Elish D

Seborrheic dermatitis (SD) is one of the most common dermatoses of infancy. SD is an inflammatory process that presents as tiny papules covered by scales typically localized to the seborrheic region. We report a case of a 2-month-old infant with SD who went on to develop atopic dermatitis (AD). Additionally, we discuss epidemiology, etiology, diagnosis, differential diagnosis, and treatment modalities for SD, as well as an association of SD and AD.

Case Report

A 2-month-old white infant presented with diffuse hyperkeratosis of the scalp of 2 weeks' duration. He also had fine macerated erythema of the retroauricular area, neck, axillae, and groin. These lesions were consistent with a clinical diagnosis of infantile seborrheic dermatitis (ISD). Application of mineral oil to the scalp resulted in softening and improvement of scalp lesions. The body lesions were ameliorated by the application of a mixture of hydrocortisone and nystatin creams to the neck, axillae, and groin. The lesions recurred, requiring periodic reapplication of the medicaments. Eventually, the lesions occurred less frequently and the scalp lesions resolved completely over the next 2 months. However, the patient developed typical atopic dermatitis (AD) as a 6-month-old, typified by erythematous excoriated plaques in the antecubital and popliteal regions. 

Comment
SD was first described by Unna in 1887.1 SD is a common chronic inflammatory disease characterized by erythema accompanied by greasy scales in the so-called seborrheic region, which includes the scalp, forehead/glabella, eyebrows, malar eminences, paranasal and nasolabial folds, retroauricular area, chest, and axillae. SD occurs most frequently in infants and adults aged 30 to 60 years. Its prevalence in immunocompetent adults is estimated to be between 1% and 3%.2 The incidence of SD is unusually high among patients with AIDS, ranging from 30% to 83%.2-4 There also is an increased incidence of SD in patients with tinea versicolor, depression, spinal cord injuries, and parkinsonism, and in patients receiving psoralen and UVA therapy.5-9 SD usually develops in neonates within the first 3 to 4 weeks of life. Spontaneous recovery generally occurs at about 6 to 7 months of age, though persistence until 2 years of age can be seen. SD in adults affects men more often than women; ISD shows no gender predilection. The occurrence of SD in prepubertal children (aged 2–5 years) is uncommon. The etiology of SD is poorly understood. SD may be hormonally dependent, which could explain why the condition appears briefly in infancy and recurs in puberty. The role of sebum excretion in the pathogenesis of SD is controversial. In fact, sebum excretion has been shown to be either normal or subnormal in many patients with SD.10,11 Commensal yeast Malassezia also has been thought to be causative.12 The response of SD to topical antifungal agents such as ketoconazole and selenium sulfide indicates that Malassezia yeast may be pathogenic. Research suggests that SD is not caused by an overgrowth of Malassezia but an abnormal host response.12 The evidence supporting this theory lies in the increased incidence of SD in immunocompromised patients. In a study of fatty acids in the serum of infants with ISD, Tollesson et al13 demonstrated evidence of impaired function of the enzyme -6-desaturase, which desaturates linoleic acid to dihomogammalinolenic and arachidonic acids. The study indicated the function of the enzyme appeared to normalize in the infants by about 6 to 7 months of age, the age at which spontaneous recovery from ISD usually occurs.13 ISD is a self-limited process that usually involves the scalp. The scalp lesions can present as small dry patches of hyperkeratosis overlying mildly erythematous skin that may become so thickened that it forms a cap, meriting its description as cradle cap (Figure).14 Scalp hyperkeratosis often is the only manifestation of ISD and usually appears 3 or 4 weeks after birth.15,16 The scales may be white, off-white, or yellowish. The central part of the face; forehead; neck; ears; and intertriginous areas such as the axillae, groin, and inner thigh folds, also may be involved. SD begins as erythematous macules and papules that gradually become confluent to form scaly patches and slightly elevated plaques.15,16 In adolescents, SD has a clinical picture similar to ISD but is focused in the head and neck region.

The diagnosis of ISD usually is straightforward and is based on clinical findings about the distribution and appearance of the lesions. However, failure to respond to therapy must lead clinicians to reconsider the diagnosis.15 ISD must be differentiated from AD, psoriasis, and tinea capitis. ISD and AD have similar sites of predilection including the face, scalp, retroauricular area, diaper area, and extensor limb surfaces. The distinction is made on clinical grounds. Axillary and anterior neck involvement favors the diagnosis of ISD, as do the lack of evidence of pruritus and the absence of oozing and weeping. Infants with AD tend to be aged 3 to 12 months and usually have at least one parent or sibling with a positive history of atopy. Sometimes, however, overlap of ISD and AD can be seen, particularly in infants aged 2 to 6 months.15,16 Our patient went on to develop AD. The relationship between ISD and infantile AD (IAD) is controversial. According to some authors, more than 50% of children with widespread ISD have or will develop AD.17 Conversely, Moises-Alfaro et al¹⁸ conducted a small and not as convincing study that led them to conclude that there is no relationship between ISD and IAD. Our patient supports the association of IAD and ISD. Recent studies have demonstrated that patients with head and neck AD have immunoglobulin E antibodies to Malassezia furfur, the yeast causative of ISD. This supports the overlap and possible progression between IAD and ISD through sensitization to cutaneous Malassezia. Inflammatory reaction to Malassezia (ie, ISD) may be the inciting event in the development of IAD, though this has not been proven so far in children.19,20 Occasionally, psoriasis has predilection for seborrheic areas (inverse psoriasis), making it difficult to clinically decide whether the patient has psoriasis or SD; however, psoriasis is more sharply demarcated.21 Rarely, both appear concurrently. In rare cases, infants are affected with a scaling eruption resembling ISD on the scalp in association with fever and other systemic signs of acute disseminated Langerhans cell histiocytosis.15 Persistent erythematous scaling (especially if hemorrhagic and therapy resistant) in an infant who is doing poorly or has hepatosplenomegaly requires a biopsy to exclude Langerhans cell histiocytosis. Severe treatment-resistant SD may be associated with human immunodeficiency virus infection and is common in infants who develop human immunodeficiency virus—related immune suppression in the first year of life.^22-24 As the immune deficiency in these patients becomes progressively worse, so does SD. SD occasionally progresses to erythroderma, a cradle cap of scales sometimes associated with nonscarring alopecia or postinflammatory hyperpigmentation or hypopigmentation.15 In prepubertal children, AD or tinea capitis are more likely diagnoses for hyperkeratotic scalp lesions than SD; therefore, tinea capitis must be excluded by a fungal culture of the scalp.25,26 When SD is diagnosed in a prepubertal child, precocious puberty should be suspected. However, AD is a more likely diagnosis for scalp hyperkeratosis, but it is not impossible to see SD in prepubertal children.27 In most instances, the diagnosis of SD is clinically obvious. When the diagnosis is not so obvious, a biopsy may be necessary to differentiate SD from other skin diseases by histologic examination. Sections of tissue of the biopsy specimens show characteristic changes, namely superficial perivascular and interstitial infiltrates of lymphocytes, slight spongiosis, scale crusts and mounds of parakeratosis that reside at the lips of infundibular ostia and at interinfundibular sites, markedly dilated venules and capillaries of the superficial plexus, and psoriasiform hyperplasia in more long-standing lesions of SD.21,28 

Therapy Therapy for SD is based on the age of the patient and the extent of the disease. The usual therapeutic approach for ISD of the scalp is conservative. In mild cases, an emollient such as white petrolatum or mineral oil may be used to soften the cradle cap so that it can be gently removed by brushing off the scales.14,15 Crusts are soaked overnight with slightly warmed oil and washed off in the morning. A mild nonmedicated shampoo should be used at the start of therapy in conjunction with brushing off scales with a baby's toothbrush. If a mild shampoo is not helpful, a shampoo containing ketoconazole 2% can be used.14,29 Coal tar—based shampoos must be avoided because of the carcinogenicity of coal tar.30 Mild topical corticosteroid lotions can be used adjunctively to reduce erythema of the scalp. Salicylic acid shampoos are contraindicated in ISD because of concerns about percutaneous absorption of the substance and the risk of metabolic acidosis and salicylism.31 ISD involving intertriginous areas is treated with gentle skin care and topical medicaments. Topical ketoconazole or nystatin are safe and effective therapies, particularly when combined with a mild topical corticosteroid.32 Topical tacrolimus ointment or pimecrolimus cream can be substituted for a topical corticosteroid; however, the use of tacrolimus and pimecrolimus is off-label and should not be used in children younger than 2 years, according to the US Food and Drug Administration.33 Calcineurin inhibitors are used in topical corticosteroid—resistant AD patients 2 years and older. Similar guidelines are prudent for SD therapy. Recently, the US Food and Drug Administration issued a warning regarding a biologic potential for skin cancers and lymphomas with the use of topical calcineurin inhibitors; however, human data have not supported these risks.33 Adolescents with SD should be treated similar to adults. Because SD is chronic, the initial therapy for the condition should be followed by a maintenance regimen. Conventional therapy for SD of the scalp is the use of a medicated shampoo 2 to 3 times per week. Shampoos containing salicylic acid, selenium sulfide, an antifungal agent, or zinc pyrithione are effective.15 In more severe cases, a topical corticosteroid in a lotion, oil, or solution base may be used once or twice daily, often in addition to a medicated shampoo. Seborrheic blepharitis is managed by the gentle removal of scales and crusts using a cotton ball dipped in diluted baby shampoo.15 In severe cases involving the eyelids, the eyelids may be covered with sodium sulfacetamide 10% solution or ketoconazole 2% cream.14,15 In our experience, nonsteroidal anti-inflammatory preparations, such as tacrolimus ointment and pimecrolimus cream, also can be used safely on the eyelids in children under the same guidelines as other cutaneous application sites. 

Conclusion

In summary, a number of factors such as immune function and heredity are important in the pathogenesis of SD. The role of Malassezia in SD needs to be clarified. In most instances, SD is easily diagnosed on clinical grounds alone. Safe and effective treatment modalities are available. More studies are needed to determine whether a relationship between SD and AD exists; however, our clinical experience supports this associator. 

Seborrheic dermatitis (SD) is one of the most common dermatoses of infancy. SD is an inflammatory process that presents as tiny papules covered by scales typically localized to the seborrheic region. We report a case of a 2-month-old infant with SD who went on to develop atopic dermatitis (AD). Additionally, we discuss epidemiology, etiology, diagnosis, differential diagnosis, and treatment modalities for SD, as well as an association of SD and AD.

Case Report

A 2-month-old white infant presented with diffuse hyperkeratosis of the scalp of 2 weeks' duration. He also had fine macerated erythema of the retroauricular area, neck, axillae, and groin. These lesions were consistent with a clinical diagnosis of infantile seborrheic dermatitis (ISD). Application of mineral oil to the scalp resulted in softening and improvement of scalp lesions. The body lesions were ameliorated by the application of a mixture of hydrocortisone and nystatin creams to the neck, axillae, and groin. The lesions recurred, requiring periodic reapplication of the medicaments. Eventually, the lesions occurred less frequently and the scalp lesions resolved completely over the next 2 months. However, the patient developed typical atopic dermatitis (AD) as a 6-month-old, typified by erythematous excoriated plaques in the antecubital and popliteal regions. 

Comment
SD was first described by Unna in 1887.1 SD is a common chronic inflammatory disease characterized by erythema accompanied by greasy scales in the so-called seborrheic region, which includes the scalp, forehead/glabella, eyebrows, malar eminences, paranasal and nasolabial folds, retroauricular area, chest, and axillae. SD occurs most frequently in infants and adults aged 30 to 60 years. Its prevalence in immunocompetent adults is estimated to be between 1% and 3%.2 The incidence of SD is unusually high among patients with AIDS, ranging from 30% to 83%.2-4 There also is an increased incidence of SD in patients with tinea versicolor, depression, spinal cord injuries, and parkinsonism, and in patients receiving psoralen and UVA therapy.5-9 SD usually develops in neonates within the first 3 to 4 weeks of life. Spontaneous recovery generally occurs at about 6 to 7 months of age, though persistence until 2 years of age can be seen. SD in adults affects men more often than women; ISD shows no gender predilection. The occurrence of SD in prepubertal children (aged 2–5 years) is uncommon. The etiology of SD is poorly understood. SD may be hormonally dependent, which could explain why the condition appears briefly in infancy and recurs in puberty. The role of sebum excretion in the pathogenesis of SD is controversial. In fact, sebum excretion has been shown to be either normal or subnormal in many patients with SD.10,11 Commensal yeast Malassezia also has been thought to be causative.12 The response of SD to topical antifungal agents such as ketoconazole and selenium sulfide indicates that Malassezia yeast may be pathogenic. Research suggests that SD is not caused by an overgrowth of Malassezia but an abnormal host response.12 The evidence supporting this theory lies in the increased incidence of SD in immunocompromised patients. In a study of fatty acids in the serum of infants with ISD, Tollesson et al13 demonstrated evidence of impaired function of the enzyme -6-desaturase, which desaturates linoleic acid to dihomogammalinolenic and arachidonic acids. The study indicated the function of the enzyme appeared to normalize in the infants by about 6 to 7 months of age, the age at which spontaneous recovery from ISD usually occurs.13 ISD is a self-limited process that usually involves the scalp. The scalp lesions can present as small dry patches of hyperkeratosis overlying mildly erythematous skin that may become so thickened that it forms a cap, meriting its description as cradle cap (Figure).14 Scalp hyperkeratosis often is the only manifestation of ISD and usually appears 3 or 4 weeks after birth.15,16 The scales may be white, off-white, or yellowish. The central part of the face; forehead; neck; ears; and intertriginous areas such as the axillae, groin, and inner thigh folds, also may be involved. SD begins as erythematous macules and papules that gradually become confluent to form scaly patches and slightly elevated plaques.15,16 In adolescents, SD has a clinical picture similar to ISD but is focused in the head and neck region.

The diagnosis of ISD usually is straightforward and is based on clinical findings about the distribution and appearance of the lesions. However, failure to respond to therapy must lead clinicians to reconsider the diagnosis.15 ISD must be differentiated from AD, psoriasis, and tinea capitis. ISD and AD have similar sites of predilection including the face, scalp, retroauricular area, diaper area, and extensor limb surfaces. The distinction is made on clinical grounds. Axillary and anterior neck involvement favors the diagnosis of ISD, as do the lack of evidence of pruritus and the absence of oozing and weeping. Infants with AD tend to be aged 3 to 12 months and usually have at least one parent or sibling with a positive history of atopy. Sometimes, however, overlap of ISD and AD can be seen, particularly in infants aged 2 to 6 months.15,16 Our patient went on to develop AD. The relationship between ISD and infantile AD (IAD) is controversial. According to some authors, more than 50% of children with widespread ISD have or will develop AD.17 Conversely, Moises-Alfaro et al¹⁸ conducted a small and not as convincing study that led them to conclude that there is no relationship between ISD and IAD. Our patient supports the association of IAD and ISD. Recent studies have demonstrated that patients with head and neck AD have immunoglobulin E antibodies to Malassezia furfur, the yeast causative of ISD. This supports the overlap and possible progression between IAD and ISD through sensitization to cutaneous Malassezia. Inflammatory reaction to Malassezia (ie, ISD) may be the inciting event in the development of IAD, though this has not been proven so far in children.19,20 Occasionally, psoriasis has predilection for seborrheic areas (inverse psoriasis), making it difficult to clinically decide whether the patient has psoriasis or SD; however, psoriasis is more sharply demarcated.21 Rarely, both appear concurrently. In rare cases, infants are affected with a scaling eruption resembling ISD on the scalp in association with fever and other systemic signs of acute disseminated Langerhans cell histiocytosis.15 Persistent erythematous scaling (especially if hemorrhagic and therapy resistant) in an infant who is doing poorly or has hepatosplenomegaly requires a biopsy to exclude Langerhans cell histiocytosis. Severe treatment-resistant SD may be associated with human immunodeficiency virus infection and is common in infants who develop human immunodeficiency virus—related immune suppression in the first year of life.^22-24 As the immune deficiency in these patients becomes progressively worse, so does SD. SD occasionally progresses to erythroderma, a cradle cap of scales sometimes associated with nonscarring alopecia or postinflammatory hyperpigmentation or hypopigmentation.15 In prepubertal children, AD or tinea capitis are more likely diagnoses for hyperkeratotic scalp lesions than SD; therefore, tinea capitis must be excluded by a fungal culture of the scalp.25,26 When SD is diagnosed in a prepubertal child, precocious puberty should be suspected. However, AD is a more likely diagnosis for scalp hyperkeratosis, but it is not impossible to see SD in prepubertal children.27 In most instances, the diagnosis of SD is clinically obvious. When the diagnosis is not so obvious, a biopsy may be necessary to differentiate SD from other skin diseases by histologic examination. Sections of tissue of the biopsy specimens show characteristic changes, namely superficial perivascular and interstitial infiltrates of lymphocytes, slight spongiosis, scale crusts and mounds of parakeratosis that reside at the lips of infundibular ostia and at interinfundibular sites, markedly dilated venules and capillaries of the superficial plexus, and psoriasiform hyperplasia in more long-standing lesions of SD.21,28 

Therapy Therapy for SD is based on the age of the patient and the extent of the disease. The usual therapeutic approach for ISD of the scalp is conservative. In mild cases, an emollient such as white petrolatum or mineral oil may be used to soften the cradle cap so that it can be gently removed by brushing off the scales.14,15 Crusts are soaked overnight with slightly warmed oil and washed off in the morning. A mild nonmedicated shampoo should be used at the start of therapy in conjunction with brushing off scales with a baby's toothbrush. If a mild shampoo is not helpful, a shampoo containing ketoconazole 2% can be used.14,29 Coal tar—based shampoos must be avoided because of the carcinogenicity of coal tar.30 Mild topical corticosteroid lotions can be used adjunctively to reduce erythema of the scalp. Salicylic acid shampoos are contraindicated in ISD because of concerns about percutaneous absorption of the substance and the risk of metabolic acidosis and salicylism.31 ISD involving intertriginous areas is treated with gentle skin care and topical medicaments. Topical ketoconazole or nystatin are safe and effective therapies, particularly when combined with a mild topical corticosteroid.32 Topical tacrolimus ointment or pimecrolimus cream can be substituted for a topical corticosteroid; however, the use of tacrolimus and pimecrolimus is off-label and should not be used in children younger than 2 years, according to the US Food and Drug Administration.33 Calcineurin inhibitors are used in topical corticosteroid—resistant AD patients 2 years and older. Similar guidelines are prudent for SD therapy. Recently, the US Food and Drug Administration issued a warning regarding a biologic potential for skin cancers and lymphomas with the use of topical calcineurin inhibitors; however, human data have not supported these risks.33 Adolescents with SD should be treated similar to adults. Because SD is chronic, the initial therapy for the condition should be followed by a maintenance regimen. Conventional therapy for SD of the scalp is the use of a medicated shampoo 2 to 3 times per week. Shampoos containing salicylic acid, selenium sulfide, an antifungal agent, or zinc pyrithione are effective.15 In more severe cases, a topical corticosteroid in a lotion, oil, or solution base may be used once or twice daily, often in addition to a medicated shampoo. Seborrheic blepharitis is managed by the gentle removal of scales and crusts using a cotton ball dipped in diluted baby shampoo.15 In severe cases involving the eyelids, the eyelids may be covered with sodium sulfacetamide 10% solution or ketoconazole 2% cream.14,15 In our experience, nonsteroidal anti-inflammatory preparations, such as tacrolimus ointment and pimecrolimus cream, also can be used safely on the eyelids in children under the same guidelines as other cutaneous application sites. 

Conclusion

In summary, a number of factors such as immune function and heredity are important in the pathogenesis of SD. The role of Malassezia in SD needs to be clarified. In most instances, SD is easily diagnosed on clinical grounds alone. Safe and effective treatment modalities are available. More studies are needed to determine whether a relationship between SD and AD exists; however, our clinical experience supports this associator. 

Seborrheic dermatitis (SD) is one of the most common dermatoses of infancy. SD is an inflammatory process that presents as tiny papules covered by scales typically localized to the seborrheic region. We report a case of a 2-month-old infant with SD who went on to develop atopic dermatitis (AD). Additionally, we discuss epidemiology, etiology, diagnosis, differential diagnosis, and treatment modalities for SD, as well as an association of SD and AD.

Case Report

A 2-month-old white infant presented with diffuse hyperkeratosis of the scalp of 2 weeks' duration. He also had fine macerated erythema of the retroauricular area, neck, axillae, and groin. These lesions were consistent with a clinical diagnosis of infantile seborrheic dermatitis (ISD). Application of mineral oil to the scalp resulted in softening and improvement of scalp lesions. The body lesions were ameliorated by the application of a mixture of hydrocortisone and nystatin creams to the neck, axillae, and groin. The lesions recurred, requiring periodic reapplication of the medicaments. Eventually, the lesions occurred less frequently and the scalp lesions resolved completely over the next 2 months. However, the patient developed typical atopic dermatitis (AD) as a 6-month-old, typified by erythematous excoriated plaques in the antecubital and popliteal regions. 

Comment
SD was first described by Unna in 1887.1 SD is a common chronic inflammatory disease characterized by erythema accompanied by greasy scales in the so-called seborrheic region, which includes the scalp, forehead/glabella, eyebrows, malar eminences, paranasal and nasolabial folds, retroauricular area, chest, and axillae. SD occurs most frequently in infants and adults aged 30 to 60 years. Its prevalence in immunocompetent adults is estimated to be between 1% and 3%.2 The incidence of SD is unusually high among patients with AIDS, ranging from 30% to 83%.2-4 There also is an increased incidence of SD in patients with tinea versicolor, depression, spinal cord injuries, and parkinsonism, and in patients receiving psoralen and UVA therapy.5-9 SD usually develops in neonates within the first 3 to 4 weeks of life. Spontaneous recovery generally occurs at about 6 to 7 months of age, though persistence until 2 years of age can be seen. SD in adults affects men more often than women; ISD shows no gender predilection. The occurrence of SD in prepubertal children (aged 2–5 years) is uncommon. The etiology of SD is poorly understood. SD may be hormonally dependent, which could explain why the condition appears briefly in infancy and recurs in puberty. The role of sebum excretion in the pathogenesis of SD is controversial. In fact, sebum excretion has been shown to be either normal or subnormal in many patients with SD.10,11 Commensal yeast Malassezia also has been thought to be causative.12 The response of SD to topical antifungal agents such as ketoconazole and selenium sulfide indicates that Malassezia yeast may be pathogenic. Research suggests that SD is not caused by an overgrowth of Malassezia but an abnormal host response.12 The evidence supporting this theory lies in the increased incidence of SD in immunocompromised patients. In a study of fatty acids in the serum of infants with ISD, Tollesson et al13 demonstrated evidence of impaired function of the enzyme -6-desaturase, which desaturates linoleic acid to dihomogammalinolenic and arachidonic acids. The study indicated the function of the enzyme appeared to normalize in the infants by about 6 to 7 months of age, the age at which spontaneous recovery from ISD usually occurs.13 ISD is a self-limited process that usually involves the scalp. The scalp lesions can present as small dry patches of hyperkeratosis overlying mildly erythematous skin that may become so thickened that it forms a cap, meriting its description as cradle cap (Figure).14 Scalp hyperkeratosis often is the only manifestation of ISD and usually appears 3 or 4 weeks after birth.15,16 The scales may be white, off-white, or yellowish. The central part of the face; forehead; neck; ears; and intertriginous areas such as the axillae, groin, and inner thigh folds, also may be involved. SD begins as erythematous macules and papules that gradually become confluent to form scaly patches and slightly elevated plaques.15,16 In adolescents, SD has a clinical picture similar to ISD but is focused in the head and neck region.

The diagnosis of ISD usually is straightforward and is based on clinical findings about the distribution and appearance of the lesions. However, failure to respond to therapy must lead clinicians to reconsider the diagnosis.15 ISD must be differentiated from AD, psoriasis, and tinea capitis. ISD and AD have similar sites of predilection including the face, scalp, retroauricular area, diaper area, and extensor limb surfaces. The distinction is made on clinical grounds. Axillary and anterior neck involvement favors the diagnosis of ISD, as do the lack of evidence of pruritus and the absence of oozing and weeping. Infants with AD tend to be aged 3 to 12 months and usually have at least one parent or sibling with a positive history of atopy. Sometimes, however, overlap of ISD and AD can be seen, particularly in infants aged 2 to 6 months.15,16 Our patient went on to develop AD. The relationship between ISD and infantile AD (IAD) is controversial. According to some authors, more than 50% of children with widespread ISD have or will develop AD.17 Conversely, Moises-Alfaro et al¹⁸ conducted a small and not as convincing study that led them to conclude that there is no relationship between ISD and IAD. Our patient supports the association of IAD and ISD. Recent studies have demonstrated that patients with head and neck AD have immunoglobulin E antibodies to Malassezia furfur, the yeast causative of ISD. This supports the overlap and possible progression between IAD and ISD through sensitization to cutaneous Malassezia. Inflammatory reaction to Malassezia (ie, ISD) may be the inciting event in the development of IAD, though this has not been proven so far in children.19,20 Occasionally, psoriasis has predilection for seborrheic areas (inverse psoriasis), making it difficult to clinically decide whether the patient has psoriasis or SD; however, psoriasis is more sharply demarcated.21 Rarely, both appear concurrently. In rare cases, infants are affected with a scaling eruption resembling ISD on the scalp in association with fever and other systemic signs of acute disseminated Langerhans cell histiocytosis.15 Persistent erythematous scaling (especially if hemorrhagic and therapy resistant) in an infant who is doing poorly or has hepatosplenomegaly requires a biopsy to exclude Langerhans cell histiocytosis. Severe treatment-resistant SD may be associated with human immunodeficiency virus infection and is common in infants who develop human immunodeficiency virus—related immune suppression in the first year of life.^22-24 As the immune deficiency in these patients becomes progressively worse, so does SD. SD occasionally progresses to erythroderma, a cradle cap of scales sometimes associated with nonscarring alopecia or postinflammatory hyperpigmentation or hypopigmentation.15 In prepubertal children, AD or tinea capitis are more likely diagnoses for hyperkeratotic scalp lesions than SD; therefore, tinea capitis must be excluded by a fungal culture of the scalp.25,26 When SD is diagnosed in a prepubertal child, precocious puberty should be suspected. However, AD is a more likely diagnosis for scalp hyperkeratosis, but it is not impossible to see SD in prepubertal children.27 In most instances, the diagnosis of SD is clinically obvious. When the diagnosis is not so obvious, a biopsy may be necessary to differentiate SD from other skin diseases by histologic examination. Sections of tissue of the biopsy specimens show characteristic changes, namely superficial perivascular and interstitial infiltrates of lymphocytes, slight spongiosis, scale crusts and mounds of parakeratosis that reside at the lips of infundibular ostia and at interinfundibular sites, markedly dilated venules and capillaries of the superficial plexus, and psoriasiform hyperplasia in more long-standing lesions of SD.21,28 

Therapy Therapy for SD is based on the age of the patient and the extent of the disease. The usual therapeutic approach for ISD of the scalp is conservative. In mild cases, an emollient such as white petrolatum or mineral oil may be used to soften the cradle cap so that it can be gently removed by brushing off the scales.14,15 Crusts are soaked overnight with slightly warmed oil and washed off in the morning. A mild nonmedicated shampoo should be used at the start of therapy in conjunction with brushing off scales with a baby's toothbrush. If a mild shampoo is not helpful, a shampoo containing ketoconazole 2% can be used.14,29 Coal tar—based shampoos must be avoided because of the carcinogenicity of coal tar.30 Mild topical corticosteroid lotions can be used adjunctively to reduce erythema of the scalp. Salicylic acid shampoos are contraindicated in ISD because of concerns about percutaneous absorption of the substance and the risk of metabolic acidosis and salicylism.31 ISD involving intertriginous areas is treated with gentle skin care and topical medicaments. Topical ketoconazole or nystatin are safe and effective therapies, particularly when combined with a mild topical corticosteroid.32 Topical tacrolimus ointment or pimecrolimus cream can be substituted for a topical corticosteroid; however, the use of tacrolimus and pimecrolimus is off-label and should not be used in children younger than 2 years, according to the US Food and Drug Administration.33 Calcineurin inhibitors are used in topical corticosteroid—resistant AD patients 2 years and older. Similar guidelines are prudent for SD therapy. Recently, the US Food and Drug Administration issued a warning regarding a biologic potential for skin cancers and lymphomas with the use of topical calcineurin inhibitors; however, human data have not supported these risks.33 Adolescents with SD should be treated similar to adults. Because SD is chronic, the initial therapy for the condition should be followed by a maintenance regimen. Conventional therapy for SD of the scalp is the use of a medicated shampoo 2 to 3 times per week. Shampoos containing salicylic acid, selenium sulfide, an antifungal agent, or zinc pyrithione are effective.15 In more severe cases, a topical corticosteroid in a lotion, oil, or solution base may be used once or twice daily, often in addition to a medicated shampoo. Seborrheic blepharitis is managed by the gentle removal of scales and crusts using a cotton ball dipped in diluted baby shampoo.15 In severe cases involving the eyelids, the eyelids may be covered with sodium sulfacetamide 10% solution or ketoconazole 2% cream.14,15 In our experience, nonsteroidal anti-inflammatory preparations, such as tacrolimus ointment and pimecrolimus cream, also can be used safely on the eyelids in children under the same guidelines as other cutaneous application sites. 

Conclusion

In summary, a number of factors such as immune function and heredity are important in the pathogenesis of SD. The role of Malassezia in SD needs to be clarified. In most instances, SD is easily diagnosed on clinical grounds alone. Safe and effective treatment modalities are available. More studies are needed to determine whether a relationship between SD and AD exists; however, our clinical experience supports this associator. 

Herpes labialis is a common condition characterized by recurrent vesicular eruptions primarily on the lips and perioral skin. Most commonly caused by herpes simplex virus type 1 (HSV-1), this condition can significantly affect quality of life in patients with multiple recurrences, which may cause pain, embarrassment, and psychosocial distress. Oral HSV is the most easily acquired herpesvirus. Approximately 50% of Americans are seropositive for HSV-1 by the time they reach adolescence—by age 50 years, 80% to 90% carry the virus.1 The first part of this series discussed oral antiviral agents in the treatment of herpes labialis. In the second part of this series, we review topical therapeutic agents that are available in the treatment of herpes labialis and its associated symptoms.

Topical Agents For many years, acyclovir ointment was the only topical agent available for herpes labialis. Over the last several years, many new topical therapies have been investigated, and 3 have been approved by the US Food and Drug Administration (FDA). Currently, the 4 approved topical treatments available for herpes labialis include acyclovir ointment and cream (Zovirax®), penciclovir cream (Denavir®), and n-docosanol cream (Abreva®)(Table).

Acyclovir—Acyclovir ointment, which was first brought to market in 1982, is of questionable value in the treatment of recurrent herpes labialis.2 Acyclovir cream, which appears to provide better absorption than the ointment, has been available in many countries outside the United States for more than a decade. To examine more comprehensively the safety and efficacy of this formulation, Spruance et al3 conducted 2 independent, identical, parallel, randomized, double-blind, vehicle-controlled, multicenter clinical trials (N=686 in study 1 and N=699 in study 2). Healthy adults with a history of recurrent herpes labialis were randomized to receive acyclovir cream 5% or vehicle control and asked to self-initiate treatment 5 times a day for 4 days starting within 1 hour of recurrence onset. The mean duration of episodes was significantly decreased in both studies (study 1: 4.3 vs 4.8 days in treated vs placebo, respectively; study 2: 4.6 vs 5.2 days in treated vs placebo, respectively)(P≤.05). In addition, lesion pain was reduced significantly for subjects in both studies, though acyclovir cream did not prevent the development of classic lesions.3

In another study, Biagioni and Lamey4 used infrared thermography to identify the prodromal stage of herpes labialis and treated the active area with acyclovir cream 5 times a day for 5 days. All patients (N=70) were evaluated at 72 hours thermographically and clinically, and localized increase in temperature over the symptomatic area was noted. The development of a clinical herpes lesion was prevented in 46% (32/70) of the patients. In the lesions that did develop (38/70), an 80% reduction in clinical lesion size was observed in 82% (31/38) of the subjects. The remaining 18% (7/38) of patients showed a reduction in healing time.4

In a recent publication, Seth et al5 reported the use of a novel liposomal acyclovir topical gel. In this study, 10 patients with recurrent, mild facial infection were subjected to double-blind clinical evaluation, using a 1% liposomal acyclovir topical gel in a 5% hydroxypropylmethyl cellulose K4M gel base. The efficacy of plain acyclovir gel and liposomal acyclovir gel was compared by application to herpetic lesions 5 times a day for up to 8 weeks. In patients treated with liposomal acyclovir gel, a significant increase in the average percentage improvement of lesion healing was observed after 2 to 3 weeks of therapy (P<.05).5

Topical acyclovir also has been evaluated in combination with a topical steroid. Evans and colleagues6 assessed the efficacy of a combination of acyclovir cream 5% and hydrocortisone cream 1% (ME-609) in treating experimentally UV radiation (UVR)–induced herpes labialis in patients with a history of recurrent herpes labialis. Starting on day 2, 380 subjects were randomized to receive ME-609 or vehicle control 6 times a day for 5 days. Fewer patients in the treatment arm developed delayed classic lesions. Statistically significant reductions in healing time (9.0 vs 10.1 days in treated and placebo groups, respectively; P=.04) and maximum lesion size (43 vs 60 mm in treated and placebo groups, respectively; P=.07) were noted in treated patients compared with patients given placebo. Overall, combination treatment with an antiviral and anti-inflammatory agent led to a reduction in the incidence of classic lesions, healing time, lesion size, and lesion tenderness.6

Penciclovir—Penciclovir, famciclovir’s active metabolite, is FDA approved for episodic treatment of herpes labialis. Topical penciclovir cream 1% applied every 2 hours for 4 days can decrease the duration of lesion healing, pain, and viral shedding, as evidenced by several studies, with some benefit in the early and late stages of lesion development.7-10 Penciclovir interferes with viral replication and significantly limits both the severity and duration of cold sores.

Spruance et al7 conducted a randomized, multicenter, double-blind, placebo-controlled, 2-arm, parallel trial to compare the safety and efficacy of penciclovir cream 1% with vehicle control cream in the treatment of recurrent herpes simplex labialis in immunocompetent patients. Treatment was self-initiated by the patient within the first hour of the first sign or symptom of a recurrence. A total of 2209 patients were enrolled and given study medication, 1573 of whom initiated treatment for a recurrence. Patients applied the medication every 2 hours during waking hours for 4 days. Healing of classic lesions was 0.7 days faster in penciclovir-treated patients compared with placebo-treated patients (median, 4.8 vs 5.5 days; P<.001). Reduction in duration of lesion pain was observed in penciclovir-treated patients compared with placebo-treated patients (median, 3.5 vs 4.1 days; P<.001). Lesion viral shedding also resolved faster in penciclovir-treated patients compared with those who received vehicle control cream (median, 3 vs 3 days; P=.003). Statistically significant reductions in time to healing and pain resolution occurred with topical penciclovir cream when treatment was initiated in the early (prodrome or erythema) stage or late (papule or vesicle) stage of the lesion.7

Boon et al8 evaluated the efficacy and tolerability of penciclovir cream versus placebo control (purified water) in treating sunlight-induced herpes labialis. Healthy patients (mean age, 38.3 years; range, 18–81 years) with a history of sunlight-induced herpes labialis self-initiated treatment with either penciclovir cream (n=266) or purified water (n=275) within one hour of development of the signs and symptoms of a recurrence.

A significant reduction in the time to lesion healing (P<.001), with a reduction in median time of up to 2 days, was noted. There was a significant reduction in maximum lesion area (P=.008), faster resolution of lesion-associated symptoms (P=.026), reduction in pain duration (P≤.040), itching (P≤.032), burning (P≤.028), and tenderness (P≤.026). The daily self-assessment of lesion attributes showed significantly fewer severe or extreme assessments of lesion size (P≤.003), noticeability (P≤.003), amount of scab or crust (P≤.003), raised or swollen area (P≤.040), soreness or tenderness (P≤.043), and overall severity (P≤.001) throughout the study.8

Recently, Raborn et al9 conducted 2 randomized, double-blind, parallel-group clinical trials to compare the efficacy and safety of topical penciclovir cream 1% for recurrent herpes labialis. Of the 4573 immunocompetent patients with a history of recurrent herpes simplex labialis (defined as 3 or more episodes per year) that were enrolled in the study, 3057 patients initiated treatment (1516 with penciclovir cream 1% and 1541 with placebo). Patients were instructed to apply medication 6 times a day for the first day and thereafter every 2 hours during waking hours for 4 consecutive days. In the treatment group, patients lost classic lesions 31% faster than did those in the placebo group and experienced 28% faster resolution of lesion pain. Significant benefits were achieved with penciclovir use whether treatment was initiated in the early stages (P=.001) or later stages (P=.0055) of the recurrence.9

Lin and associates10 compared the efficacy of topical penciclovir cream 1% versus acyclovir cream 3% in the treatment of herpes labialis. In a randomized, double-blind, multicenter trial, 248 patients with a history of herpes labialis were randomly allocated to 1 of the 2 treatment groups (n=124 each) to receive either penciclovir cream 1% or acyclovir cream 3%. Before treatment (day 0) and at every visit (days 3, 5, and 7), signs and symptoms scores were recorded by the same physician. Two hundred twenty-five patients completed the study. No significant differences were noted in efficacy, clinical cure rate, and safety between the 2 groups; however, a trend toward a shorter time to resolution of symptoms, cessation of new blisters, and loss of crust (P≤.008) was noted in penciclovir-treated patients compared with acyclovir-treated patients. In addition, signs and symptoms scores in penciclovir-treated patients were significantly lower than those in the acyclovir-treated patients on days 5 (P<.01) and 7 (P<.05), supporting the finding that topical penciclovir cream 1% is at least as convenient and effective as acyclovir cream 3% in the treatment of herpes labialis.10

A susceptibility program was established by Sarisky et al11 to assess the resistance profile for serial HSV isolates from immunocompetent patients with recurrent herpes labialis. The isolates were obtained throughout a 4-day treatment period with topical penciclovir cream 1% or placebo. Two isolates (2/1035; 0.19%), representing 0.34% of the patients (2/585), were confirmed to be penciclovir resistant. These were highly resistant to penciclovir (50% inhibiting concentration [IC50], >55 µg/mL) and were isolated less than 17 hours after the start of patient-initiated treatment. However, subsequent isolates on days 2 and 3 from the same patients were completely susceptible to penciclovir cream (IC50, <2.0 µg/mL). None of the patients were found to have penciclovir-resistant species at the end of acute treatment, regardless of treatment group. Overall, the prevalence of penciclovir resistance was found to be similar to that of acyclovir resistance (ie, 0.3%) reported in immunocompetent untreated populations.11

N-docosanol—Docosanol is a compound that inhibits herpes virus replication by blocking fusion of the viral envelope with the plasma membrane and can potentially limit both the duration and severity of herpes labialis.2 Presently, docosanol 10% cream is approved by the FDA as an over-the-counter agent for application 5 times a day during episodes of herpes labialis. In one small clinical trial with 63 patients, n-docosanol 10% cream significantly reduced the healing time of patients’ herpes labialis episodes compared with stearic acid–containing placebo cream.12 Application of n-docosanol 10% cream early in the prodrome or erythema stage of a recurrent episode of herpes labialis shortened mean healing time by approximately 3 days compared with late treatment with n-docosanol 10% cream and early or late treatment with the placebo. A subsequent larger study with 846 patients found no benefit.13 Because of a concern that the vehicle may have had a beneficial effect on herpes labialis and masked an effect by n-docosanol, a polyethylene glycol control preparation was created.14

With this new preparation, Sacks et al15 conducted studies to determine whether docosanol 10% cream is efficacious compared with placebo in the topical treatment of episodes of acute herpes simplex labialis. Two identical double-blind, placebo-controlled studies were conducted at a total of 21 sites. Otherwise healthy adults, with documented histories of herpes labialis, were randomized to receive either docosanol or polyethylene glycol placebo. Subjects were instructed to initiate therapy in the prodrome or erythema stage of an episode. Treatment was administered 5 times a day until healing occurred (ie, the crust fell off spontaneously, or there was no longer evidence of an active lesion) with twice-daily visits. The median time to healing in the 370 docosanol-treated patients was 4.1 days, 18 hours shorter than that observed in the 367 placebo-treated patients (P=.008). The docosanol group also exhibited reduced times from treatment initiation to (1) cessation of pain and all other symptoms (itching, burning, and/or tingling; P=.002), (2) complete healing of classic lesions (P=.023), and (3) cessation of the ulcer or soft-crust stage of classic lesions (P<.001). Aborted episodes were experienced in 40% of docosanol recipients versus 34% of placebo recipients (P=.109). Adverse experiences with docosanol were mild and similar to those with placebo. The authors concluded that docosanol applied 5 times a day is safe and effective in the treatment of recurrent herpes labialis.15

Because in vitro studies have shown that n-docosanol can enhance the antiviral activity of nucleoside analogs against the replication of herpesviruses, clinical studies of this combination will be of interest.2

Comparative Efficacy of Topical Treatments
McKeough and Spruance14 evaluated the comparative efficacy of penciclovir cream, acyclovir cream, n-docosanol cream, and acyclovir ointment in a guinea pig model of cutaneous HSV-1 disease. The backs of guinea pigs were infected with HSV-1 using a vaccination instrument. Active treatments and corresponding vehicle controls were applied for 3 to 5 days beginning 24 hours after inoculation. After completion of treatment, the animals were killed, and the severity of the infection was assessed from the number of lesions, total lesion area, and lesion virus titer.14

Penciclovir cream effected modest reductions in lesion number (19%), area (38%), and virus titer (88%) compared with its vehicle control, and each of these differences was significantly greater (P<.05) than the reductions effected by acyclovir ointment (0%, 21%, and 75%, respectively). The acyclovir cream effect (reductions of 4%, 28%, and 77%, respectively) was less than that of penciclovir cream, and this difference was confirmed by 2 additional head-to-head experiments. Two experiments with n-docosanol cream failed to show statistically significant differences by any parameter between n-docosanol cream and vehicle control-treated sites or between n-docosanol and untreated infection sites.14

In this model, the efficacy of penciclovir cream was greater than acyclovir cream, acyclovir cream was greater than or equal to acyclovir ointment, and acyclovir ointment was greater than n-docosanol cream. The authors noted that because their model was designed to evaluate compounds that function primarily through antiviral activity, the negative findings with n-docosanol in these studies do not exclude that it might work clinically through other mechanisms.14

Herpes labialis is a common condition characterized by recurrent vesicular eruptions primarily on the lips and perioral skin. Most commonly caused by herpes simplex virus type 1 (HSV-1), this condition can significantly affect quality of life in patients with multiple recurrences, which may cause pain, embarrassment, and psychosocial distress. Oral HSV is the most easily acquired herpesvirus. Approximately 50% of Americans are seropositive for HSV-1 by the time they reach adolescence—by age 50 years, 80% to 90% carry the virus.1 The first part of this series discussed oral antiviral agents in the treatment of herpes labialis. In the second part of this series, we review topical therapeutic agents that are available in the treatment of herpes labialis and its associated symptoms.

Topical Agents For many years, acyclovir ointment was the only topical agent available for herpes labialis. Over the last several years, many new topical therapies have been investigated, and 3 have been approved by the US Food and Drug Administration (FDA). Currently, the 4 approved topical treatments available for herpes labialis include acyclovir ointment and cream (Zovirax®), penciclovir cream (Denavir®), and n-docosanol cream (Abreva®)(Table).

Acyclovir—Acyclovir ointment, which was first brought to market in 1982, is of questionable value in the treatment of recurrent herpes labialis.2 Acyclovir cream, which appears to provide better absorption than the ointment, has been available in many countries outside the United States for more than a decade. To examine more comprehensively the safety and efficacy of this formulation, Spruance et al3 conducted 2 independent, identical, parallel, randomized, double-blind, vehicle-controlled, multicenter clinical trials (N=686 in study 1 and N=699 in study 2). Healthy adults with a history of recurrent herpes labialis were randomized to receive acyclovir cream 5% or vehicle control and asked to self-initiate treatment 5 times a day for 4 days starting within 1 hour of recurrence onset. The mean duration of episodes was significantly decreased in both studies (study 1: 4.3 vs 4.8 days in treated vs placebo, respectively; study 2: 4.6 vs 5.2 days in treated vs placebo, respectively)(P≤.05). In addition, lesion pain was reduced significantly for subjects in both studies, though acyclovir cream did not prevent the development of classic lesions.3

In another study, Biagioni and Lamey4 used infrared thermography to identify the prodromal stage of herpes labialis and treated the active area with acyclovir cream 5 times a day for 5 days. All patients (N=70) were evaluated at 72 hours thermographically and clinically, and localized increase in temperature over the symptomatic area was noted. The development of a clinical herpes lesion was prevented in 46% (32/70) of the patients. In the lesions that did develop (38/70), an 80% reduction in clinical lesion size was observed in 82% (31/38) of the subjects. The remaining 18% (7/38) of patients showed a reduction in healing time.4

In a recent publication, Seth et al5 reported the use of a novel liposomal acyclovir topical gel. In this study, 10 patients with recurrent, mild facial infection were subjected to double-blind clinical evaluation, using a 1% liposomal acyclovir topical gel in a 5% hydroxypropylmethyl cellulose K4M gel base. The efficacy of plain acyclovir gel and liposomal acyclovir gel was compared by application to herpetic lesions 5 times a day for up to 8 weeks. In patients treated with liposomal acyclovir gel, a significant increase in the average percentage improvement of lesion healing was observed after 2 to 3 weeks of therapy (P<.05).5

Topical acyclovir also has been evaluated in combination with a topical steroid. Evans and colleagues6 assessed the efficacy of a combination of acyclovir cream 5% and hydrocortisone cream 1% (ME-609) in treating experimentally UV radiation (UVR)–induced herpes labialis in patients with a history of recurrent herpes labialis. Starting on day 2, 380 subjects were randomized to receive ME-609 or vehicle control 6 times a day for 5 days. Fewer patients in the treatment arm developed delayed classic lesions. Statistically significant reductions in healing time (9.0 vs 10.1 days in treated and placebo groups, respectively; P=.04) and maximum lesion size (43 vs 60 mm in treated and placebo groups, respectively; P=.07) were noted in treated patients compared with patients given placebo. Overall, combination treatment with an antiviral and anti-inflammatory agent led to a reduction in the incidence of classic lesions, healing time, lesion size, and lesion tenderness.6

Penciclovir—Penciclovir, famciclovir’s active metabolite, is FDA approved for episodic treatment of herpes labialis. Topical penciclovir cream 1% applied every 2 hours for 4 days can decrease the duration of lesion healing, pain, and viral shedding, as evidenced by several studies, with some benefit in the early and late stages of lesion development.7-10 Penciclovir interferes with viral replication and significantly limits both the severity and duration of cold sores.

Spruance et al7 conducted a randomized, multicenter, double-blind, placebo-controlled, 2-arm, parallel trial to compare the safety and efficacy of penciclovir cream 1% with vehicle control cream in the treatment of recurrent herpes simplex labialis in immunocompetent patients. Treatment was self-initiated by the patient within the first hour of the first sign or symptom of a recurrence. A total of 2209 patients were enrolled and given study medication, 1573 of whom initiated treatment for a recurrence. Patients applied the medication every 2 hours during waking hours for 4 days. Healing of classic lesions was 0.7 days faster in penciclovir-treated patients compared with placebo-treated patients (median, 4.8 vs 5.5 days; P<.001). Reduction in duration of lesion pain was observed in penciclovir-treated patients compared with placebo-treated patients (median, 3.5 vs 4.1 days; P<.001). Lesion viral shedding also resolved faster in penciclovir-treated patients compared with those who received vehicle control cream (median, 3 vs 3 days; P=.003). Statistically significant reductions in time to healing and pain resolution occurred with topical penciclovir cream when treatment was initiated in the early (prodrome or erythema) stage or late (papule or vesicle) stage of the lesion.7

Boon et al8 evaluated the efficacy and tolerability of penciclovir cream versus placebo control (purified water) in treating sunlight-induced herpes labialis. Healthy patients (mean age, 38.3 years; range, 18–81 years) with a history of sunlight-induced herpes labialis self-initiated treatment with either penciclovir cream (n=266) or purified water (n=275) within one hour of development of the signs and symptoms of a recurrence.

A significant reduction in the time to lesion healing (P<.001), with a reduction in median time of up to 2 days, was noted. There was a significant reduction in maximum lesion area (P=.008), faster resolution of lesion-associated symptoms (P=.026), reduction in pain duration (P≤.040), itching (P≤.032), burning (P≤.028), and tenderness (P≤.026). The daily self-assessment of lesion attributes showed significantly fewer severe or extreme assessments of lesion size (P≤.003), noticeability (P≤.003), amount of scab or crust (P≤.003), raised or swollen area (P≤.040), soreness or tenderness (P≤.043), and overall severity (P≤.001) throughout the study.8

Recently, Raborn et al9 conducted 2 randomized, double-blind, parallel-group clinical trials to compare the efficacy and safety of topical penciclovir cream 1% for recurrent herpes labialis. Of the 4573 immunocompetent patients with a history of recurrent herpes simplex labialis (defined as 3 or more episodes per year) that were enrolled in the study, 3057 patients initiated treatment (1516 with penciclovir cream 1% and 1541 with placebo). Patients were instructed to apply medication 6 times a day for the first day and thereafter every 2 hours during waking hours for 4 consecutive days. In the treatment group, patients lost classic lesions 31% faster than did those in the placebo group and experienced 28% faster resolution of lesion pain. Significant benefits were achieved with penciclovir use whether treatment was initiated in the early stages (P=.001) or later stages (P=.0055) of the recurrence.9

Lin and associates10 compared the efficacy of topical penciclovir cream 1% versus acyclovir cream 3% in the treatment of herpes labialis. In a randomized, double-blind, multicenter trial, 248 patients with a history of herpes labialis were randomly allocated to 1 of the 2 treatment groups (n=124 each) to receive either penciclovir cream 1% or acyclovir cream 3%. Before treatment (day 0) and at every visit (days 3, 5, and 7), signs and symptoms scores were recorded by the same physician. Two hundred twenty-five patients completed the study. No significant differences were noted in efficacy, clinical cure rate, and safety between the 2 groups; however, a trend toward a shorter time to resolution of symptoms, cessation of new blisters, and loss of crust (P≤.008) was noted in penciclovir-treated patients compared with acyclovir-treated patients. In addition, signs and symptoms scores in penciclovir-treated patients were significantly lower than those in the acyclovir-treated patients on days 5 (P<.01) and 7 (P<.05), supporting the finding that topical penciclovir cream 1% is at least as convenient and effective as acyclovir cream 3% in the treatment of herpes labialis.10

A susceptibility program was established by Sarisky et al11 to assess the resistance profile for serial HSV isolates from immunocompetent patients with recurrent herpes labialis. The isolates were obtained throughout a 4-day treatment period with topical penciclovir cream 1% or placebo. Two isolates (2/1035; 0.19%), representing 0.34% of the patients (2/585), were confirmed to be penciclovir resistant. These were highly resistant to penciclovir (50% inhibiting concentration [IC50], >55 µg/mL) and were isolated less than 17 hours after the start of patient-initiated treatment. However, subsequent isolates on days 2 and 3 from the same patients were completely susceptible to penciclovir cream (IC50, <2.0 µg/mL). None of the patients were found to have penciclovir-resistant species at the end of acute treatment, regardless of treatment group. Overall, the prevalence of penciclovir resistance was found to be similar to that of acyclovir resistance (ie, 0.3%) reported in immunocompetent untreated populations.11

N-docosanol—Docosanol is a compound that inhibits herpes virus replication by blocking fusion of the viral envelope with the plasma membrane and can potentially limit both the duration and severity of herpes labialis.2 Presently, docosanol 10% cream is approved by the FDA as an over-the-counter agent for application 5 times a day during episodes of herpes labialis. In one small clinical trial with 63 patients, n-docosanol 10% cream significantly reduced the healing time of patients’ herpes labialis episodes compared with stearic acid–containing placebo cream.12 Application of n-docosanol 10% cream early in the prodrome or erythema stage of a recurrent episode of herpes labialis shortened mean healing time by approximately 3 days compared with late treatment with n-docosanol 10% cream and early or late treatment with the placebo. A subsequent larger study with 846 patients found no benefit.13 Because of a concern that the vehicle may have had a beneficial effect on herpes labialis and masked an effect by n-docosanol, a polyethylene glycol control preparation was created.14

With this new preparation, Sacks et al15 conducted studies to determine whether docosanol 10% cream is efficacious compared with placebo in the topical treatment of episodes of acute herpes simplex labialis. Two identical double-blind, placebo-controlled studies were conducted at a total of 21 sites. Otherwise healthy adults, with documented histories of herpes labialis, were randomized to receive either docosanol or polyethylene glycol placebo. Subjects were instructed to initiate therapy in the prodrome or erythema stage of an episode. Treatment was administered 5 times a day until healing occurred (ie, the crust fell off spontaneously, or there was no longer evidence of an active lesion) with twice-daily visits. The median time to healing in the 370 docosanol-treated patients was 4.1 days, 18 hours shorter than that observed in the 367 placebo-treated patients (P=.008). The docosanol group also exhibited reduced times from treatment initiation to (1) cessation of pain and all other symptoms (itching, burning, and/or tingling; P=.002), (2) complete healing of classic lesions (P=.023), and (3) cessation of the ulcer or soft-crust stage of classic lesions (P<.001). Aborted episodes were experienced in 40% of docosanol recipients versus 34% of placebo recipients (P=.109). Adverse experiences with docosanol were mild and similar to those with placebo. The authors concluded that docosanol applied 5 times a day is safe and effective in the treatment of recurrent herpes labialis.15

Because in vitro studies have shown that n-docosanol can enhance the antiviral activity of nucleoside analogs against the replication of herpesviruses, clinical studies of this combination will be of interest.2

Comparative Efficacy of Topical Treatments
McKeough and Spruance14 evaluated the comparative efficacy of penciclovir cream, acyclovir cream, n-docosanol cream, and acyclovir ointment in a guinea pig model of cutaneous HSV-1 disease. The backs of guinea pigs were infected with HSV-1 using a vaccination instrument. Active treatments and corresponding vehicle controls were applied for 3 to 5 days beginning 24 hours after inoculation. After completion of treatment, the animals were killed, and the severity of the infection was assessed from the number of lesions, total lesion area, and lesion virus titer.14

Penciclovir cream effected modest reductions in lesion number (19%), area (38%), and virus titer (88%) compared with its vehicle control, and each of these differences was significantly greater (P<.05) than the reductions effected by acyclovir ointment (0%, 21%, and 75%, respectively). The acyclovir cream effect (reductions of 4%, 28%, and 77%, respectively) was less than that of penciclovir cream, and this difference was confirmed by 2 additional head-to-head experiments. Two experiments with n-docosanol cream failed to show statistically significant differences by any parameter between n-docosanol cream and vehicle control-treated sites or between n-docosanol and untreated infection sites.14

In this model, the efficacy of penciclovir cream was greater than acyclovir cream, acyclovir cream was greater than or equal to acyclovir ointment, and acyclovir ointment was greater than n-docosanol cream. The authors noted that because their model was designed to evaluate compounds that function primarily through antiviral activity, the negative findings with n-docosanol in these studies do not exclude that it might work clinically through other mechanisms.14

Herpes labialis is a common condition characterized by recurrent vesicular eruptions primarily on the lips and perioral skin. Most commonly caused by herpes simplex virus type 1 (HSV-1), this condition can significantly affect quality of life in patients with multiple recurrences, which may cause pain, embarrassment, and psychosocial distress. Oral HSV is the most easily acquired herpesvirus. Approximately 50% of Americans are seropositive for HSV-1 by the time they reach adolescence—by age 50 years, 80% to 90% carry the virus.1 The first part of this series discussed oral antiviral agents in the treatment of herpes labialis. In the second part of this series, we review topical therapeutic agents that are available in the treatment of herpes labialis and its associated symptoms.

Topical Agents For many years, acyclovir ointment was the only topical agent available for herpes labialis. Over the last several years, many new topical therapies have been investigated, and 3 have been approved by the US Food and Drug Administration (FDA). Currently, the 4 approved topical treatments available for herpes labialis include acyclovir ointment and cream (Zovirax®), penciclovir cream (Denavir®), and n-docosanol cream (Abreva®)(Table).

Acyclovir—Acyclovir ointment, which was first brought to market in 1982, is of questionable value in the treatment of recurrent herpes labialis.2 Acyclovir cream, which appears to provide better absorption than the ointment, has been available in many countries outside the United States for more than a decade. To examine more comprehensively the safety and efficacy of this formulation, Spruance et al3 conducted 2 independent, identical, parallel, randomized, double-blind, vehicle-controlled, multicenter clinical trials (N=686 in study 1 and N=699 in study 2). Healthy adults with a history of recurrent herpes labialis were randomized to receive acyclovir cream 5% or vehicle control and asked to self-initiate treatment 5 times a day for 4 days starting within 1 hour of recurrence onset. The mean duration of episodes was significantly decreased in both studies (study 1: 4.3 vs 4.8 days in treated vs placebo, respectively; study 2: 4.6 vs 5.2 days in treated vs placebo, respectively)(P≤.05). In addition, lesion pain was reduced significantly for subjects in both studies, though acyclovir cream did not prevent the development of classic lesions.3

In another study, Biagioni and Lamey4 used infrared thermography to identify the prodromal stage of herpes labialis and treated the active area with acyclovir cream 5 times a day for 5 days. All patients (N=70) were evaluated at 72 hours thermographically and clinically, and localized increase in temperature over the symptomatic area was noted. The development of a clinical herpes lesion was prevented in 46% (32/70) of the patients. In the lesions that did develop (38/70), an 80% reduction in clinical lesion size was observed in 82% (31/38) of the subjects. The remaining 18% (7/38) of patients showed a reduction in healing time.4

In a recent publication, Seth et al5 reported the use of a novel liposomal acyclovir topical gel. In this study, 10 patients with recurrent, mild facial infection were subjected to double-blind clinical evaluation, using a 1% liposomal acyclovir topical gel in a 5% hydroxypropylmethyl cellulose K4M gel base. The efficacy of plain acyclovir gel and liposomal acyclovir gel was compared by application to herpetic lesions 5 times a day for up to 8 weeks. In patients treated with liposomal acyclovir gel, a significant increase in the average percentage improvement of lesion healing was observed after 2 to 3 weeks of therapy (P<.05).5

Topical acyclovir also has been evaluated in combination with a topical steroid. Evans and colleagues6 assessed the efficacy of a combination of acyclovir cream 5% and hydrocortisone cream 1% (ME-609) in treating experimentally UV radiation (UVR)–induced herpes labialis in patients with a history of recurrent herpes labialis. Starting on day 2, 380 subjects were randomized to receive ME-609 or vehicle control 6 times a day for 5 days. Fewer patients in the treatment arm developed delayed classic lesions. Statistically significant reductions in healing time (9.0 vs 10.1 days in treated and placebo groups, respectively; P=.04) and maximum lesion size (43 vs 60 mm in treated and placebo groups, respectively; P=.07) were noted in treated patients compared with patients given placebo. Overall, combination treatment with an antiviral and anti-inflammatory agent led to a reduction in the incidence of classic lesions, healing time, lesion size, and lesion tenderness.6

Penciclovir—Penciclovir, famciclovir’s active metabolite, is FDA approved for episodic treatment of herpes labialis. Topical penciclovir cream 1% applied every 2 hours for 4 days can decrease the duration of lesion healing, pain, and viral shedding, as evidenced by several studies, with some benefit in the early and late stages of lesion development.7-10 Penciclovir interferes with viral replication and significantly limits both the severity and duration of cold sores.

Spruance et al7 conducted a randomized, multicenter, double-blind, placebo-controlled, 2-arm, parallel trial to compare the safety and efficacy of penciclovir cream 1% with vehicle control cream in the treatment of recurrent herpes simplex labialis in immunocompetent patients. Treatment was self-initiated by the patient within the first hour of the first sign or symptom of a recurrence. A total of 2209 patients were enrolled and given study medication, 1573 of whom initiated treatment for a recurrence. Patients applied the medication every 2 hours during waking hours for 4 days. Healing of classic lesions was 0.7 days faster in penciclovir-treated patients compared with placebo-treated patients (median, 4.8 vs 5.5 days; P<.001). Reduction in duration of lesion pain was observed in penciclovir-treated patients compared with placebo-treated patients (median, 3.5 vs 4.1 days; P<.001). Lesion viral shedding also resolved faster in penciclovir-treated patients compared with those who received vehicle control cream (median, 3 vs 3 days; P=.003). Statistically significant reductions in time to healing and pain resolution occurred with topical penciclovir cream when treatment was initiated in the early (prodrome or erythema) stage or late (papule or vesicle) stage of the lesion.7

Boon et al8 evaluated the efficacy and tolerability of penciclovir cream versus placebo control (purified water) in treating sunlight-induced herpes labialis. Healthy patients (mean age, 38.3 years; range, 18–81 years) with a history of sunlight-induced herpes labialis self-initiated treatment with either penciclovir cream (n=266) or purified water (n=275) within one hour of development of the signs and symptoms of a recurrence.

A significant reduction in the time to lesion healing (P<.001), with a reduction in median time of up to 2 days, was noted. There was a significant reduction in maximum lesion area (P=.008), faster resolution of lesion-associated symptoms (P=.026), reduction in pain duration (P≤.040), itching (P≤.032), burning (P≤.028), and tenderness (P≤.026). The daily self-assessment of lesion attributes showed significantly fewer severe or extreme assessments of lesion size (P≤.003), noticeability (P≤.003), amount of scab or crust (P≤.003), raised or swollen area (P≤.040), soreness or tenderness (P≤.043), and overall severity (P≤.001) throughout the study.8

Recently, Raborn et al9 conducted 2 randomized, double-blind, parallel-group clinical trials to compare the efficacy and safety of topical penciclovir cream 1% for recurrent herpes labialis. Of the 4573 immunocompetent patients with a history of recurrent herpes simplex labialis (defined as 3 or more episodes per year) that were enrolled in the study, 3057 patients initiated treatment (1516 with penciclovir cream 1% and 1541 with placebo). Patients were instructed to apply medication 6 times a day for the first day and thereafter every 2 hours during waking hours for 4 consecutive days. In the treatment group, patients lost classic lesions 31% faster than did those in the placebo group and experienced 28% faster resolution of lesion pain. Significant benefits were achieved with penciclovir use whether treatment was initiated in the early stages (P=.001) or later stages (P=.0055) of the recurrence.9

Lin and associates10 compared the efficacy of topical penciclovir cream 1% versus acyclovir cream 3% in the treatment of herpes labialis. In a randomized, double-blind, multicenter trial, 248 patients with a history of herpes labialis were randomly allocated to 1 of the 2 treatment groups (n=124 each) to receive either penciclovir cream 1% or acyclovir cream 3%. Before treatment (day 0) and at every visit (days 3, 5, and 7), signs and symptoms scores were recorded by the same physician. Two hundred twenty-five patients completed the study. No significant differences were noted in efficacy, clinical cure rate, and safety between the 2 groups; however, a trend toward a shorter time to resolution of symptoms, cessation of new blisters, and loss of crust (P≤.008) was noted in penciclovir-treated patients compared with acyclovir-treated patients. In addition, signs and symptoms scores in penciclovir-treated patients were significantly lower than those in the acyclovir-treated patients on days 5 (P<.01) and 7 (P<.05), supporting the finding that topical penciclovir cream 1% is at least as convenient and effective as acyclovir cream 3% in the treatment of herpes labialis.10

A susceptibility program was established by Sarisky et al11 to assess the resistance profile for serial HSV isolates from immunocompetent patients with recurrent herpes labialis. The isolates were obtained throughout a 4-day treatment period with topical penciclovir cream 1% or placebo. Two isolates (2/1035; 0.19%), representing 0.34% of the patients (2/585), were confirmed to be penciclovir resistant. These were highly resistant to penciclovir (50% inhibiting concentration [IC50], >55 µg/mL) and were isolated less than 17 hours after the start of patient-initiated treatment. However, subsequent isolates on days 2 and 3 from the same patients were completely susceptible to penciclovir cream (IC50, <2.0 µg/mL). None of the patients were found to have penciclovir-resistant species at the end of acute treatment, regardless of treatment group. Overall, the prevalence of penciclovir resistance was found to be similar to that of acyclovir resistance (ie, 0.3%) reported in immunocompetent untreated populations.11

N-docosanol—Docosanol is a compound that inhibits herpes virus replication by blocking fusion of the viral envelope with the plasma membrane and can potentially limit both the duration and severity of herpes labialis.2 Presently, docosanol 10% cream is approved by the FDA as an over-the-counter agent for application 5 times a day during episodes of herpes labialis. In one small clinical trial with 63 patients, n-docosanol 10% cream significantly reduced the healing time of patients’ herpes labialis episodes compared with stearic acid–containing placebo cream.12 Application of n-docosanol 10% cream early in the prodrome or erythema stage of a recurrent episode of herpes labialis shortened mean healing time by approximately 3 days compared with late treatment with n-docosanol 10% cream and early or late treatment with the placebo. A subsequent larger study with 846 patients found no benefit.13 Because of a concern that the vehicle may have had a beneficial effect on herpes labialis and masked an effect by n-docosanol, a polyethylene glycol control preparation was created.14

With this new preparation, Sacks et al15 conducted studies to determine whether docosanol 10% cream is efficacious compared with placebo in the topical treatment of episodes of acute herpes simplex labialis. Two identical double-blind, placebo-controlled studies were conducted at a total of 21 sites. Otherwise healthy adults, with documented histories of herpes labialis, were randomized to receive either docosanol or polyethylene glycol placebo. Subjects were instructed to initiate therapy in the prodrome or erythema stage of an episode. Treatment was administered 5 times a day until healing occurred (ie, the crust fell off spontaneously, or there was no longer evidence of an active lesion) with twice-daily visits. The median time to healing in the 370 docosanol-treated patients was 4.1 days, 18 hours shorter than that observed in the 367 placebo-treated patients (P=.008). The docosanol group also exhibited reduced times from treatment initiation to (1) cessation of pain and all other symptoms (itching, burning, and/or tingling; P=.002), (2) complete healing of classic lesions (P=.023), and (3) cessation of the ulcer or soft-crust stage of classic lesions (P<.001). Aborted episodes were experienced in 40% of docosanol recipients versus 34% of placebo recipients (P=.109). Adverse experiences with docosanol were mild and similar to those with placebo. The authors concluded that docosanol applied 5 times a day is safe and effective in the treatment of recurrent herpes labialis.15

Because in vitro studies have shown that n-docosanol can enhance the antiviral activity of nucleoside analogs against the replication of herpesviruses, clinical studies of this combination will be of interest.2

Comparative Efficacy of Topical Treatments
McKeough and Spruance14 evaluated the comparative efficacy of penciclovir cream, acyclovir cream, n-docosanol cream, and acyclovir ointment in a guinea pig model of cutaneous HSV-1 disease. The backs of guinea pigs were infected with HSV-1 using a vaccination instrument. Active treatments and corresponding vehicle controls were applied for 3 to 5 days beginning 24 hours after inoculation. After completion of treatment, the animals were killed, and the severity of the infection was assessed from the number of lesions, total lesion area, and lesion virus titer.14

Penciclovir cream effected modest reductions in lesion number (19%), area (38%), and virus titer (88%) compared with its vehicle control, and each of these differences was significantly greater (P<.05) than the reductions effected by acyclovir ointment (0%, 21%, and 75%, respectively). The acyclovir cream effect (reductions of 4%, 28%, and 77%, respectively) was less than that of penciclovir cream, and this difference was confirmed by 2 additional head-to-head experiments. Two experiments with n-docosanol cream failed to show statistically significant differences by any parameter between n-docosanol cream and vehicle control-treated sites or between n-docosanol and untreated infection sites.14

In this model, the efficacy of penciclovir cream was greater than acyclovir cream, acyclovir cream was greater than or equal to acyclovir ointment, and acyclovir ointment was greater than n-docosanol cream. The authors noted that because their model was designed to evaluate compounds that function primarily through antiviral activity, the negative findings with n-docosanol in these studies do not exclude that it might work clinically through other mechanisms.14

Given the prevalence of herpes labialis, effective therapy has the potential to affect the lives of many and presents a challenge for clinicians. Over the last several years, most of the focus of herpes research has been on the treatment of genital herpes. Recently, however, several studies have been published examining the efficacy of therapies specifically for herpes labialis. Several therapeutic agents, both prescription and over-the-counter, are available for controlling and managing the disease. In this series of articles, we review oral and topical therapeutic agents that are available in the treatment of herpes labialis and its associated symptoms. This article will review oral treatment options.

Herpes labialis is a common condition characterized by recurrent vesicular eruptions primarily on the lips and perioral skin. Most commonly caused by herpes simplex virus type 1 (HSV-1), this condition can significantly affect quality of life in patients with multiple recurrences, which may cause pain, embarrassment, and psychosocial distress. Oral HSV is the most easily acquired herpesvirus. Approximately 50% of Americans are seropositive for HSV-1 by the time they reach adolescence—by age 50 years, 80% to 90% carry the virus.1

Over the last several years, most clinical investigation of herpes infection has concerned genital disease. Therefore, the treatment of orolabial disease with oral therapies often was extrapolated from this data rather than based on direct study of the condition itself. Recently, however, several studies have been conducted to evaluate the efficacy of therapies specifically for herpes labialis. Although the virus responsible for the disease is not eradicated, several therapeutic agents, both prescription and over-the-counter, are available for controlling and managing the disease. In the first of this series of articles, we review oral therapeutic agents that are available in the treatment of herpes labialis and its associated symptoms. 

Oral Agents

Three oral antiviral agents, acyclovir, valacyclovir, and famciclovir, are available for the treatment of herpes labialis. However, only valacyclovir has been specifically approved by the US Food and Drug Administration (FDA) for the episodic treatment of this condition. All 3 agents are acyclic guanosine analogs that competitively inhibit viral DNA polymerase after phosphorylation by the viral thymidine kinase and by the cellular kinases. Unlike acyclovir and valacyclovir, penciclovir and famciclovir are not obligate DNA chain terminators and would be expected to have lower efficacy.

Acyclovir—Little literature exists for oral acyclovir in the treatment of herpes labialis. In a study by Raborn et al,2 oral acyclovir (200 mg 5 times a day for 5 days) reduced the time to loss of crust by 1 day (7 vs 8 days) but did not alter the duration of pain or time to complete healing. When treatment is started during the prodrome or erythema stage at 400 mg 5 times a day for 5 days, the mean duration of pain is reduced by 36%, and the time to loss of crust is reduced by 27%.2 Therefore, according to Vander Straten et al,3 oral acyclovir therapy has modest clinical benefit and cannot be recommended for routine therapy of herpes labialis. However, it may be helpful in patients whose recurrence is associated with protracted illness.

Oral acyclovir has been shown to alter the severity of sun-induced herpes labialis.4 Administration of acyclovir 200 mg 5 times a day in skiers resulted in a similar frequency of HSV reactivation in treatment and placebo recipients, but significantly fewer lesions formed on days 5 to 7 among those on acyclovir.4 Although not approved by the FDA, long-term suppression of herpes labialis with oral acyclovir has been shown to result in a 53% reduction in the number of clinical recurrences.5

Long-term use of acyclovir (up to 10 years) for HSV suppression is effective and well tolerated.6 Acyclovir is approved for use in children and has been monitored in more than 1000 pregnant women. The incidence of acyclovir resistance is estimated to be less than 0.5% among immunocompetent patients and 5% among immunocompromised patients. Primary infection responds well to oral acyclovir.6 In infants and children, acyclovir tablets can be crushed easily and mixed with food or dispersed in water or juice.

Valacyclovir—Unlike the parent drug acyclovir, valacyclovir has greater bioavailability (3 to 5 times that of acyclovir) and rapidly metabolizes to acyclovir and L-valine after absorption.3 As such, both agents have identical mechanisms of action, efficacy, and safety profiles. In previous studies, valacyclovir has been shown to be as effective as acyclovir in the treatment of first-episode genital herpes, recurrent genital herpes, and long-term suppression of genital herpes.3

Chosidow and colleagues7 evaluated the efficacy of the administration of a single course of valacyclovir in the prodromal phase of herpes labialis. In a randomized, double-blind clinical trial, 249 patients with similar baseline characteristics and recurrent disease were randomized to receive a 500-, 1000-, or 2000-mg dose of valacyclovir. The major outcome variable measure, the rate of aborted lesions on day 3, was not significantly different among the treatment groups, and a dose response was not observed. Although a placebo group was not included in this study, it was concluded that a single dose of valacyclovir was not beneficial in patients with recurrent herpes facialis.7

In a randomized, double-blind, placebo-controlled study, Spruance et al8 showed that a 1-day valacyclovir treatment regimen for cold sores is safe and effective. Treatment was administered in a 1-day regimen (2 g of valacyclovir twice a day for 1 day), 2-day regimen (2 g of valacyclovir twice a day for 1 day and then 1 g of valacyclovir twice a day for 1 day), or placebo. Patients were instructed to initiate treatment at the first symptoms of a cold sore. With a single day of treatment, median and mean durations of the episode were reduced by 1 and 1.1 days, respectively, compared with placebo. The 2-day treatment regimen led to a reduction in median and mean durations of the episode by 0.5 and 0.7 days, respectively, compared with placebo. In addition, the suppression of cold sore development increased dose dependently by 6.4% (P=.096) and by 8.5% (P=.061) in the 1-day treatment and 2-day treatment groups, respectively, compared with placebo. Other variables evaluated in the study (eg, time to healing of lesion and cessation of pain or discomfort) also were reduced with valacyclovir compared with placebo. The authors concluded that a 1-day regimen of oral valacyclovir was efficacious against recurrent herpes labialis.8

Similarly, Baker and Eisen9 investigated the efficacy of oral valacyclovir in the suppression of herpes labialis. Two identical, randomized, double-blind, parallel-group studies were conducted to evaluate the efficacy of oral valacyclovir 500 mg (n=49) versus placebo (n=49) once a day for 16 weeks among patients with a history of 4 or more episodes of herpes labialis in the previous year. During the 4-month treatment period, 60% of patients in the valacyclovir group, compared with only 38% in the placebo group, were recurrence free. In addition, mean time to first recurrence was significantly longer with valacyclovir (13.1 weeks) compared with placebo (9.6 weeks). The authors concluded that oral valacyclovir 500 mg once a day for 4 months is effective and well tolerated in the prevention of recurrent herpes labialis. They suggested that additional research with larger numbers of patients be conducted to corroborate and extend these findings.9 The development of orofacial herpes labialis often is associated with laser resurfacing. Gilbert and McBurney10 reported that valacyclovir is safe and effective as prophylaxis against such recurrences.

Famciclovir—This agent has been investigated in the treatment of herpes labialis in 2 small trials. In a double-blind, dose-ranging, placebo-controlled, multicenter trial, Spruance and McKeough11 evaluated the efficacy of famciclovir in treating experimentally UV radiation (UVR)–induced herpes simplex labialis. In the study, patients received a 125-, 250-, or 500-mg dose of famciclovir or placebo 3 times a day for 5 days, beginning 48 hours after UVR exposure. Although there was no significant difference in the number of lesions between the famciclovir group and the placebo group, mean maximal lesion size was reduced dose dependently; the largest diameter was observed with the placebo, and the smallest was seen with a 500-mg dose of famciclovir. In addition, median time to healing was faster in the 500-mg famciclovir treatment group than in the placebo group.11

In a second study with experimentally UVR-induced herpes simplex labialis, Spruance and McKeough12 combined famciclovir 500 mg 3 times a day for 5 days with either topical fluocinonide 0.05% gel 3 times a day for 5 days or vehicle control gel. Patients using combination therapy experienced significantly reduced medium maximum lesion size, and the number of patients who had pain was reduced by approximately half compared with the control group (59% vs 100%).12

Famciclovir is not approved by the FDA for the treatment of herpes labialis. Although the drug has not been studied as suppressive therapy for this indication, Wall et al13 showed that famciclovir 125 or 250 mg twice a day, begun 1 to 2 days before laser resurfacing and continued for 5 days after surgery, reduced orofacial herpes outbreaks compared with placebo.

Several safe and effective therapeutic oral options exist in the treatment of herpes labialis (Table). Part II of this series will review topical therapies.

Given the prevalence of herpes labialis, effective therapy has the potential to affect the lives of many and presents a challenge for clinicians. Over the last several years, most of the focus of herpes research has been on the treatment of genital herpes. Recently, however, several studies have been published examining the efficacy of therapies specifically for herpes labialis. Several therapeutic agents, both prescription and over-the-counter, are available for controlling and managing the disease. In this series of articles, we review oral and topical therapeutic agents that are available in the treatment of herpes labialis and its associated symptoms. This article will review oral treatment options.

Herpes labialis is a common condition characterized by recurrent vesicular eruptions primarily on the lips and perioral skin. Most commonly caused by herpes simplex virus type 1 (HSV-1), this condition can significantly affect quality of life in patients with multiple recurrences, which may cause pain, embarrassment, and psychosocial distress. Oral HSV is the most easily acquired herpesvirus. Approximately 50% of Americans are seropositive for HSV-1 by the time they reach adolescence—by age 50 years, 80% to 90% carry the virus.1

Over the last several years, most clinical investigation of herpes infection has concerned genital disease. Therefore, the treatment of orolabial disease with oral therapies often was extrapolated from this data rather than based on direct study of the condition itself. Recently, however, several studies have been conducted to evaluate the efficacy of therapies specifically for herpes labialis. Although the virus responsible for the disease is not eradicated, several therapeutic agents, both prescription and over-the-counter, are available for controlling and managing the disease. In the first of this series of articles, we review oral therapeutic agents that are available in the treatment of herpes labialis and its associated symptoms. 

Oral Agents

Three oral antiviral agents, acyclovir, valacyclovir, and famciclovir, are available for the treatment of herpes labialis. However, only valacyclovir has been specifically approved by the US Food and Drug Administration (FDA) for the episodic treatment of this condition. All 3 agents are acyclic guanosine analogs that competitively inhibit viral DNA polymerase after phosphorylation by the viral thymidine kinase and by the cellular kinases. Unlike acyclovir and valacyclovir, penciclovir and famciclovir are not obligate DNA chain terminators and would be expected to have lower efficacy.

Acyclovir—Little literature exists for oral acyclovir in the treatment of herpes labialis. In a study by Raborn et al,2 oral acyclovir (200 mg 5 times a day for 5 days) reduced the time to loss of crust by 1 day (7 vs 8 days) but did not alter the duration of pain or time to complete healing. When treatment is started during the prodrome or erythema stage at 400 mg 5 times a day for 5 days, the mean duration of pain is reduced by 36%, and the time to loss of crust is reduced by 27%.2 Therefore, according to Vander Straten et al,3 oral acyclovir therapy has modest clinical benefit and cannot be recommended for routine therapy of herpes labialis. However, it may be helpful in patients whose recurrence is associated with protracted illness.

Oral acyclovir has been shown to alter the severity of sun-induced herpes labialis.4 Administration of acyclovir 200 mg 5 times a day in skiers resulted in a similar frequency of HSV reactivation in treatment and placebo recipients, but significantly fewer lesions formed on days 5 to 7 among those on acyclovir.4 Although not approved by the FDA, long-term suppression of herpes labialis with oral acyclovir has been shown to result in a 53% reduction in the number of clinical recurrences.5

Long-term use of acyclovir (up to 10 years) for HSV suppression is effective and well tolerated.6 Acyclovir is approved for use in children and has been monitored in more than 1000 pregnant women. The incidence of acyclovir resistance is estimated to be less than 0.5% among immunocompetent patients and 5% among immunocompromised patients. Primary infection responds well to oral acyclovir.6 In infants and children, acyclovir tablets can be crushed easily and mixed with food or dispersed in water or juice.

Valacyclovir—Unlike the parent drug acyclovir, valacyclovir has greater bioavailability (3 to 5 times that of acyclovir) and rapidly metabolizes to acyclovir and L-valine after absorption.3 As such, both agents have identical mechanisms of action, efficacy, and safety profiles. In previous studies, valacyclovir has been shown to be as effective as acyclovir in the treatment of first-episode genital herpes, recurrent genital herpes, and long-term suppression of genital herpes.3

Chosidow and colleagues7 evaluated the efficacy of the administration of a single course of valacyclovir in the prodromal phase of herpes labialis. In a randomized, double-blind clinical trial, 249 patients with similar baseline characteristics and recurrent disease were randomized to receive a 500-, 1000-, or 2000-mg dose of valacyclovir. The major outcome variable measure, the rate of aborted lesions on day 3, was not significantly different among the treatment groups, and a dose response was not observed. Although a placebo group was not included in this study, it was concluded that a single dose of valacyclovir was not beneficial in patients with recurrent herpes facialis.7

In a randomized, double-blind, placebo-controlled study, Spruance et al8 showed that a 1-day valacyclovir treatment regimen for cold sores is safe and effective. Treatment was administered in a 1-day regimen (2 g of valacyclovir twice a day for 1 day), 2-day regimen (2 g of valacyclovir twice a day for 1 day and then 1 g of valacyclovir twice a day for 1 day), or placebo. Patients were instructed to initiate treatment at the first symptoms of a cold sore. With a single day of treatment, median and mean durations of the episode were reduced by 1 and 1.1 days, respectively, compared with placebo. The 2-day treatment regimen led to a reduction in median and mean durations of the episode by 0.5 and 0.7 days, respectively, compared with placebo. In addition, the suppression of cold sore development increased dose dependently by 6.4% (P=.096) and by 8.5% (P=.061) in the 1-day treatment and 2-day treatment groups, respectively, compared with placebo. Other variables evaluated in the study (eg, time to healing of lesion and cessation of pain or discomfort) also were reduced with valacyclovir compared with placebo. The authors concluded that a 1-day regimen of oral valacyclovir was efficacious against recurrent herpes labialis.8

Similarly, Baker and Eisen9 investigated the efficacy of oral valacyclovir in the suppression of herpes labialis. Two identical, randomized, double-blind, parallel-group studies were conducted to evaluate the efficacy of oral valacyclovir 500 mg (n=49) versus placebo (n=49) once a day for 16 weeks among patients with a history of 4 or more episodes of herpes labialis in the previous year. During the 4-month treatment period, 60% of patients in the valacyclovir group, compared with only 38% in the placebo group, were recurrence free. In addition, mean time to first recurrence was significantly longer with valacyclovir (13.1 weeks) compared with placebo (9.6 weeks). The authors concluded that oral valacyclovir 500 mg once a day for 4 months is effective and well tolerated in the prevention of recurrent herpes labialis. They suggested that additional research with larger numbers of patients be conducted to corroborate and extend these findings.9 The development of orofacial herpes labialis often is associated with laser resurfacing. Gilbert and McBurney10 reported that valacyclovir is safe and effective as prophylaxis against such recurrences.

Famciclovir—This agent has been investigated in the treatment of herpes labialis in 2 small trials. In a double-blind, dose-ranging, placebo-controlled, multicenter trial, Spruance and McKeough11 evaluated the efficacy of famciclovir in treating experimentally UV radiation (UVR)–induced herpes simplex labialis. In the study, patients received a 125-, 250-, or 500-mg dose of famciclovir or placebo 3 times a day for 5 days, beginning 48 hours after UVR exposure. Although there was no significant difference in the number of lesions between the famciclovir group and the placebo group, mean maximal lesion size was reduced dose dependently; the largest diameter was observed with the placebo, and the smallest was seen with a 500-mg dose of famciclovir. In addition, median time to healing was faster in the 500-mg famciclovir treatment group than in the placebo group.11

In a second study with experimentally UVR-induced herpes simplex labialis, Spruance and McKeough12 combined famciclovir 500 mg 3 times a day for 5 days with either topical fluocinonide 0.05% gel 3 times a day for 5 days or vehicle control gel. Patients using combination therapy experienced significantly reduced medium maximum lesion size, and the number of patients who had pain was reduced by approximately half compared with the control group (59% vs 100%).12

Famciclovir is not approved by the FDA for the treatment of herpes labialis. Although the drug has not been studied as suppressive therapy for this indication, Wall et al13 showed that famciclovir 125 or 250 mg twice a day, begun 1 to 2 days before laser resurfacing and continued for 5 days after surgery, reduced orofacial herpes outbreaks compared with placebo.

Several safe and effective therapeutic oral options exist in the treatment of herpes labialis (Table). Part II of this series will review topical therapies.

Given the prevalence of herpes labialis, effective therapy has the potential to affect the lives of many and presents a challenge for clinicians. Over the last several years, most of the focus of herpes research has been on the treatment of genital herpes. Recently, however, several studies have been published examining the efficacy of therapies specifically for herpes labialis. Several therapeutic agents, both prescription and over-the-counter, are available for controlling and managing the disease. In this series of articles, we review oral and topical therapeutic agents that are available in the treatment of herpes labialis and its associated symptoms. This article will review oral treatment options.

Herpes labialis is a common condition characterized by recurrent vesicular eruptions primarily on the lips and perioral skin. Most commonly caused by herpes simplex virus type 1 (HSV-1), this condition can significantly affect quality of life in patients with multiple recurrences, which may cause pain, embarrassment, and psychosocial distress. Oral HSV is the most easily acquired herpesvirus. Approximately 50% of Americans are seropositive for HSV-1 by the time they reach adolescence—by age 50 years, 80% to 90% carry the virus.1

Over the last several years, most clinical investigation of herpes infection has concerned genital disease. Therefore, the treatment of orolabial disease with oral therapies often was extrapolated from this data rather than based on direct study of the condition itself. Recently, however, several studies have been conducted to evaluate the efficacy of therapies specifically for herpes labialis. Although the virus responsible for the disease is not eradicated, several therapeutic agents, both prescription and over-the-counter, are available for controlling and managing the disease. In the first of this series of articles, we review oral therapeutic agents that are available in the treatment of herpes labialis and its associated symptoms. 

Oral Agents

Three oral antiviral agents, acyclovir, valacyclovir, and famciclovir, are available for the treatment of herpes labialis. However, only valacyclovir has been specifically approved by the US Food and Drug Administration (FDA) for the episodic treatment of this condition. All 3 agents are acyclic guanosine analogs that competitively inhibit viral DNA polymerase after phosphorylation by the viral thymidine kinase and by the cellular kinases. Unlike acyclovir and valacyclovir, penciclovir and famciclovir are not obligate DNA chain terminators and would be expected to have lower efficacy.

Acyclovir—Little literature exists for oral acyclovir in the treatment of herpes labialis. In a study by Raborn et al,2 oral acyclovir (200 mg 5 times a day for 5 days) reduced the time to loss of crust by 1 day (7 vs 8 days) but did not alter the duration of pain or time to complete healing. When treatment is started during the prodrome or erythema stage at 400 mg 5 times a day for 5 days, the mean duration of pain is reduced by 36%, and the time to loss of crust is reduced by 27%.2 Therefore, according to Vander Straten et al,3 oral acyclovir therapy has modest clinical benefit and cannot be recommended for routine therapy of herpes labialis. However, it may be helpful in patients whose recurrence is associated with protracted illness.

Oral acyclovir has been shown to alter the severity of sun-induced herpes labialis.4 Administration of acyclovir 200 mg 5 times a day in skiers resulted in a similar frequency of HSV reactivation in treatment and placebo recipients, but significantly fewer lesions formed on days 5 to 7 among those on acyclovir.4 Although not approved by the FDA, long-term suppression of herpes labialis with oral acyclovir has been shown to result in a 53% reduction in the number of clinical recurrences.5

Long-term use of acyclovir (up to 10 years) for HSV suppression is effective and well tolerated.6 Acyclovir is approved for use in children and has been monitored in more than 1000 pregnant women. The incidence of acyclovir resistance is estimated to be less than 0.5% among immunocompetent patients and 5% among immunocompromised patients. Primary infection responds well to oral acyclovir.6 In infants and children, acyclovir tablets can be crushed easily and mixed with food or dispersed in water or juice.

Valacyclovir—Unlike the parent drug acyclovir, valacyclovir has greater bioavailability (3 to 5 times that of acyclovir) and rapidly metabolizes to acyclovir and L-valine after absorption.3 As such, both agents have identical mechanisms of action, efficacy, and safety profiles. In previous studies, valacyclovir has been shown to be as effective as acyclovir in the treatment of first-episode genital herpes, recurrent genital herpes, and long-term suppression of genital herpes.3

Chosidow and colleagues7 evaluated the efficacy of the administration of a single course of valacyclovir in the prodromal phase of herpes labialis. In a randomized, double-blind clinical trial, 249 patients with similar baseline characteristics and recurrent disease were randomized to receive a 500-, 1000-, or 2000-mg dose of valacyclovir. The major outcome variable measure, the rate of aborted lesions on day 3, was not significantly different among the treatment groups, and a dose response was not observed. Although a placebo group was not included in this study, it was concluded that a single dose of valacyclovir was not beneficial in patients with recurrent herpes facialis.7

In a randomized, double-blind, placebo-controlled study, Spruance et al8 showed that a 1-day valacyclovir treatment regimen for cold sores is safe and effective. Treatment was administered in a 1-day regimen (2 g of valacyclovir twice a day for 1 day), 2-day regimen (2 g of valacyclovir twice a day for 1 day and then 1 g of valacyclovir twice a day for 1 day), or placebo. Patients were instructed to initiate treatment at the first symptoms of a cold sore. With a single day of treatment, median and mean durations of the episode were reduced by 1 and 1.1 days, respectively, compared with placebo. The 2-day treatment regimen led to a reduction in median and mean durations of the episode by 0.5 and 0.7 days, respectively, compared with placebo. In addition, the suppression of cold sore development increased dose dependently by 6.4% (P=.096) and by 8.5% (P=.061) in the 1-day treatment and 2-day treatment groups, respectively, compared with placebo. Other variables evaluated in the study (eg, time to healing of lesion and cessation of pain or discomfort) also were reduced with valacyclovir compared with placebo. The authors concluded that a 1-day regimen of oral valacyclovir was efficacious against recurrent herpes labialis.8

Similarly, Baker and Eisen9 investigated the efficacy of oral valacyclovir in the suppression of herpes labialis. Two identical, randomized, double-blind, parallel-group studies were conducted to evaluate the efficacy of oral valacyclovir 500 mg (n=49) versus placebo (n=49) once a day for 16 weeks among patients with a history of 4 or more episodes of herpes labialis in the previous year. During the 4-month treatment period, 60% of patients in the valacyclovir group, compared with only 38% in the placebo group, were recurrence free. In addition, mean time to first recurrence was significantly longer with valacyclovir (13.1 weeks) compared with placebo (9.6 weeks). The authors concluded that oral valacyclovir 500 mg once a day for 4 months is effective and well tolerated in the prevention of recurrent herpes labialis. They suggested that additional research with larger numbers of patients be conducted to corroborate and extend these findings.9 The development of orofacial herpes labialis often is associated with laser resurfacing. Gilbert and McBurney10 reported that valacyclovir is safe and effective as prophylaxis against such recurrences.

Famciclovir—This agent has been investigated in the treatment of herpes labialis in 2 small trials. In a double-blind, dose-ranging, placebo-controlled, multicenter trial, Spruance and McKeough11 evaluated the efficacy of famciclovir in treating experimentally UV radiation (UVR)–induced herpes simplex labialis. In the study, patients received a 125-, 250-, or 500-mg dose of famciclovir or placebo 3 times a day for 5 days, beginning 48 hours after UVR exposure. Although there was no significant difference in the number of lesions between the famciclovir group and the placebo group, mean maximal lesion size was reduced dose dependently; the largest diameter was observed with the placebo, and the smallest was seen with a 500-mg dose of famciclovir. In addition, median time to healing was faster in the 500-mg famciclovir treatment group than in the placebo group.11

In a second study with experimentally UVR-induced herpes simplex labialis, Spruance and McKeough12 combined famciclovir 500 mg 3 times a day for 5 days with either topical fluocinonide 0.05% gel 3 times a day for 5 days or vehicle control gel. Patients using combination therapy experienced significantly reduced medium maximum lesion size, and the number of patients who had pain was reduced by approximately half compared with the control group (59% vs 100%).12

Famciclovir is not approved by the FDA for the treatment of herpes labialis. Although the drug has not been studied as suppressive therapy for this indication, Wall et al13 showed that famciclovir 125 or 250 mg twice a day, begun 1 to 2 days before laser resurfacing and continued for 5 days after surgery, reduced orofacial herpes outbreaks compared with placebo.

Several safe and effective therapeutic oral options exist in the treatment of herpes labialis (Table). Part II of this series will review topical therapies.