patients with calciphylaxis become bedridden or require use of a wheelchair.¹⁷ Pain is characteristically severe throughout the course of the disease; it may even precede the appearance of the skin lesions.¹⁸ Because the pain is associated with ischemia, it tends to be relatively refractory to treatment with opioids. Rare extracutaneous vascular calcifications may lead to visual impairment, gastrointestinal tract bleeding, and myopathy.^5,9,19,20

Diagnosis

Considering the high morbidity and mortality associated with calciphylaxis, it is important to provide accurate and timely diagnosis; however, there currently are no validated diagnostic criteria for calciphylaxis. Careful correlation of clinical and histologic findings is required. Calciphylaxis biopsies have demonstrated medial calcification and proliferation of the intima of small- to medium-sized arteries.²¹ Lobular and septal panniculitis and extravascular soft-tissue calcification, particularly stippled calcification of the eccrine sweat glands, also has been seen.^2,22 Special calcium stains (eg, von Kossa, Alizarin red) increase the sensitivity of biopsy by highlighting subtle areas of intravascular and extravascular calcification.^5,23 Sufficient sampling of subcutaneous tissue and specimen evaluation by an experienced dermatopathologist are necessary to ensure proper interpretation of the histologic findings.

Despite these measures, skin biopsies may be nondiagnostic or falsely negative; therefore, when there is high clinical suspicion, it may be appropriate to move forward with a presumptive diagnosis of calciphylaxis even if the histologic findings are nondiagnostic.^1,9,24 It also is worth noting that localized progression and ulceration may occur following skin biopsy, such that biopsy may even be contraindicated in certain cases (eg, penile calciphylaxis).

[embed:render:related:node:66981]

Standard laboratory workup for calciphylaxis includes evaluation for associated risk factors as well as exclusion of other conditions in the differential diagnosis (Table 2). Blood tests to evaluate for risk factors include liver and renal function tests, a complete metabolic panel, parathyroid hormone level, and serum albumin level.⁵ Elevated calcium and phosphate levels may signal disturbed calcium and phosphate homeostasis but are neither sensitive nor specific for the diagnosis.²⁵ Complete blood cell count, blood cultures, thorough hypercoagulability workup (including but not limited to antiphospholipid antibodies, proteins C and S, factor V Leiden, antithrombin III, homocysteine, methylenetetrahydrofolate reductase mutation, and cryoglobulins), rheumatoid factor, antineutrophil cytoplasmic antibodies, and antinuclear antibody testing may be relevant to help identify contributing factors or mimickers of calciphylaxis.⁵ Various imaging modalities also have been used to evaluate for the presence of soft-tissue calcification in areas of suspected calciphylaxis, including radiography, mammography, computed tomography, ultrasonography, nuclear bone scintigraphy, and spectroscopy.^2,26,27 Unfortunately, there currently is no standardized reproducible imaging modality for reliable diagnosis of calciphylaxis. Ultimately, histologic and radiographic findings should always be interpreted in the context of relevant clinical findings.^2,9

CT102006395_t2.JPG

Prevention

Reduction of the net calcium phosphorus product may help reduce the risk of calciphylaxis in ESRD patients, which can be accomplished by using non–calcium-phosphate binders, adequate dialysis, and restricting use of vitamin D and vitamin K antagonists.^2,5 There are limited data regarding the benefits of using bisphosphonates and cinacalcet in ESRD patients on dialysis to prevent calciphylaxis.^28,29

Management

Management of calciphylaxis is multifactorial. Besides dermatology and nephrology, specialists in pain management, wound care, plastic surgery, and nutrition are critical partners in management.^1,5,9,30 Nephrologists can help optimize calcium and phosphate balance and ensure adequate dialysis. Pain specialists can aid in creating aggressive multiagent pain regimens that target the neuropathic/ischemic and physical aspects of calciphylaxis pain. When appropriate, nutrition specialists can help establish high-protein, low-phosphorus diets, and wound specialists can provide access to advanced wound dressings and adjunctive hyperbaric oxygen therapy. Plastic surgeons can provide conservative debridement procedures in a subset of patients, usually those with distal stable disease.

The limited understanding of the etiopathogenesis of calciphylaxis and the lack of data on its management are reflected in the limited treatment options for the disease (Table 3).^2,5,9 There are no formal algorithms for the treatment of calciphylaxis. Therapeutic trials are scarce, and most of the current treatment recommendations are based on small retrospective reports or case series. Sodium thiosulfate has been the most widely used treatment option since 2004, when its use in calciphylaxis was first reported.³¹ Sodium thiosulfate chelates calcium and is thought to have antioxidant and vasodilatory properties.³² There are a few promising clinical trials and large-scale studies (Table 4) that aim to evaluate the efficacy of existing treatments (eg, sodium thiosulfate) as well as novel treatment options such as lanthanum carbonate, SNF472 (hexasodium phytate), and vitamin K.^33-36

[embed:render:related:node:66994]

CT102006395_t3.JPG

CT102006395_t4.JPG

Prognosis

Calciphylaxis is a potentially fatal condition with a poor prognosis and a median survival rate of approximately 1 year following the appearance of skin lesions.^37-39 Patients with proximal lesions and those on peritoneal dialysis (as opposed to hemodialysis) have a worse prognosis.⁴⁰ Mortality rates are estimated to be 30% at 6 months, 50% at 12 months, and 80% at 2 years, with sepsis secondary to infection of cutaneous ulcers being the leading cause of death.^37-39 The impact of calciphylaxis on patient quality of life and activities of daily living is severe.^8,17

Future Directions

Multi-institution cohort studies and collaborative registries are needed to provide updated information related to the epidemiology, diagnosis, treatment, morbidity, and mortality associated with calciphylaxis and to help formulate evidence-based diagnostic criteria. Radiographic and histologic studies, as well as other tools for early and accurate diagnosis of calciphylaxis, should be studied for feasibility, accuracy, and reproducibility. The incidence of nonuremic calciphylaxis points toward pathogenic pathways besides those based on the bone-mineral axis. Basic science research directed at improving understanding of the pathophysiology of calciphylaxis would be helpful in devising new treatment strategies targeting these pathways. Establishment of a collaborative, multi-institutional calciphylaxis working group would enable experts to formulate therapeutic guidelines based on current evidence. Such a group could facilitate initiation of large prospective studies to establish the efficacy of existing and new treatment modalities for calciphylaxis. A working group within the Society for Dermatology Hospitalists has been tasked with addressing these issues and is currently establishing a multicenter calciphylaxis database.

[embed:render:podcast_episode_embedded:node:201513]

Calciphylaxis, also known as calcific uremic arteriolopathy, is a painful skin condition classically seen in patients with end-stage renal disease (ESRD), particularly those on chronic dialysis.^1,2 It also has increasingly been reported in patients with normal renal function and calcium and phosphate homeostasis.^3,4 Effective diagnosis and management of calciphylaxis remains challenging for physicians.^2,5 The condition is characterized by tissue ischemia caused by calcification of cutaneous arteriolar vessels. As a result, calciphylaxis is associated with high mortality rates, ranging from 60% to 80%.^5,6 Excruciating pain and nonhealing ulcers often lead to recurrent hospitalizations and infectious complications,⁷ and poor nutritional status, chronic pain, depression, and insomnia can further complicate recovery and lead to poor quality of life.⁸

We provide an update on calciphylaxis etiopathogenesis, diagnosis, and management. We also highlight some challenges faced in managing this potentially fatal condition.

Epidemiology

Calciphylaxis is considered a rare dermatosis with an estimated annual incidence of 1% to 4% in ESRD patients on dialysis. Recent data suggest that incidence of calciphylaxis is rising,^5,7,9 which may stem from an increased use of calcium-based phosphate binders, an actual rise in disease incidence, and/or increased recognition of the disease.⁵ It is difficult to estimate the exact disease burden of calciphylaxis because the diagnostic criteria are not well defined, often leading to missed or delayed diagnosis.^3,10 Furthermore, there is no centralized registry for calciphylaxis cases.³

[embed:render:related:node:67241]

Etiology and Pathogenesis

Calciphylaxis is thought to have a multifactorial etiology with the exact cause or trigger unknown.⁷ A long list of risk factors and triggers is associated with the condition (Table 1). Calciphylaxis primarily affects small arteries (40–600 μm in diameter) that become calcified due to an imbalance between inhibitors and promoters of calcification.^2,11 Fetuin-A and matrix Gla protein inhibit vascular calcification and are downregulated in calciphylaxis.^12,13 Dysfunctional calcium, phosphate, and parathyroid hormone regulatory pathways provide an increased substrate for the process of calcification, which causes endothelial damage and microthrombosis, resulting in tissue ischemia and infarction.^14,15 Notably, there is growing interest in the role of vitamin K in the pathogenesis of calciphylaxis. Vitamin K inhibits vascular calcification, possibly by increasing the circulating levels of carboxylated matrix Gla protein.¹⁶

CT102006395_t1.JPG

Clinical Features

Calciphylaxis is most commonly seen on the legs, abdomen, and buttocks.² Patients with ESRD commonly develop proximal lesions affecting adipose-rich sites and have a poor prognosis. Distal lesions are more common in patients with nonuremic calciphylaxis, and mortality rates are lower in this population.²

Early lesions present as painful skin nodules or indurated plaques that often are rock-hard or firm to palpation with overlying mottling or a livedoid pattern (Figure, A). Early lesions progress from livedo reticularis to livedo racemosa and then to retiform purpura (Figure, B). Purpuric lesions later evolve into black eschars (Figure, C), then to necrotic, ulcerated, malodorous plaques or nodules in later stages of the disease (Figure, D). Lesions also may develop a gangrenous sclerotic appearance.^2,5

ct102006395_f1.png

Although most patients with calciphylaxis have ESRD, nonuremic patients also can develop the disease. Those with calciphylaxis who do not have renal dysfunction frequently have other risk factors for the disease and often report another notable health problem in the weeks or months prior to presentation.⁴ More than half of patients with calciphylaxis become bedridden or require use of a wheelchair.¹⁷ Pain is characteristically severe throughout the course of the disease; it may even precede the appearance of the skin lesions.¹⁸ Because the pain is associated with ischemia, it tends to be relatively refractory to treatment with opioids. Rare extracutaneous vascular calcifications may lead to visual impairment, gastrointestinal tract bleeding, and myopathy.^5,9,19,20

Diagnosis

Considering the high morbidity and mortality associated with calciphylaxis, it is important to provide accurate and timely diagnosis; however, there currently are no validated diagnostic criteria for calciphylaxis. Careful correlation of clinical and histologic findings is required. Calciphylaxis biopsies have demonstrated medial calcification and proliferation of the intima of small- to medium-sized arteries.²¹ Lobular and septal panniculitis and extravascular soft-tissue calcification, particularly stippled calcification of the eccrine sweat glands, also has been seen.^2,22 Special calcium stains (eg, von Kossa, Alizarin red) increase the sensitivity of biopsy by highlighting subtle areas of intravascular and extravascular calcification.^5,23 Sufficient sampling of subcutaneous tissue and specimen evaluation by an experienced dermatopathologist are necessary to ensure proper interpretation of the histologic findings.

Despite these measures, skin biopsies may be nondiagnostic or falsely negative; therefore, when there is high clinical suspicion, it may be appropriate to move forward with a presumptive diagnosis of calciphylaxis even if the histologic findings are nondiagnostic.^1,9,24 It also is worth noting that localized progression and ulceration may occur following skin biopsy, such that biopsy may even be contraindicated in certain cases (eg, penile calciphylaxis).

[embed:render:related:node:66981]

Standard laboratory workup for calciphylaxis includes evaluation for associated risk factors as well as exclusion of other conditions in the differential diagnosis (Table 2). Blood tests to evaluate for risk factors include liver and renal function tests, a complete metabolic panel, parathyroid hormone level, and serum albumin level.⁵ Elevated calcium and phosphate levels may signal disturbed calcium and phosphate homeostasis but are neither sensitive nor specific for the diagnosis.²⁵ Complete blood cell count, blood cultures, thorough hypercoagulability workup (including but not limited to antiphospholipid antibodies, proteins C and S, factor V Leiden, antithrombin III, homocysteine, methylenetetrahydrofolate reductase mutation, and cryoglobulins), rheumatoid factor, antineutrophil cytoplasmic antibodies, and antinuclear antibody testing may be relevant to help identify contributing factors or mimickers of calciphylaxis.⁵ Various imaging modalities also have been used to evaluate for the presence of soft-tissue calcification in areas of suspected calciphylaxis, including radiography, mammography, computed tomography, ultrasonography, nuclear bone scintigraphy, and spectroscopy.^2,26,27 Unfortunately, there currently is no standardized reproducible imaging modality for reliable diagnosis of calciphylaxis. Ultimately, histologic and radiographic findings should always be interpreted in the context of relevant clinical findings.^2,9

CT102006395_t2.JPG

Prevention

Reduction of the net calcium phosphorus product may help reduce the risk of calciphylaxis in ESRD patients, which can be accomplished by using non–calcium-phosphate binders, adequate dialysis, and restricting use of vitamin D and vitamin K antagonists.^2,5 There are limited data regarding the benefits of using bisphosphonates and cinacalcet in ESRD patients on dialysis to prevent calciphylaxis.^28,29

Management

Management of calciphylaxis is multifactorial. Besides dermatology and nephrology, specialists in pain management, wound care, plastic surgery, and nutrition are critical partners in management.^1,5,9,30 Nephrologists can help optimize calcium and phosphate balance and ensure adequate dialysis. Pain specialists can aid in creating aggressive multiagent pain regimens that target the neuropathic/ischemic and physical aspects of calciphylaxis pain. When appropriate, nutrition specialists can help establish high-protein, low-phosphorus diets, and wound specialists can provide access to advanced wound dressings and adjunctive hyperbaric oxygen therapy. Plastic surgeons can provide conservative debridement procedures in a subset of patients, usually those with distal stable disease.

The limited understanding of the etiopathogenesis of calciphylaxis and the lack of data on its management are reflected in the limited treatment options for the disease (Table 3).^2,5,9 There are no formal algorithms for the treatment of calciphylaxis. Therapeutic trials are scarce, and most of the current treatment recommendations are based on small retrospective reports or case series. Sodium thiosulfate has been the most widely used treatment option since 2004, when its use in calciphylaxis was first reported.³¹ Sodium thiosulfate chelates calcium and is thought to have antioxidant and vasodilatory properties.³² There are a few promising clinical trials and large-scale studies (Table 4) that aim to evaluate the efficacy of existing treatments (eg, sodium thiosulfate) as well as novel treatment options such as lanthanum carbonate, SNF472 (hexasodium phytate), and vitamin K.^33-36

[embed:render:related:node:66994]

CT102006395_t3.JPG

CT102006395_t4.JPG

Prognosis

Calciphylaxis is a potentially fatal condition with a poor prognosis and a median survival rate of approximately 1 year following the appearance of skin lesions.^37-39 Patients with proximal lesions and those on peritoneal dialysis (as opposed to hemodialysis) have a worse prognosis.⁴⁰ Mortality rates are estimated to be 30% at 6 months, 50% at 12 months, and 80% at 2 years, with sepsis secondary to infection of cutaneous ulcers being the leading cause of death.^37-39 The impact of calciphylaxis on patient quality of life and activities of daily living is severe.^8,17

Future Directions

Multi-institution cohort studies and collaborative registries are needed to provide updated information related to the epidemiology, diagnosis, treatment, morbidity, and mortality associated with calciphylaxis and to help formulate evidence-based diagnostic criteria. Radiographic and histologic studies, as well as other tools for early and accurate diagnosis of calciphylaxis, should be studied for feasibility, accuracy, and reproducibility. The incidence of nonuremic calciphylaxis points toward pathogenic pathways besides those based on the bone-mineral axis. Basic science research directed at improving understanding of the pathophysiology of calciphylaxis would be helpful in devising new treatment strategies targeting these pathways. Establishment of a collaborative, multi-institutional calciphylaxis working group would enable experts to formulate therapeutic guidelines based on current evidence. Such a group could facilitate initiation of large prospective studies to establish the efficacy of existing and new treatment modalities for calciphylaxis. A working group within the Society for Dermatology Hospitalists has been tasked with addressing these issues and is currently establishing a multicenter calciphylaxis database.

Drug rash with eosinophilia and systemic symptoms (DRESS syndrome), also known as drug-induced hypersensitivity syndrome, is an uncommon severe systemic hypersensitivity drug reaction. It is estimated to occur in 1 in every 1000 to 10,000 drug exposures.¹ It can affect patients of all ages and typically presents 2 to 6 weeks after exposure to a culprit medication. Classically, DRESS syndrome presents with often widespread rash, facial edema, systemic symptoms such as fever, lymphadenopathy, and evidence of visceral organ involvement. Peripheral blood eosinophilia is frequently but not universally observed.^1,2

Even with proper management, reported DRESS syndrome mortality rates worldwide are approximately 10%² or higher depending on the degree and type of other organ involvement (eg, cardiac).³ Beyond the acute manifestations of DRESS syndrome, this condition is unique in that some patients develop late-onset sequelae such as myocarditis or autoimmune conditions even years after the initial cutaneous eruption.⁴ Therefore, longitudinal evaluation is a key component of management.

The clinical myths and pearls presented here highlight some of the commonly held assumptions regarding DRESS syndrome in an effort to illuminate subtleties of managing patients with this condition (Table).

CT102005322_Table.JPG

Myth: DRESS syndrome may only be diagnosed when the clinical criteria satisfy one of the established scoring systems.

Patients with DRESS syndrome can have heterogeneous manifestations. As a result, patients may develop a drug hypersensitivity with biological behavior and a natural history compatible with DRESS syndrome that does not fulfill published diagnostic criteria.⁵ The syndrome also may reveal its component manifestations gradually, thus delaying the diagnosis. The terms mini-DRESS and skirt syndrome have been employed to describe drug eruptions that clearly have systemic symptoms and more complex and pernicious biologic behavior than a simple drug exanthema but do not meet DRESS syndrome criteria. Ultimately, it is important to note that in clinical practice, DRESS syndrome exists on a spectrum of severity and the diagnosis remains a clinical one.

Pearl: The most commonly involved organ in DRESS syndrome is the liver.

Liver involvement is the most common visceral organ involved in DRESS syndrome and is estimated to occur in approximately 45.0% to 86.1% of cases.^6,7 If a patient develops the characteristic rash, peripheral blood eosinophilia, and evidence of liver injury, DRESS syndrome must be included in the differential diagnosis.

Hepatitis presenting in DRESS syndrome can be hepatocellular, cholestatic, or mixed.^6,7 Case series are varied in whether the transaminitis of DRESS syndrome tends to be more hepatocellular⁸ or cholestatic.⁷ Liver dysfunction in DRESS syndrome often lasts longer than in other severe cutaneous adverse drug reactions, and patients may improve anywhere from a few days in milder cases to months to achieve resolution of abnormalities.^6,7 Severe hepatic involvement is thought to be the most notable cause of mortality.⁹

Pearl: New-onset proteinuria, hematuria, and sterile pyuria indicate acute interstitial nephritis that may be associated with DRESS syndrome.

Acute interstitial nephritis (AIN) is a drug-induced form of acute kidney injury that can co-occur with DRESS syndrome. Acute interstitial nephritis can present with some combination of acute kidney injury, morbilliform eruption, eosinophilia, fever, and sometimes eosinophiluria. Although AIN can be distinct from DRESS syndrome, there are cases of DRESS syndrome associated with AIN.¹⁰ In the correct clinical context, urinalysis may help by showing new-onset proteinuria, new-onset hematuria, and sterile pyuria. More common causes of acute kidney injury such as prerenal etiologies and acute tubular necrosis have a bland urinary sediment.

Myth: If the eruption is not morbilliform, then it is not DRESS syndrome.

The most common morphology of DRESS syndrome is a morbilliform eruption (Figure 1), but urticarial and atypical targetoid (erythema multiforme–like) eruptions also have been described.⁹ Rarely, DRESS syndrome secondary to use of allopurinol or anticonvulsants may have a pustular morphology (Figure 2), which is distinguished from acute generalized exanthematous pustulosis by its delayed onset, more severe visceral involvement, and prolonged course.¹¹

ct102005322_fig1.png

ct102005322_fig2.png

Another reported variant demonstrates overlapping features between Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS syndrome. It may present with mucositis, atypical targetoid lesions, and vesiculobullous lesions.¹² It is unclear whether this reported variant is indeed a true subtype of DRESS syndrome, as Stevens-Johnson syndrome/toxic epidermal necrolysis may present with systemic symptoms, lymphadenopathy, hepatic, renal, and pulmonary complications, among other systemic disturbances.¹²

Pearl: Facial edema noted during physical examination is an important clue of DRESS syndrome.

Perhaps the most helpful findings in the diagnosis of DRESS syndrome are facial edema and anasarca (Figure 3), as facial edema is not a usual finding in sepsis. Facial edema can be severe enough that the patient’s features are dramatically altered. It may be useful to ask family members if the patient’s face appears swollen or to compare the current appearance to the patient’s driver’s license photograph. An important complication to note is laryngeal edema, which may complicate airway management and may manifest as respiratory distress, stridor, and the need for emergent intubation.¹³

ct102005322_fig3.png

Myth: Patients who have had an allergic reaction to sulfonamide antibiotics will have a cross-reaction to nonantibiotic sulfonamides.

A common question is, if a patient has had a prior allergy to sulfonamide antibiotics, then are nonantibiotic sulfones such as a sulfonylurea, thiazide diuretic, or furosemide likely to cause a a cross-reaction? In one study (N=969), only 9.9% of patients with a prior sulfone antibiotic allergy developed hypersensitivity when exposed to a nonantibiotic sulfone, which is thought to be due to an overall increased propensity for hypersensitivity rather than a true cross-reaction. In fact, the risk for developing a hypersensitivity reaction to penicillin (14.0% [717/5115]) was higher than the risk for developing a reaction from a nonantibiotic sulfone among these patients.¹⁴ This study bolsters the argument that if there are other potential culprit medications and the time course for a patient’s nonantibiotic sulfone is not consistent with the timeline for DRESS syndrome, it may be beneficial to look for a different causative agent.

Pearl: Vancomycin is an important cause of DRESS syndrome.

Guidelines for treating endocarditis and osteomyelitis caused by methicillin-resistant Staphylococcus aureus infection recommend intravenous vancomycin for 4 to 6 weeks.¹⁵ This duration is within the relevant time frame of exposure for the development of DRESS syndrome de novo.

One case series noted that 37.5% (12/32) of DRESS syndrome cases in a 3-year period were caused by vancomycin, which notably was the most common medication associated with DRESS syndrome.¹⁶ There were caveats to this case series in that no standardized drug causality score was used and the sample size over the 3-year period was small; however, the increased use (and misuse) of antibiotics and perhaps increased recognition of rash in outpatient parenteral antibiotic therapy clinics may play a role if vancomycin-induced DRESS syndrome is indeed becoming more common.

Myth: Myocarditis secondary to DRESS syndrome will present with chest pain at the time of the cutaneous eruption.

Few patients with DRESS syndrome–associated myocarditis actually are symptomatic during their hospitalization.⁴ In asymptomatic patients, the primary team and consultants should be vigilant for the potential of subclinical myocarditis or the possibility of developing cardiac involvement after discharge, as myocarditis secondary to DRESS syndrome may present any time from rash onset up to 4 months later.⁴ Therefore, DRESS patients should be especially attentive to any new cardiac symptoms and notify their provider if any develop.

Although no standard cardiac screening guidelines exist for DRESS syndrome, some have recommended that baseline cardiac screening tests including electrocardiogram, troponin levels, and echocardiogram be considered at the time of diagnosis.⁵ If any testing is abnormal, DRESS syndrome–associated myocarditis should be suspected and an endomyocardial biopsy, which is the diagnostic gold standard, may be necessary.⁴ If the cardiac screening tests are normal, some investigators recommend serial outpatient echocardiograms for all DRESS patients, even those who remain asymptomatic.¹⁷ An alternative is an empiric approach in which a thorough review of systems is performed and testing is done if patients develop symptoms that are concerning for myocarditis.

Pearl: Steroids are not the only treatment used to control DRESS syndrome.

A prolonged taper of systemic steroids is the first-line treatment of DRESS syndrome. Steroids at the equivalent of 1 to 2 mg/kg daily (once or divided into 2 doses) of prednisone typically are used. For severe and/or recalcitrant DRESS syndrome, 2 mg/kg daily (once or divided into 2 doses) typically is used, and less than 1 mg/kg daily may be used for mini-DRESS syndrome.

Clinical improvement of DRESS syndrome has been demonstrated in several case reports with intravenous immunoglobulin, cyclosporine, cyclophosphamide, mycophenolate mofetil, and plasmapheresis.^18-21 Each of these therapies typically were initiated as second-line therapeutic agents when initial treatment with steroids failed. It is important to note that large prospective studies regarding these treatments are lacking; however, there have been case reports of acute necrotizing eosinophilic myocarditis that did not respond to the combination of steroids and cyclosporine.^4,22

Although there have been successful case reports using intravenous immunoglobulin, a 2012 prospective open-label clinical trial reported notable side effects in 5 of 6 (83.3%) patients with only 1 of 6 (16.6%) achieving the primary end point of control of fever/symptoms at day 7 and clinical remission without steroids on day 30.²³

Pearl: DRESS patients need to be monitored for long-term sequelae such as autoimmune disease.

Several autoimmune conditions may develop as a delayed complication of DRESS syndrome, including autoimmune thyroiditis, systemic lupus erythematosus, type 1 diabetes mellitus, and autoimmune hemolytic anemia.^24-26 Incidence rates of autoimmunity following DRESS syndrome range from 3% to 5% among small case series.^24,25

Autoimmune thyroiditis, which may present as Graves disease, Hashimoto thyroiditis, or painless thyroiditis, is the most common autoimmune disorder to develop in DRESS patients and appears from several weeks to up to 3 years after DRESS.²⁴ Therefore, all DRESS patients should be monitored longitudinally for several years for signs or symptoms suggestive of an autoimmune condition.^5,24,26

Because no guidelines exist regarding serial monitoring for autoimmune sequelae, it may be reasonable to check thyroid function tests at the time of diagnosis and regularly for at least 2 years after diagnosis.⁵ Alternatively, clinicians may consider an empiric approach to laboratory testing that is guided by the development of clinical symptoms.

Pearl: Small cases series suggest differences between adult and pediatric DRESS syndrome, but there are no large studies in children.

Small case series have suggested there may be noteworthy differences between DRESS syndrome in adults and children. Although human herpesvirus 6 (HHV-6) positivity in DRESS syndrome in adults may be as high as 80%, 13% of pediatric patients in one cohort tested positive for HHV-6, though the study size was limited at 29 total patients.²⁷ In children, DRESS syndrome secondary to antibiotics was associated with a shorter latency time as compared to cases secondary to nonantibiotics. In contrast to the typical 2- to 6-week timeline, Sasidharanpillai et al²⁸ reported an average onset 5.8 days after drug administration in antibiotic-associated DRESS syndrome compared to 23.9 days for anticonvulsants, though this study only included 11 total patients. Other reports have suggested a similar trend.²⁷

The role of HHV-6 positivity in pediatric DRESS syndrome and its influence on prognosis remains unclear. One study showed a worse prognosis for pediatric patients with positive HHV-6 antibodies.²⁷ However, with such a small sample size—only 4 HHV-6–positive patients of 29 pediatric DRESS cases—larger studies are needed to better characterize the relationship between HHV-6 positivity and prognosis.

Drug rash with eosinophilia and systemic symptoms (DRESS syndrome), also known as drug-induced hypersensitivity syndrome, is an uncommon severe systemic hypersensitivity drug reaction. It is estimated to occur in 1 in every 1000 to 10,000 drug exposures.¹ It can affect patients of all ages and typically presents 2 to 6 weeks after exposure to a culprit medication. Classically, DRESS syndrome presents with often widespread rash, facial edema, systemic symptoms such as fever, lymphadenopathy, and evidence of visceral organ involvement. Peripheral blood eosinophilia is frequently but not universally observed.^1,2

Even with proper management, reported DRESS syndrome mortality rates worldwide are approximately 10%² or higher depending on the degree and type of other organ involvement (eg, cardiac).³ Beyond the acute manifestations of DRESS syndrome, this condition is unique in that some patients develop late-onset sequelae such as myocarditis or autoimmune conditions even years after the initial cutaneous eruption.⁴ Therefore, longitudinal evaluation is a key component of management.

The clinical myths and pearls presented here highlight some of the commonly held assumptions regarding DRESS syndrome in an effort to illuminate subtleties of managing patients with this condition (Table).

CT102005322_Table.JPG

Myth: DRESS syndrome may only be diagnosed when the clinical criteria satisfy one of the established scoring systems.

Patients with DRESS syndrome can have heterogeneous manifestations. As a result, patients may develop a drug hypersensitivity with biological behavior and a natural history compatible with DRESS syndrome that does not fulfill published diagnostic criteria.⁵ The syndrome also may reveal its component manifestations gradually, thus delaying the diagnosis. The terms mini-DRESS and skirt syndrome have been employed to describe drug eruptions that clearly have systemic symptoms and more complex and pernicious biologic behavior than a simple drug exanthema but do not meet DRESS syndrome criteria. Ultimately, it is important to note that in clinical practice, DRESS syndrome exists on a spectrum of severity and the diagnosis remains a clinical one.

Pearl: The most commonly involved organ in DRESS syndrome is the liver.

Liver involvement is the most common visceral organ involved in DRESS syndrome and is estimated to occur in approximately 45.0% to 86.1% of cases.^6,7 If a patient develops the characteristic rash, peripheral blood eosinophilia, and evidence of liver injury, DRESS syndrome must be included in the differential diagnosis.

Hepatitis presenting in DRESS syndrome can be hepatocellular, cholestatic, or mixed.^6,7 Case series are varied in whether the transaminitis of DRESS syndrome tends to be more hepatocellular⁸ or cholestatic.⁷ Liver dysfunction in DRESS syndrome often lasts longer than in other severe cutaneous adverse drug reactions, and patients may improve anywhere from a few days in milder cases to months to achieve resolution of abnormalities.^6,7 Severe hepatic involvement is thought to be the most notable cause of mortality.⁹

Pearl: New-onset proteinuria, hematuria, and sterile pyuria indicate acute interstitial nephritis that may be associated with DRESS syndrome.

Acute interstitial nephritis (AIN) is a drug-induced form of acute kidney injury that can co-occur with DRESS syndrome. Acute interstitial nephritis can present with some combination of acute kidney injury, morbilliform eruption, eosinophilia, fever, and sometimes eosinophiluria. Although AIN can be distinct from DRESS syndrome, there are cases of DRESS syndrome associated with AIN.¹⁰ In the correct clinical context, urinalysis may help by showing new-onset proteinuria, new-onset hematuria, and sterile pyuria. More common causes of acute kidney injury such as prerenal etiologies and acute tubular necrosis have a bland urinary sediment.

Myth: If the eruption is not morbilliform, then it is not DRESS syndrome.

The most common morphology of DRESS syndrome is a morbilliform eruption (Figure 1), but urticarial and atypical targetoid (erythema multiforme–like) eruptions also have been described.⁹ Rarely, DRESS syndrome secondary to use of allopurinol or anticonvulsants may have a pustular morphology (Figure 2), which is distinguished from acute generalized exanthematous pustulosis by its delayed onset, more severe visceral involvement, and prolonged course.¹¹

ct102005322_fig1.png

ct102005322_fig2.png

Another reported variant demonstrates overlapping features between Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS syndrome. It may present with mucositis, atypical targetoid lesions, and vesiculobullous lesions.¹² It is unclear whether this reported variant is indeed a true subtype of DRESS syndrome, as Stevens-Johnson syndrome/toxic epidermal necrolysis may present with systemic symptoms, lymphadenopathy, hepatic, renal, and pulmonary complications, among other systemic disturbances.¹²

Pearl: Facial edema noted during physical examination is an important clue of DRESS syndrome.

Perhaps the most helpful findings in the diagnosis of DRESS syndrome are facial edema and anasarca (Figure 3), as facial edema is not a usual finding in sepsis. Facial edema can be severe enough that the patient’s features are dramatically altered. It may be useful to ask family members if the patient’s face appears swollen or to compare the current appearance to the patient’s driver’s license photograph. An important complication to note is laryngeal edema, which may complicate airway management and may manifest as respiratory distress, stridor, and the need for emergent intubation.¹³

ct102005322_fig3.png

Myth: Patients who have had an allergic reaction to sulfonamide antibiotics will have a cross-reaction to nonantibiotic sulfonamides.

A common question is, if a patient has had a prior allergy to sulfonamide antibiotics, then are nonantibiotic sulfones such as a sulfonylurea, thiazide diuretic, or furosemide likely to cause a a cross-reaction? In one study (N=969), only 9.9% of patients with a prior sulfone antibiotic allergy developed hypersensitivity when exposed to a nonantibiotic sulfone, which is thought to be due to an overall increased propensity for hypersensitivity rather than a true cross-reaction. In fact, the risk for developing a hypersensitivity reaction to penicillin (14.0% [717/5115]) was higher than the risk for developing a reaction from a nonantibiotic sulfone among these patients.¹⁴ This study bolsters the argument that if there are other potential culprit medications and the time course for a patient’s nonantibiotic sulfone is not consistent with the timeline for DRESS syndrome, it may be beneficial to look for a different causative agent.

Pearl: Vancomycin is an important cause of DRESS syndrome.

Guidelines for treating endocarditis and osteomyelitis caused by methicillin-resistant Staphylococcus aureus infection recommend intravenous vancomycin for 4 to 6 weeks.¹⁵ This duration is within the relevant time frame of exposure for the development of DRESS syndrome de novo.

One case series noted that 37.5% (12/32) of DRESS syndrome cases in a 3-year period were caused by vancomycin, which notably was the most common medication associated with DRESS syndrome.¹⁶ There were caveats to this case series in that no standardized drug causality score was used and the sample size over the 3-year period was small; however, the increased use (and misuse) of antibiotics and perhaps increased recognition of rash in outpatient parenteral antibiotic therapy clinics may play a role if vancomycin-induced DRESS syndrome is indeed becoming more common.

Myth: Myocarditis secondary to DRESS syndrome will present with chest pain at the time of the cutaneous eruption.

Few patients with DRESS syndrome–associated myocarditis actually are symptomatic during their hospitalization.⁴ In asymptomatic patients, the primary team and consultants should be vigilant for the potential of subclinical myocarditis or the possibility of developing cardiac involvement after discharge, as myocarditis secondary to DRESS syndrome may present any time from rash onset up to 4 months later.⁴ Therefore, DRESS patients should be especially attentive to any new cardiac symptoms and notify their provider if any develop.

Although no standard cardiac screening guidelines exist for DRESS syndrome, some have recommended that baseline cardiac screening tests including electrocardiogram, troponin levels, and echocardiogram be considered at the time of diagnosis.⁵ If any testing is abnormal, DRESS syndrome–associated myocarditis should be suspected and an endomyocardial biopsy, which is the diagnostic gold standard, may be necessary.⁴ If the cardiac screening tests are normal, some investigators recommend serial outpatient echocardiograms for all DRESS patients, even those who remain asymptomatic.¹⁷ An alternative is an empiric approach in which a thorough review of systems is performed and testing is done if patients develop symptoms that are concerning for myocarditis.

Pearl: Steroids are not the only treatment used to control DRESS syndrome.

A prolonged taper of systemic steroids is the first-line treatment of DRESS syndrome. Steroids at the equivalent of 1 to 2 mg/kg daily (once or divided into 2 doses) of prednisone typically are used. For severe and/or recalcitrant DRESS syndrome, 2 mg/kg daily (once or divided into 2 doses) typically is used, and less than 1 mg/kg daily may be used for mini-DRESS syndrome.

Clinical improvement of DRESS syndrome has been demonstrated in several case reports with intravenous immunoglobulin, cyclosporine, cyclophosphamide, mycophenolate mofetil, and plasmapheresis.^18-21 Each of these therapies typically were initiated as second-line therapeutic agents when initial treatment with steroids failed. It is important to note that large prospective studies regarding these treatments are lacking; however, there have been case reports of acute necrotizing eosinophilic myocarditis that did not respond to the combination of steroids and cyclosporine.^4,22

Although there have been successful case reports using intravenous immunoglobulin, a 2012 prospective open-label clinical trial reported notable side effects in 5 of 6 (83.3%) patients with only 1 of 6 (16.6%) achieving the primary end point of control of fever/symptoms at day 7 and clinical remission without steroids on day 30.²³

Pearl: DRESS patients need to be monitored for long-term sequelae such as autoimmune disease.

Several autoimmune conditions may develop as a delayed complication of DRESS syndrome, including autoimmune thyroiditis, systemic lupus erythematosus, type 1 diabetes mellitus, and autoimmune hemolytic anemia.^24-26 Incidence rates of autoimmunity following DRESS syndrome range from 3% to 5% among small case series.^24,25

Autoimmune thyroiditis, which may present as Graves disease, Hashimoto thyroiditis, or painless thyroiditis, is the most common autoimmune disorder to develop in DRESS patients and appears from several weeks to up to 3 years after DRESS.²⁴ Therefore, all DRESS patients should be monitored longitudinally for several years for signs or symptoms suggestive of an autoimmune condition.^5,24,26

Because no guidelines exist regarding serial monitoring for autoimmune sequelae, it may be reasonable to check thyroid function tests at the time of diagnosis and regularly for at least 2 years after diagnosis.⁵ Alternatively, clinicians may consider an empiric approach to laboratory testing that is guided by the development of clinical symptoms.

Pearl: Small cases series suggest differences between adult and pediatric DRESS syndrome, but there are no large studies in children.

Small case series have suggested there may be noteworthy differences between DRESS syndrome in adults and children. Although human herpesvirus 6 (HHV-6) positivity in DRESS syndrome in adults may be as high as 80%, 13% of pediatric patients in one cohort tested positive for HHV-6, though the study size was limited at 29 total patients.²⁷ In children, DRESS syndrome secondary to antibiotics was associated with a shorter latency time as compared to cases secondary to nonantibiotics. In contrast to the typical 2- to 6-week timeline, Sasidharanpillai et al²⁸ reported an average onset 5.8 days after drug administration in antibiotic-associated DRESS syndrome compared to 23.9 days for anticonvulsants, though this study only included 11 total patients. Other reports have suggested a similar trend.²⁷

The role of HHV-6 positivity in pediatric DRESS syndrome and its influence on prognosis remains unclear. One study showed a worse prognosis for pediatric patients with positive HHV-6 antibodies.²⁷ However, with such a small sample size—only 4 HHV-6–positive patients of 29 pediatric DRESS cases—larger studies are needed to better characterize the relationship between HHV-6 positivity and prognosis.

Drug rash with eosinophilia and systemic symptoms (DRESS syndrome), also known as drug-induced hypersensitivity syndrome, is an uncommon severe systemic hypersensitivity drug reaction. It is estimated to occur in 1 in every 1000 to 10,000 drug exposures.¹ It can affect patients of all ages and typically presents 2 to 6 weeks after exposure to a culprit medication. Classically, DRESS syndrome presents with often widespread rash, facial edema, systemic symptoms such as fever, lymphadenopathy, and evidence of visceral organ involvement. Peripheral blood eosinophilia is frequently but not universally observed.^1,2

Even with proper management, reported DRESS syndrome mortality rates worldwide are approximately 10%² or higher depending on the degree and type of other organ involvement (eg, cardiac).³ Beyond the acute manifestations of DRESS syndrome, this condition is unique in that some patients develop late-onset sequelae such as myocarditis or autoimmune conditions even years after the initial cutaneous eruption.⁴ Therefore, longitudinal evaluation is a key component of management.

The clinical myths and pearls presented here highlight some of the commonly held assumptions regarding DRESS syndrome in an effort to illuminate subtleties of managing patients with this condition (Table).

CT102005322_Table.JPG

Myth: DRESS syndrome may only be diagnosed when the clinical criteria satisfy one of the established scoring systems.

Patients with DRESS syndrome can have heterogeneous manifestations. As a result, patients may develop a drug hypersensitivity with biological behavior and a natural history compatible with DRESS syndrome that does not fulfill published diagnostic criteria.⁵ The syndrome also may reveal its component manifestations gradually, thus delaying the diagnosis. The terms mini-DRESS and skirt syndrome have been employed to describe drug eruptions that clearly have systemic symptoms and more complex and pernicious biologic behavior than a simple drug exanthema but do not meet DRESS syndrome criteria. Ultimately, it is important to note that in clinical practice, DRESS syndrome exists on a spectrum of severity and the diagnosis remains a clinical one.

Pearl: The most commonly involved organ in DRESS syndrome is the liver.

Liver involvement is the most common visceral organ involved in DRESS syndrome and is estimated to occur in approximately 45.0% to 86.1% of cases.^6,7 If a patient develops the characteristic rash, peripheral blood eosinophilia, and evidence of liver injury, DRESS syndrome must be included in the differential diagnosis.

Hepatitis presenting in DRESS syndrome can be hepatocellular, cholestatic, or mixed.^6,7 Case series are varied in whether the transaminitis of DRESS syndrome tends to be more hepatocellular⁸ or cholestatic.⁷ Liver dysfunction in DRESS syndrome often lasts longer than in other severe cutaneous adverse drug reactions, and patients may improve anywhere from a few days in milder cases to months to achieve resolution of abnormalities.^6,7 Severe hepatic involvement is thought to be the most notable cause of mortality.⁹

Pearl: New-onset proteinuria, hematuria, and sterile pyuria indicate acute interstitial nephritis that may be associated with DRESS syndrome.

Acute interstitial nephritis (AIN) is a drug-induced form of acute kidney injury that can co-occur with DRESS syndrome. Acute interstitial nephritis can present with some combination of acute kidney injury, morbilliform eruption, eosinophilia, fever, and sometimes eosinophiluria. Although AIN can be distinct from DRESS syndrome, there are cases of DRESS syndrome associated with AIN.¹⁰ In the correct clinical context, urinalysis may help by showing new-onset proteinuria, new-onset hematuria, and sterile pyuria. More common causes of acute kidney injury such as prerenal etiologies and acute tubular necrosis have a bland urinary sediment.

Myth: If the eruption is not morbilliform, then it is not DRESS syndrome.

The most common morphology of DRESS syndrome is a morbilliform eruption (Figure 1), but urticarial and atypical targetoid (erythema multiforme–like) eruptions also have been described.⁹ Rarely, DRESS syndrome secondary to use of allopurinol or anticonvulsants may have a pustular morphology (Figure 2), which is distinguished from acute generalized exanthematous pustulosis by its delayed onset, more severe visceral involvement, and prolonged course.¹¹

ct102005322_fig1.png

ct102005322_fig2.png

Another reported variant demonstrates overlapping features between Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS syndrome. It may present with mucositis, atypical targetoid lesions, and vesiculobullous lesions.¹² It is unclear whether this reported variant is indeed a true subtype of DRESS syndrome, as Stevens-Johnson syndrome/toxic epidermal necrolysis may present with systemic symptoms, lymphadenopathy, hepatic, renal, and pulmonary complications, among other systemic disturbances.¹²

Pearl: Facial edema noted during physical examination is an important clue of DRESS syndrome.

Perhaps the most helpful findings in the diagnosis of DRESS syndrome are facial edema and anasarca (Figure 3), as facial edema is not a usual finding in sepsis. Facial edema can be severe enough that the patient’s features are dramatically altered. It may be useful to ask family members if the patient’s face appears swollen or to compare the current appearance to the patient’s driver’s license photograph. An important complication to note is laryngeal edema, which may complicate airway management and may manifest as respiratory distress, stridor, and the need for emergent intubation.¹³

ct102005322_fig3.png

Myth: Patients who have had an allergic reaction to sulfonamide antibiotics will have a cross-reaction to nonantibiotic sulfonamides.

A common question is, if a patient has had a prior allergy to sulfonamide antibiotics, then are nonantibiotic sulfones such as a sulfonylurea, thiazide diuretic, or furosemide likely to cause a a cross-reaction? In one study (N=969), only 9.9% of patients with a prior sulfone antibiotic allergy developed hypersensitivity when exposed to a nonantibiotic sulfone, which is thought to be due to an overall increased propensity for hypersensitivity rather than a true cross-reaction. In fact, the risk for developing a hypersensitivity reaction to penicillin (14.0% [717/5115]) was higher than the risk for developing a reaction from a nonantibiotic sulfone among these patients.¹⁴ This study bolsters the argument that if there are other potential culprit medications and the time course for a patient’s nonantibiotic sulfone is not consistent with the timeline for DRESS syndrome, it may be beneficial to look for a different causative agent.

Pearl: Vancomycin is an important cause of DRESS syndrome.

Guidelines for treating endocarditis and osteomyelitis caused by methicillin-resistant Staphylococcus aureus infection recommend intravenous vancomycin for 4 to 6 weeks.¹⁵ This duration is within the relevant time frame of exposure for the development of DRESS syndrome de novo.

One case series noted that 37.5% (12/32) of DRESS syndrome cases in a 3-year period were caused by vancomycin, which notably was the most common medication associated with DRESS syndrome.¹⁶ There were caveats to this case series in that no standardized drug causality score was used and the sample size over the 3-year period was small; however, the increased use (and misuse) of antibiotics and perhaps increased recognition of rash in outpatient parenteral antibiotic therapy clinics may play a role if vancomycin-induced DRESS syndrome is indeed becoming more common.

Myth: Myocarditis secondary to DRESS syndrome will present with chest pain at the time of the cutaneous eruption.

Few patients with DRESS syndrome–associated myocarditis actually are symptomatic during their hospitalization.⁴ In asymptomatic patients, the primary team and consultants should be vigilant for the potential of subclinical myocarditis or the possibility of developing cardiac involvement after discharge, as myocarditis secondary to DRESS syndrome may present any time from rash onset up to 4 months later.⁴ Therefore, DRESS patients should be especially attentive to any new cardiac symptoms and notify their provider if any develop.

Although no standard cardiac screening guidelines exist for DRESS syndrome, some have recommended that baseline cardiac screening tests including electrocardiogram, troponin levels, and echocardiogram be considered at the time of diagnosis.⁵ If any testing is abnormal, DRESS syndrome–associated myocarditis should be suspected and an endomyocardial biopsy, which is the diagnostic gold standard, may be necessary.⁴ If the cardiac screening tests are normal, some investigators recommend serial outpatient echocardiograms for all DRESS patients, even those who remain asymptomatic.¹⁷ An alternative is an empiric approach in which a thorough review of systems is performed and testing is done if patients develop symptoms that are concerning for myocarditis.

Pearl: Steroids are not the only treatment used to control DRESS syndrome.

A prolonged taper of systemic steroids is the first-line treatment of DRESS syndrome. Steroids at the equivalent of 1 to 2 mg/kg daily (once or divided into 2 doses) of prednisone typically are used. For severe and/or recalcitrant DRESS syndrome, 2 mg/kg daily (once or divided into 2 doses) typically is used, and less than 1 mg/kg daily may be used for mini-DRESS syndrome.

Clinical improvement of DRESS syndrome has been demonstrated in several case reports with intravenous immunoglobulin, cyclosporine, cyclophosphamide, mycophenolate mofetil, and plasmapheresis.^18-21 Each of these therapies typically were initiated as second-line therapeutic agents when initial treatment with steroids failed. It is important to note that large prospective studies regarding these treatments are lacking; however, there have been case reports of acute necrotizing eosinophilic myocarditis that did not respond to the combination of steroids and cyclosporine.^4,22

Although there have been successful case reports using intravenous immunoglobulin, a 2012 prospective open-label clinical trial reported notable side effects in 5 of 6 (83.3%) patients with only 1 of 6 (16.6%) achieving the primary end point of control of fever/symptoms at day 7 and clinical remission without steroids on day 30.²³

Pearl: DRESS patients need to be monitored for long-term sequelae such as autoimmune disease.

Several autoimmune conditions may develop as a delayed complication of DRESS syndrome, including autoimmune thyroiditis, systemic lupus erythematosus, type 1 diabetes mellitus, and autoimmune hemolytic anemia.^24-26 Incidence rates of autoimmunity following DRESS syndrome range from 3% to 5% among small case series.^24,25

Autoimmune thyroiditis, which may present as Graves disease, Hashimoto thyroiditis, or painless thyroiditis, is the most common autoimmune disorder to develop in DRESS patients and appears from several weeks to up to 3 years after DRESS.²⁴ Therefore, all DRESS patients should be monitored longitudinally for several years for signs or symptoms suggestive of an autoimmune condition.^5,24,26

Because no guidelines exist regarding serial monitoring for autoimmune sequelae, it may be reasonable to check thyroid function tests at the time of diagnosis and regularly for at least 2 years after diagnosis.⁵ Alternatively, clinicians may consider an empiric approach to laboratory testing that is guided by the development of clinical symptoms.

Pearl: Small cases series suggest differences between adult and pediatric DRESS syndrome, but there are no large studies in children.

Small case series have suggested there may be noteworthy differences between DRESS syndrome in adults and children. Although human herpesvirus 6 (HHV-6) positivity in DRESS syndrome in adults may be as high as 80%, 13% of pediatric patients in one cohort tested positive for HHV-6, though the study size was limited at 29 total patients.²⁷ In children, DRESS syndrome secondary to antibiotics was associated with a shorter latency time as compared to cases secondary to nonantibiotics. In contrast to the typical 2- to 6-week timeline, Sasidharanpillai et al²⁸ reported an average onset 5.8 days after drug administration in antibiotic-associated DRESS syndrome compared to 23.9 days for anticonvulsants, though this study only included 11 total patients. Other reports have suggested a similar trend.²⁷

The role of HHV-6 positivity in pediatric DRESS syndrome and its influence on prognosis remains unclear. One study showed a worse prognosis for pediatric patients with positive HHV-6 antibodies.²⁷ However, with such a small sample size—only 4 HHV-6–positive patients of 29 pediatric DRESS cases—larger studies are needed to better characterize the relationship between HHV-6 positivity and prognosis.