Pediatrics

Molluscum contagiosum virus (MCV) infection causes the cutaneous lesions we call molluscum. Molluscum has become common in the last 30 years. Deciding the best course of therapy requires some fundamental understanding about how MCV relates to the following factors: epidemiology, childhood immunity and vaccination, clinical features, comorbidities, and quality of life. Treatment depends on many factors, including presence or absence of atopic dermatitis (AD) and/or pruritus, other symptoms, cosmetic location, and the child’s concern about the lesions. Therapeutics include destructive and immunologic therapies, the latter geared toward increasing immune response.

Epidemiology

Molluscum contagiosum virus is the solo member of the Molluscipoxvirus genus. Infection with MCV causes benign growth or tumors in the skin (ie, molluscum). The infection is slow to clear because the virus reduces the host’s immunity.^1,2 Molluscum contagiosum virus is a double-stranded DNA virus that affects keratinocytes and genetically carries the tools for its own replication (ie, DNA-dependent RNA polymerase). The virus has a few subtypes—I/Ia, II, III, and IV—with MCV-I predominating in children and healthy humans and MCV-II in patients with human immunodeficiency virus.^1,2 Typing is experimental and is not standardly performed in clinical practice. Molluscum contagiosum virus produces a variety of factors that block the host’s immune response, prolonging infection and preventing erythema and inflammatory response.³

Molluscum contagiosum virus is transmitted through skin-to-skin contact and fomites, including shared towels, bathtubs, spas, bath sponges, and pool equipment.^2,4,5 Transmission from household contact and bathing together has been noted in pediatric patients with MCV. Based on the data it can be posited that the lesions are softer when wet and more readily release viral particles or fomites, and fomites may be left on surfaces, especially when a child is wet.^6,7 Propensity for infection occurs in patients with AD and in immunosuppressed hosts, including children with human immunodeficiency virus and iatrogenic immunosuppression caused by chemotherapy.^1,2,8 Contact sports can increase the risk of transmission, and outbreaks have occurred in pools,^5,9 day-care facilities,¹⁰ and sports settings.¹¹ Cases of congenital and vertically transmitted molluscum have been documented.^12,13 Sexual transmission of MCV may be seen in adolescents who are sexually active. Although child-to-child transmission can occur in the groin area from shared equipment, transmission via sexual abuse also is possible.¹⁴ Bargman¹⁵ has mentioned the isolated genital location and lack of contact with other infected children as concerning features. Latency of new lesion appearance is anywhere from 1 to 50 days from the date of inoculation; therefore, new lesions are possible and expected even after therapy has been effective in eradicating visible lesions.¹⁰ Although clearance has been reported in 6 to 12 months, one pediatric study demonstrated 70% clearance by 1.5 years, suggesting the disease often is more prolonged.¹⁶ One-third of children will experience signs of inflammation, such as pruritus and/or erythema. Rare side effects include bacterial superinfection and hypersensitivity.²

One Dutch study from 1994, the largest database survey of children to date, cited a 17% cumulative incidence of molluscum in children by reviewing the data from 103 general practices.¹⁷ In a survey and review of molluscum by Braue et al,¹⁸ annual rates in populations vary but seem to maximize at approximately 6% to 7%. Sturt et al¹⁹ reviewed the prevalence in the indigenous West Sepik section of New Guinea and noted annual incidence rates of 6% in children younger than 10 years (range, 1.8%–10.9%). Epidemics occur and can produce large numbers of cases in a short time period.¹⁸ The cumulative prevalence in early childhood may be as high as 22%, as Sturt et al¹⁹ observed in children younger than 10 years.

Rising incidence and therefore rising lifetime prevalence appear to have been an issue in the last few decades. Data from the Indian Health Service have demonstrated increases in MCV in Native American children between 2001 and 2005.²⁰ In adults, the data support a steady increase of molluscum from 1988-2007, with a 3-fold increase from 1988-1997 to 1998-2007 in a Spanish study.²¹ Better population-based data are needed.

Childhood Immunity and Vaccination

Sequence homology between MC133L, a protein of MCV, with vaccinia virus suggests overlapping genes.²² Therefore, it is conceptually possible that the rise in incidence of MCV since the 1980s relates to the loss of herd immunity to variola due to lack of vaccination for smallpox, which has not been offered in the United States since 1972.²³ Childhood immunity to MCV varies among studies, but it appears that children do develop antibodies to molluscum in the setting of forming an immune response. Because the rise in molluscum incidence began after the smallpox vaccine was discontinued, the factors appear related; however, the scientific data do not support the theory of a relationship. Mitchell²⁴ has shown that a patient can develop antibodies in response to ground molluscum bodies inoculated into the skin; however, vaccination against molluscum and natural infection do not appear to produce antibodies that would cross-react and protect against other poxviruses, including vaccinia or fowl pox infections.²⁵ Cell-mediated immunity also is required to clear MCV and may account for the inflammatory appearance of lesions as they resolve.²⁶

Demonstrated factors that account for the rise in MCV incidence, aside from alterations in vaccination practices, include spread through sports,⁹ swimming,¹¹ and AD,⁷ which have become more commonplace in the United States in the last few decades, supporting the theory that they may be the cause of the increase in childhood MCV infections. Another cause may be the ability of MCV to create factors that stem host immune response.¹

Clinical Features

Molluscum lesions have a typical appearance of pearly papules with a central dell. These lesions are lighter to flesh colored and measure 1 to 3 mm.^2,4,5 The lesions cluster in the axillae and extremities and average from 10 to 20 per child.⁶ Lesions clear spontaneously, but new ones will continue to form until immunity is developed. Specific clinical appearances of lesions that are not pearly papules are not infrequent. Table 1 contains a short list of the manifold clinical appearances of molluscum lesions in children.^1,2,7,27-35 In particular, certain clinical appearances should be considered. In small children, head and neck lesions resembling milia are not uncommon. Giant or wartlike lesions can appear on the head, neck, or gluteal region in children and are clinical mimics of condyloma or other warts (Figure 1). Giant lesions also can grow in the subcutaneous space and mimic a cyst or abscess.²⁷ Erosive lesions mimicking eczema vaccinatum can be seen (Figure 2), but dermoscopy may demonstrate central dells in some lesions. Other viral processes mimicked include Gianotti Crosti–like lesions (Figure 3) that appear when a papular id reaction forms over the extremities or a localized version in the axilla, mimicking unilateral laterothoracic exanthema.^2,36,37 Hypersensitivity reactions are commonly noted with clearance and can be papular or demonstrate swelling and erythema, termed the beginning-of-the-end sign.³⁸

Pruritus, erythema, and swelling can occur with clearance but do not appear in all patients. Addressing pruritus is important to prevent disease spread, as patients are likely to inoculate other areas of the skin with virus when they scratch, and lesion number is reduced with dermatitis interventions.³⁶

Comorbidities

Molluscum lesions can occur in any child; however, the impaired immunologic status and skin barrier in patients with AD is ripe for the extensive spread of lesions that is associated with higher lesion count.³⁶ Children with molluscum infection can experience new-onset dermatitis or triggering of AD flares, especially on the extremities, such as the antecubital and popliteal regions.⁷ A study of children with MCV infection demonstrated that treatment of active dermatitis reduced spread. The authors mentioned autoinoculation as the mechanism; however, these data also suggest supporting barrier state as a factor in disease spread.³⁶ Superinfection can occur prior to⁶ or after therapy for lesions,³⁷ but it is unclear if this relates to the underlying atopic diathesis. Children with molluscum have been described to have warts, psoriasis, family history of atopy, diabetes mellitus, and pityriasis alba,⁷ while immunosuppression of any kind is associated with molluscum and high lesion count or prolonged disease in childhood.^1,2

Quality of Life

Children with molluscum who have higher lesion counts appear to be at risk for severe effects on their quality of life. Approximately 10% of children with MCV infection have been documented to have severe impairments on quality of life.³⁹ In my practice, quality of life in children with MCV appears to be affected by many factors (Table 2).^7,18,39

Treatments

Proper Skin Care and Treatment of AD
Therapy for AD and/or pruritus appears to limit lesion number in children with MCV and rashes or itch.^7,36 I recommend barrier repair agents, including emollients and syndet bar cleansers, to prevent small breaks in the skin that occur with xerosis and AD and that increase itch and risk of spread. Therapy for AD and molluscum dermatitis is similar and overlapping. There is always a concern about the spread of MCV when using topical calcineurin inhibitors. I, therefore, focus the dermatitis therapeutics on topical corticosteroid–based care.^6,40

Prevention of Spread
Prevention of spread begins with hygiene interventions. Cobathing is common in children with MCV and should be held off when possible. It is important for the child with MCV to avoid sharing bath towels and equipment²³ and having bare skin come in contact with mats in sports. I request that children with MCV wear bathing suits that cover the areas affected.

Reassurance
The most important therapy is reassurance.⁴¹ Many parents/guardians are truly unaware that the MCV infection can last for more than a year and therefore worry over normal disease course. When counseled as to the benign course of illness and given instructions on proper skin care, the parent/guardian of a child with MCV will often opt against therapy of uncomplicated cases. On the other hand, there are medical reasons for treatment, and they support the need for intervention (Table 3). Seventy percent of lesions resolve in 1.5 years; however, of the residual infections, some may last as long as 4 years.¹⁶ It is not recommended to stop children from attending school because of MCV.

Conclusion

Molluscum is a cutaneous viral infection that is common in children and has associated morbidities, including AD, pruritus, poor quality of life in some cases, and risk of contagion. Addressing the disease includes understanding its natural history and explaining it to parents/guardians. Therapeutics can be offered in cases where need is demonstrated, such as with lesions that spread and cause discomfort. Choice of therapeutics depends on the practitioner’s experience, the child’s clinical appearance, availability of therapy, and review of options with the parents/guardians. When avoidance of intervention is desired, barrier enhancement and treatment of symptomatic dermatitis are still beneficial, as are household (eg, not sharing towels) and activity (eg, adhesive bandages over active lesions) interventions to reduce transmission.

Molluscum contagiosum virus (MCV) infection causes the cutaneous lesions we call molluscum. Molluscum has become common in the last 30 years. Deciding the best course of therapy requires some fundamental understanding about how MCV relates to the following factors: epidemiology, childhood immunity and vaccination, clinical features, comorbidities, and quality of life. Treatment depends on many factors, including presence or absence of atopic dermatitis (AD) and/or pruritus, other symptoms, cosmetic location, and the child’s concern about the lesions. Therapeutics include destructive and immunologic therapies, the latter geared toward increasing immune response.

Epidemiology

Molluscum contagiosum virus is the solo member of the Molluscipoxvirus genus. Infection with MCV causes benign growth or tumors in the skin (ie, molluscum). The infection is slow to clear because the virus reduces the host’s immunity.^1,2 Molluscum contagiosum virus is a double-stranded DNA virus that affects keratinocytes and genetically carries the tools for its own replication (ie, DNA-dependent RNA polymerase). The virus has a few subtypes—I/Ia, II, III, and IV—with MCV-I predominating in children and healthy humans and MCV-II in patients with human immunodeficiency virus.^1,2 Typing is experimental and is not standardly performed in clinical practice. Molluscum contagiosum virus produces a variety of factors that block the host’s immune response, prolonging infection and preventing erythema and inflammatory response.³

Molluscum contagiosum virus is transmitted through skin-to-skin contact and fomites, including shared towels, bathtubs, spas, bath sponges, and pool equipment.^2,4,5 Transmission from household contact and bathing together has been noted in pediatric patients with MCV. Based on the data it can be posited that the lesions are softer when wet and more readily release viral particles or fomites, and fomites may be left on surfaces, especially when a child is wet.^6,7 Propensity for infection occurs in patients with AD and in immunosuppressed hosts, including children with human immunodeficiency virus and iatrogenic immunosuppression caused by chemotherapy.^1,2,8 Contact sports can increase the risk of transmission, and outbreaks have occurred in pools,^5,9 day-care facilities,¹⁰ and sports settings.¹¹ Cases of congenital and vertically transmitted molluscum have been documented.^12,13 Sexual transmission of MCV may be seen in adolescents who are sexually active. Although child-to-child transmission can occur in the groin area from shared equipment, transmission via sexual abuse also is possible.¹⁴ Bargman¹⁵ has mentioned the isolated genital location and lack of contact with other infected children as concerning features. Latency of new lesion appearance is anywhere from 1 to 50 days from the date of inoculation; therefore, new lesions are possible and expected even after therapy has been effective in eradicating visible lesions.¹⁰ Although clearance has been reported in 6 to 12 months, one pediatric study demonstrated 70% clearance by 1.5 years, suggesting the disease often is more prolonged.¹⁶ One-third of children will experience signs of inflammation, such as pruritus and/or erythema. Rare side effects include bacterial superinfection and hypersensitivity.²

One Dutch study from 1994, the largest database survey of children to date, cited a 17% cumulative incidence of molluscum in children by reviewing the data from 103 general practices.¹⁷ In a survey and review of molluscum by Braue et al,¹⁸ annual rates in populations vary but seem to maximize at approximately 6% to 7%. Sturt et al¹⁹ reviewed the prevalence in the indigenous West Sepik section of New Guinea and noted annual incidence rates of 6% in children younger than 10 years (range, 1.8%–10.9%). Epidemics occur and can produce large numbers of cases in a short time period.¹⁸ The cumulative prevalence in early childhood may be as high as 22%, as Sturt et al¹⁹ observed in children younger than 10 years.

Rising incidence and therefore rising lifetime prevalence appear to have been an issue in the last few decades. Data from the Indian Health Service have demonstrated increases in MCV in Native American children between 2001 and 2005.²⁰ In adults, the data support a steady increase of molluscum from 1988-2007, with a 3-fold increase from 1988-1997 to 1998-2007 in a Spanish study.²¹ Better population-based data are needed.

Childhood Immunity and Vaccination

Sequence homology between MC133L, a protein of MCV, with vaccinia virus suggests overlapping genes.²² Therefore, it is conceptually possible that the rise in incidence of MCV since the 1980s relates to the loss of herd immunity to variola due to lack of vaccination for smallpox, which has not been offered in the United States since 1972.²³ Childhood immunity to MCV varies among studies, but it appears that children do develop antibodies to molluscum in the setting of forming an immune response. Because the rise in molluscum incidence began after the smallpox vaccine was discontinued, the factors appear related; however, the scientific data do not support the theory of a relationship. Mitchell²⁴ has shown that a patient can develop antibodies in response to ground molluscum bodies inoculated into the skin; however, vaccination against molluscum and natural infection do not appear to produce antibodies that would cross-react and protect against other poxviruses, including vaccinia or fowl pox infections.²⁵ Cell-mediated immunity also is required to clear MCV and may account for the inflammatory appearance of lesions as they resolve.²⁶

Demonstrated factors that account for the rise in MCV incidence, aside from alterations in vaccination practices, include spread through sports,⁹ swimming,¹¹ and AD,⁷ which have become more commonplace in the United States in the last few decades, supporting the theory that they may be the cause of the increase in childhood MCV infections. Another cause may be the ability of MCV to create factors that stem host immune response.¹

Clinical Features

Molluscum lesions have a typical appearance of pearly papules with a central dell. These lesions are lighter to flesh colored and measure 1 to 3 mm.^2,4,5 The lesions cluster in the axillae and extremities and average from 10 to 20 per child.⁶ Lesions clear spontaneously, but new ones will continue to form until immunity is developed. Specific clinical appearances of lesions that are not pearly papules are not infrequent. Table 1 contains a short list of the manifold clinical appearances of molluscum lesions in children.^1,2,7,27-35 In particular, certain clinical appearances should be considered. In small children, head and neck lesions resembling milia are not uncommon. Giant or wartlike lesions can appear on the head, neck, or gluteal region in children and are clinical mimics of condyloma or other warts (Figure 1). Giant lesions also can grow in the subcutaneous space and mimic a cyst or abscess.²⁷ Erosive lesions mimicking eczema vaccinatum can be seen (Figure 2), but dermoscopy may demonstrate central dells in some lesions. Other viral processes mimicked include Gianotti Crosti–like lesions (Figure 3) that appear when a papular id reaction forms over the extremities or a localized version in the axilla, mimicking unilateral laterothoracic exanthema.^2,36,37 Hypersensitivity reactions are commonly noted with clearance and can be papular or demonstrate swelling and erythema, termed the beginning-of-the-end sign.³⁸

Pruritus, erythema, and swelling can occur with clearance but do not appear in all patients. Addressing pruritus is important to prevent disease spread, as patients are likely to inoculate other areas of the skin with virus when they scratch, and lesion number is reduced with dermatitis interventions.³⁶

Comorbidities

Molluscum lesions can occur in any child; however, the impaired immunologic status and skin barrier in patients with AD is ripe for the extensive spread of lesions that is associated with higher lesion count.³⁶ Children with molluscum infection can experience new-onset dermatitis or triggering of AD flares, especially on the extremities, such as the antecubital and popliteal regions.⁷ A study of children with MCV infection demonstrated that treatment of active dermatitis reduced spread. The authors mentioned autoinoculation as the mechanism; however, these data also suggest supporting barrier state as a factor in disease spread.³⁶ Superinfection can occur prior to⁶ or after therapy for lesions,³⁷ but it is unclear if this relates to the underlying atopic diathesis. Children with molluscum have been described to have warts, psoriasis, family history of atopy, diabetes mellitus, and pityriasis alba,⁷ while immunosuppression of any kind is associated with molluscum and high lesion count or prolonged disease in childhood.^1,2

Quality of Life

Children with molluscum who have higher lesion counts appear to be at risk for severe effects on their quality of life. Approximately 10% of children with MCV infection have been documented to have severe impairments on quality of life.³⁹ In my practice, quality of life in children with MCV appears to be affected by many factors (Table 2).^7,18,39

Treatments

Proper Skin Care and Treatment of AD
Therapy for AD and/or pruritus appears to limit lesion number in children with MCV and rashes or itch.^7,36 I recommend barrier repair agents, including emollients and syndet bar cleansers, to prevent small breaks in the skin that occur with xerosis and AD and that increase itch and risk of spread. Therapy for AD and molluscum dermatitis is similar and overlapping. There is always a concern about the spread of MCV when using topical calcineurin inhibitors. I, therefore, focus the dermatitis therapeutics on topical corticosteroid–based care.^6,40

Prevention of Spread
Prevention of spread begins with hygiene interventions. Cobathing is common in children with MCV and should be held off when possible. It is important for the child with MCV to avoid sharing bath towels and equipment²³ and having bare skin come in contact with mats in sports. I request that children with MCV wear bathing suits that cover the areas affected.

Reassurance
The most important therapy is reassurance.⁴¹ Many parents/guardians are truly unaware that the MCV infection can last for more than a year and therefore worry over normal disease course. When counseled as to the benign course of illness and given instructions on proper skin care, the parent/guardian of a child with MCV will often opt against therapy of uncomplicated cases. On the other hand, there are medical reasons for treatment, and they support the need for intervention (Table 3). Seventy percent of lesions resolve in 1.5 years; however, of the residual infections, some may last as long as 4 years.¹⁶ It is not recommended to stop children from attending school because of MCV.

Conclusion

Molluscum is a cutaneous viral infection that is common in children and has associated morbidities, including AD, pruritus, poor quality of life in some cases, and risk of contagion. Addressing the disease includes understanding its natural history and explaining it to parents/guardians. Therapeutics can be offered in cases where need is demonstrated, such as with lesions that spread and cause discomfort. Choice of therapeutics depends on the practitioner’s experience, the child’s clinical appearance, availability of therapy, and review of options with the parents/guardians. When avoidance of intervention is desired, barrier enhancement and treatment of symptomatic dermatitis are still beneficial, as are household (eg, not sharing towels) and activity (eg, adhesive bandages over active lesions) interventions to reduce transmission.

Molluscum contagiosum virus (MCV) infection causes the cutaneous lesions we call molluscum. Molluscum has become common in the last 30 years. Deciding the best course of therapy requires some fundamental understanding about how MCV relates to the following factors: epidemiology, childhood immunity and vaccination, clinical features, comorbidities, and quality of life. Treatment depends on many factors, including presence or absence of atopic dermatitis (AD) and/or pruritus, other symptoms, cosmetic location, and the child’s concern about the lesions. Therapeutics include destructive and immunologic therapies, the latter geared toward increasing immune response.

Epidemiology

Molluscum contagiosum virus is the solo member of the Molluscipoxvirus genus. Infection with MCV causes benign growth or tumors in the skin (ie, molluscum). The infection is slow to clear because the virus reduces the host’s immunity.^1,2 Molluscum contagiosum virus is a double-stranded DNA virus that affects keratinocytes and genetically carries the tools for its own replication (ie, DNA-dependent RNA polymerase). The virus has a few subtypes—I/Ia, II, III, and IV—with MCV-I predominating in children and healthy humans and MCV-II in patients with human immunodeficiency virus.^1,2 Typing is experimental and is not standardly performed in clinical practice. Molluscum contagiosum virus produces a variety of factors that block the host’s immune response, prolonging infection and preventing erythema and inflammatory response.³

Molluscum contagiosum virus is transmitted through skin-to-skin contact and fomites, including shared towels, bathtubs, spas, bath sponges, and pool equipment.^2,4,5 Transmission from household contact and bathing together has been noted in pediatric patients with MCV. Based on the data it can be posited that the lesions are softer when wet and more readily release viral particles or fomites, and fomites may be left on surfaces, especially when a child is wet.^6,7 Propensity for infection occurs in patients with AD and in immunosuppressed hosts, including children with human immunodeficiency virus and iatrogenic immunosuppression caused by chemotherapy.^1,2,8 Contact sports can increase the risk of transmission, and outbreaks have occurred in pools,^5,9 day-care facilities,¹⁰ and sports settings.¹¹ Cases of congenital and vertically transmitted molluscum have been documented.^12,13 Sexual transmission of MCV may be seen in adolescents who are sexually active. Although child-to-child transmission can occur in the groin area from shared equipment, transmission via sexual abuse also is possible.¹⁴ Bargman¹⁵ has mentioned the isolated genital location and lack of contact with other infected children as concerning features. Latency of new lesion appearance is anywhere from 1 to 50 days from the date of inoculation; therefore, new lesions are possible and expected even after therapy has been effective in eradicating visible lesions.¹⁰ Although clearance has been reported in 6 to 12 months, one pediatric study demonstrated 70% clearance by 1.5 years, suggesting the disease often is more prolonged.¹⁶ One-third of children will experience signs of inflammation, such as pruritus and/or erythema. Rare side effects include bacterial superinfection and hypersensitivity.²

One Dutch study from 1994, the largest database survey of children to date, cited a 17% cumulative incidence of molluscum in children by reviewing the data from 103 general practices.¹⁷ In a survey and review of molluscum by Braue et al,¹⁸ annual rates in populations vary but seem to maximize at approximately 6% to 7%. Sturt et al¹⁹ reviewed the prevalence in the indigenous West Sepik section of New Guinea and noted annual incidence rates of 6% in children younger than 10 years (range, 1.8%–10.9%). Epidemics occur and can produce large numbers of cases in a short time period.¹⁸ The cumulative prevalence in early childhood may be as high as 22%, as Sturt et al¹⁹ observed in children younger than 10 years.

Rising incidence and therefore rising lifetime prevalence appear to have been an issue in the last few decades. Data from the Indian Health Service have demonstrated increases in MCV in Native American children between 2001 and 2005.²⁰ In adults, the data support a steady increase of molluscum from 1988-2007, with a 3-fold increase from 1988-1997 to 1998-2007 in a Spanish study.²¹ Better population-based data are needed.

Childhood Immunity and Vaccination

Sequence homology between MC133L, a protein of MCV, with vaccinia virus suggests overlapping genes.²² Therefore, it is conceptually possible that the rise in incidence of MCV since the 1980s relates to the loss of herd immunity to variola due to lack of vaccination for smallpox, which has not been offered in the United States since 1972.²³ Childhood immunity to MCV varies among studies, but it appears that children do develop antibodies to molluscum in the setting of forming an immune response. Because the rise in molluscum incidence began after the smallpox vaccine was discontinued, the factors appear related; however, the scientific data do not support the theory of a relationship. Mitchell²⁴ has shown that a patient can develop antibodies in response to ground molluscum bodies inoculated into the skin; however, vaccination against molluscum and natural infection do not appear to produce antibodies that would cross-react and protect against other poxviruses, including vaccinia or fowl pox infections.²⁵ Cell-mediated immunity also is required to clear MCV and may account for the inflammatory appearance of lesions as they resolve.²⁶

Demonstrated factors that account for the rise in MCV incidence, aside from alterations in vaccination practices, include spread through sports,⁹ swimming,¹¹ and AD,⁷ which have become more commonplace in the United States in the last few decades, supporting the theory that they may be the cause of the increase in childhood MCV infections. Another cause may be the ability of MCV to create factors that stem host immune response.¹

Clinical Features

Molluscum lesions have a typical appearance of pearly papules with a central dell. These lesions are lighter to flesh colored and measure 1 to 3 mm.^2,4,5 The lesions cluster in the axillae and extremities and average from 10 to 20 per child.⁶ Lesions clear spontaneously, but new ones will continue to form until immunity is developed. Specific clinical appearances of lesions that are not pearly papules are not infrequent. Table 1 contains a short list of the manifold clinical appearances of molluscum lesions in children.^1,2,7,27-35 In particular, certain clinical appearances should be considered. In small children, head and neck lesions resembling milia are not uncommon. Giant or wartlike lesions can appear on the head, neck, or gluteal region in children and are clinical mimics of condyloma or other warts (Figure 1). Giant lesions also can grow in the subcutaneous space and mimic a cyst or abscess.²⁷ Erosive lesions mimicking eczema vaccinatum can be seen (Figure 2), but dermoscopy may demonstrate central dells in some lesions. Other viral processes mimicked include Gianotti Crosti–like lesions (Figure 3) that appear when a papular id reaction forms over the extremities or a localized version in the axilla, mimicking unilateral laterothoracic exanthema.^2,36,37 Hypersensitivity reactions are commonly noted with clearance and can be papular or demonstrate swelling and erythema, termed the beginning-of-the-end sign.³⁸

Pruritus, erythema, and swelling can occur with clearance but do not appear in all patients. Addressing pruritus is important to prevent disease spread, as patients are likely to inoculate other areas of the skin with virus when they scratch, and lesion number is reduced with dermatitis interventions.³⁶

Comorbidities

Molluscum lesions can occur in any child; however, the impaired immunologic status and skin barrier in patients with AD is ripe for the extensive spread of lesions that is associated with higher lesion count.³⁶ Children with molluscum infection can experience new-onset dermatitis or triggering of AD flares, especially on the extremities, such as the antecubital and popliteal regions.⁷ A study of children with MCV infection demonstrated that treatment of active dermatitis reduced spread. The authors mentioned autoinoculation as the mechanism; however, these data also suggest supporting barrier state as a factor in disease spread.³⁶ Superinfection can occur prior to⁶ or after therapy for lesions,³⁷ but it is unclear if this relates to the underlying atopic diathesis. Children with molluscum have been described to have warts, psoriasis, family history of atopy, diabetes mellitus, and pityriasis alba,⁷ while immunosuppression of any kind is associated with molluscum and high lesion count or prolonged disease in childhood.^1,2

Quality of Life

Children with molluscum who have higher lesion counts appear to be at risk for severe effects on their quality of life. Approximately 10% of children with MCV infection have been documented to have severe impairments on quality of life.³⁹ In my practice, quality of life in children with MCV appears to be affected by many factors (Table 2).^7,18,39

Treatments

Proper Skin Care and Treatment of AD
Therapy for AD and/or pruritus appears to limit lesion number in children with MCV and rashes or itch.^7,36 I recommend barrier repair agents, including emollients and syndet bar cleansers, to prevent small breaks in the skin that occur with xerosis and AD and that increase itch and risk of spread. Therapy for AD and molluscum dermatitis is similar and overlapping. There is always a concern about the spread of MCV when using topical calcineurin inhibitors. I, therefore, focus the dermatitis therapeutics on topical corticosteroid–based care.^6,40

Prevention of Spread
Prevention of spread begins with hygiene interventions. Cobathing is common in children with MCV and should be held off when possible. It is important for the child with MCV to avoid sharing bath towels and equipment²³ and having bare skin come in contact with mats in sports. I request that children with MCV wear bathing suits that cover the areas affected.

Reassurance
The most important therapy is reassurance.⁴¹ Many parents/guardians are truly unaware that the MCV infection can last for more than a year and therefore worry over normal disease course. When counseled as to the benign course of illness and given instructions on proper skin care, the parent/guardian of a child with MCV will often opt against therapy of uncomplicated cases. On the other hand, there are medical reasons for treatment, and they support the need for intervention (Table 3). Seventy percent of lesions resolve in 1.5 years; however, of the residual infections, some may last as long as 4 years.¹⁶ It is not recommended to stop children from attending school because of MCV.

Conclusion

Molluscum is a cutaneous viral infection that is common in children and has associated morbidities, including AD, pruritus, poor quality of life in some cases, and risk of contagion. Addressing the disease includes understanding its natural history and explaining it to parents/guardians. Therapeutics can be offered in cases where need is demonstrated, such as with lesions that spread and cause discomfort. Choice of therapeutics depends on the practitioner’s experience, the child’s clinical appearance, availability of therapy, and review of options with the parents/guardians. When avoidance of intervention is desired, barrier enhancement and treatment of symptomatic dermatitis are still beneficial, as are household (eg, not sharing towels) and activity (eg, adhesive bandages over active lesions) interventions to reduce transmission.

The pediatric population has a unique product exposure profile due to the many care products specifically marketed for use in children. In fact, the prevalence of allergic contact dermatitis (ACD) in children may be as high as 24.5% in the United States.¹ In patch tested children, relevant positive reaction rates of 56.7% and 48% have been reported by the North American Contact Dermatitis Group and the Pediatric Contact Dermatitis Registry, respectively.^2,3 In this article, we provide an overview of current trends in pediatric patch testing as well as specific considerations in this patient population.

Patch Test Reactions in Children

Several publications have documented pediatric patch test reactions. The North American Contact Dermatitis Group reported patch test results in 883 children from the United States and Canada (2005-2012).² The most common reactions were nickel (28.1%), cobalt (12.3%), neomycin (7.1%), balsam of Peru (5.7%), lanolin (5.5%), and fragrance mix I (5.2%). When compared to adults, children were more likely to have relevant positive patch tests to nickel, cobalt, and compositae mix.² In comparison, data from the Pediatric Contact Dermatitis Registry showed that the most common reactions in 1142 children in the United States (2015-2016) were nickel (22%), fragrance mix I (11%), cobalt (9.1%), balsam of Peru (8.4%), neomycin (7.2%), and propylene glycol (6.8%).³

Allergen sensitivities may vary based on geographic region. In Spain, children showed the highest sensitivities to thiomersal (10.2%), cobalt (9.1%), colophony (9.1%), paraphenylenediamine (8.3%), mercury (7.9%), potassium dichromate (7.9%), and nickel (6.4%).⁴

Pediatric Patch Testing Pearls

History of Product Use
From diapers to drama club, pediatric exposures and sources of ACD are not the same as those seen in adults. Because obtaining a medical history from a toddler can be exasperating, the patient’s caregivers should be asked about potential exposures, ranging from personal care products and diapers to school activities, hobbies, and sports.^5,6 It is important to keep in mind that the patient’s primary caregiver may not be the only individual who applies products to the child.⁷

Application of Allergens
Children are not merely small adults, but they usually do have smaller backs than adult patients. This reduced surface area means that the patch tester must carefully select the allergens to be patch tested. For reference, the back of a typical 6-year-old child can fit 40 to 60 allergens during patch testing.⁸

Patch Test Chambers
In children, the use of plastic patch test chambers may be preferred over aluminum chambers. Children with persistent pruritic subcutaneous nodules induced by aluminum-based vaccines also may have delayed-type sensitivity reactions to aluminum.⁹ These patients could react to the aluminum present in some patch test chambers, making interpretation of the results difficult. The authors (A.R.A. and M.R.) typically use plastic chambers in the pediatric population.

Managing Expectations
As with other procedures in the pediatric population, patch testing can elicit emotions of fear, anxiety, and distrust. Video distraction and/or role-playing games may help capture the attention of children and can be particularly helpful during patch application. Children may be apprehensive about the term allergy testing if they are familiar with the term needle testing from previous allergies.⁵

Securing Patches
Young children can be quite active, posing another challenge for keeping patches in place. We recommend using extra tape to secure the patches in place on a child’s back. In addition, a large transparent film dressing (ie, 12×8 in) can be used if quick application is needed. For extra precaution, the use of a tight T-shirt or favorite onesie during the patch test process may be helpful, making it more difficult for little fingers to remove tape edges.

Duration of Patch Testing
Some authors have proposed application of patch tests for 24 hours in pediatric patients, as compared to 48 hours in adults.¹⁰ This recommendation is based on a theory that the reduced application period will decrease the risk for irritant reactions in pediatric patients.

Pediatric Patch Test Screening Series

A summary of the published screening series for patch testing in the pediatric population is provided (Table).

The T.R.U.E. Test (SmartPractice) is approved by the US Food and Drug Administration for use in patients 6 years and older¹¹; however, it may not adequately represent allergen exposures in the pediatric population. Brankov and Jacob¹⁴ found that 10 (40%) of their proposed top 25 pediatric allergens were not detected using the T.R.U.E. Test.

In 2014, the North American Pediatric Patch Test Series was proposed as a basic screening panel for children aged 6 to 12 years.¹² This series of 20 allergens was developed based on a literature review of pediatric patch test results and case reports as well as a database review. The authors proposed additional allergens to be considered based on patient history.¹²

More recently, a 2017 American Contact Dermatitis Society physician work group proposed the Pediatric Baseline Patch Test Series. This series of 38 allergens for children aged 6 to 18 years was developed based on expert consensus.⁸ Studies to determine the efficacy of this series have yet to be conducted, but it may have high sensitivity in detecting relevant allergens in children as demonstrated by a theoretical detection rate of 84%.¹⁴

There are 2 recommended patch test series for allergic diaper dermatitis.¹⁵ The first series focuses on 23 potential allergens found in wet wipes and topical diaper preparations. The second series contains 10 potential allergens found in diapers. These series contain common topical medications for children including corticosteroids, antimicrobials, and sensitizers specific to diapers such as rubbers and adhesives.¹⁵

Similar to adults, it may be difficult to designate one screening panel that can identify all relevant allergens in children; thus, it is always important to obtain a thorough exposure history and customize testing to suspected allergens and/or patient products based on history and clinical relevance.

Unique Pediatric Allergens

Hobbies
Sports gear such as shin guards and splints often contain allergens such as formaldehyde resin, thiuram mix, and dialkyl thioureas.¹⁶ Perioral dermatitis may be caused by musical instrument mouthpieces containing nickel.⁶

Preservatives
Commonly reported causes of ACD in children include methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI) found in wet wipes. A 2016 analysis of diaper wipes showed a low prevalence of MI (6.3%) and MCI (1.6%) in these products, which may reflect the industry’s awareness of these potential allergens and a subsequent change in the preservatives they utilize.¹⁷ However, the prevalence of MCI/MI contact allergy may be on the rise due to the popularity of homemade slime, which is made from common household products such as laundry detergent, dishwashing soap, and liquid glue. The Pediatric Baseline Patch Test Series captures most of the potential allergens in these homemade slime recipes and is recommended for use in pediatric patients suspected of having dermatitis secondary to playing with slime.^8,18

Toilet Seat Dermatitis
Toilet seat dermatitis presents as a pruritic dermatitis on the posterior upper thighs and buttocks. Although most cases of toilet seat dermatitis are irritant rather than allergic, potential allergens include plastics, fragrances, and components of cleaning products. Thus, physicians should maintain a high index of suspicion for ACD to toilet seats.¹⁹

Fragrance and Natural Ingredients
A 2018 study evaluating personal care products marketed specifically for infants and children found that 55% of products (294/533) contained at least 1 common allergen, with fragrance being the most common (48% [255/533]). Other common allergens include betaines (18%), propylene glycol (9%), lanolin (6%), and MCI/MI (3%).²⁰ Caregivers should be advised against the myth that natural products are safer and less allergenic and should be provided with resources such as the Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) for safe alternative personal care products.

Metal Allergens
Nickel, the American Contact Dermatitis Society 2008 Allergen of the Year, is another common allergen that affects children. Nickel allergy, commonly thought to affect the ears due to jewelry and ear piercing, may actually be found in a wide range of daily items such as braces, eyeglasses, keys, zippers, school chairs, electronics, toys, and even food.^3,6,21,22 With increased use of electronics in children of all ages, nickel found in mobile phones and other devices may be of particular concern. Caregivers can use a case or cover for metallic-appearing electronics.

Final Interpretation

Pediatric ACD is common. With limited surface area for patch testing in children, we recommend customized panels based on patient history and exposure. It is important for clinicians to recognize the unique causes of ACD in children and develop age-appropriate management plans.

The pediatric population has a unique product exposure profile due to the many care products specifically marketed for use in children. In fact, the prevalence of allergic contact dermatitis (ACD) in children may be as high as 24.5% in the United States.¹ In patch tested children, relevant positive reaction rates of 56.7% and 48% have been reported by the North American Contact Dermatitis Group and the Pediatric Contact Dermatitis Registry, respectively.^2,3 In this article, we provide an overview of current trends in pediatric patch testing as well as specific considerations in this patient population.

Patch Test Reactions in Children

Several publications have documented pediatric patch test reactions. The North American Contact Dermatitis Group reported patch test results in 883 children from the United States and Canada (2005-2012).² The most common reactions were nickel (28.1%), cobalt (12.3%), neomycin (7.1%), balsam of Peru (5.7%), lanolin (5.5%), and fragrance mix I (5.2%). When compared to adults, children were more likely to have relevant positive patch tests to nickel, cobalt, and compositae mix.² In comparison, data from the Pediatric Contact Dermatitis Registry showed that the most common reactions in 1142 children in the United States (2015-2016) were nickel (22%), fragrance mix I (11%), cobalt (9.1%), balsam of Peru (8.4%), neomycin (7.2%), and propylene glycol (6.8%).³

Allergen sensitivities may vary based on geographic region. In Spain, children showed the highest sensitivities to thiomersal (10.2%), cobalt (9.1%), colophony (9.1%), paraphenylenediamine (8.3%), mercury (7.9%), potassium dichromate (7.9%), and nickel (6.4%).⁴

Pediatric Patch Testing Pearls

History of Product Use
From diapers to drama club, pediatric exposures and sources of ACD are not the same as those seen in adults. Because obtaining a medical history from a toddler can be exasperating, the patient’s caregivers should be asked about potential exposures, ranging from personal care products and diapers to school activities, hobbies, and sports.^5,6 It is important to keep in mind that the patient’s primary caregiver may not be the only individual who applies products to the child.⁷

Application of Allergens
Children are not merely small adults, but they usually do have smaller backs than adult patients. This reduced surface area means that the patch tester must carefully select the allergens to be patch tested. For reference, the back of a typical 6-year-old child can fit 40 to 60 allergens during patch testing.⁸

Patch Test Chambers
In children, the use of plastic patch test chambers may be preferred over aluminum chambers. Children with persistent pruritic subcutaneous nodules induced by aluminum-based vaccines also may have delayed-type sensitivity reactions to aluminum.⁹ These patients could react to the aluminum present in some patch test chambers, making interpretation of the results difficult. The authors (A.R.A. and M.R.) typically use plastic chambers in the pediatric population.

Managing Expectations
As with other procedures in the pediatric population, patch testing can elicit emotions of fear, anxiety, and distrust. Video distraction and/or role-playing games may help capture the attention of children and can be particularly helpful during patch application. Children may be apprehensive about the term allergy testing if they are familiar with the term needle testing from previous allergies.⁵

Securing Patches
Young children can be quite active, posing another challenge for keeping patches in place. We recommend using extra tape to secure the patches in place on a child’s back. In addition, a large transparent film dressing (ie, 12×8 in) can be used if quick application is needed. For extra precaution, the use of a tight T-shirt or favorite onesie during the patch test process may be helpful, making it more difficult for little fingers to remove tape edges.

Duration of Patch Testing
Some authors have proposed application of patch tests for 24 hours in pediatric patients, as compared to 48 hours in adults.¹⁰ This recommendation is based on a theory that the reduced application period will decrease the risk for irritant reactions in pediatric patients.

Pediatric Patch Test Screening Series

A summary of the published screening series for patch testing in the pediatric population is provided (Table).

The T.R.U.E. Test (SmartPractice) is approved by the US Food and Drug Administration for use in patients 6 years and older¹¹; however, it may not adequately represent allergen exposures in the pediatric population. Brankov and Jacob¹⁴ found that 10 (40%) of their proposed top 25 pediatric allergens were not detected using the T.R.U.E. Test.

In 2014, the North American Pediatric Patch Test Series was proposed as a basic screening panel for children aged 6 to 12 years.¹² This series of 20 allergens was developed based on a literature review of pediatric patch test results and case reports as well as a database review. The authors proposed additional allergens to be considered based on patient history.¹²

More recently, a 2017 American Contact Dermatitis Society physician work group proposed the Pediatric Baseline Patch Test Series. This series of 38 allergens for children aged 6 to 18 years was developed based on expert consensus.⁸ Studies to determine the efficacy of this series have yet to be conducted, but it may have high sensitivity in detecting relevant allergens in children as demonstrated by a theoretical detection rate of 84%.¹⁴

There are 2 recommended patch test series for allergic diaper dermatitis.¹⁵ The first series focuses on 23 potential allergens found in wet wipes and topical diaper preparations. The second series contains 10 potential allergens found in diapers. These series contain common topical medications for children including corticosteroids, antimicrobials, and sensitizers specific to diapers such as rubbers and adhesives.¹⁵

Similar to adults, it may be difficult to designate one screening panel that can identify all relevant allergens in children; thus, it is always important to obtain a thorough exposure history and customize testing to suspected allergens and/or patient products based on history and clinical relevance.

Unique Pediatric Allergens

Hobbies
Sports gear such as shin guards and splints often contain allergens such as formaldehyde resin, thiuram mix, and dialkyl thioureas.¹⁶ Perioral dermatitis may be caused by musical instrument mouthpieces containing nickel.⁶

Preservatives
Commonly reported causes of ACD in children include methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI) found in wet wipes. A 2016 analysis of diaper wipes showed a low prevalence of MI (6.3%) and MCI (1.6%) in these products, which may reflect the industry’s awareness of these potential allergens and a subsequent change in the preservatives they utilize.¹⁷ However, the prevalence of MCI/MI contact allergy may be on the rise due to the popularity of homemade slime, which is made from common household products such as laundry detergent, dishwashing soap, and liquid glue. The Pediatric Baseline Patch Test Series captures most of the potential allergens in these homemade slime recipes and is recommended for use in pediatric patients suspected of having dermatitis secondary to playing with slime.^8,18

Toilet Seat Dermatitis
Toilet seat dermatitis presents as a pruritic dermatitis on the posterior upper thighs and buttocks. Although most cases of toilet seat dermatitis are irritant rather than allergic, potential allergens include plastics, fragrances, and components of cleaning products. Thus, physicians should maintain a high index of suspicion for ACD to toilet seats.¹⁹

Fragrance and Natural Ingredients
A 2018 study evaluating personal care products marketed specifically for infants and children found that 55% of products (294/533) contained at least 1 common allergen, with fragrance being the most common (48% [255/533]). Other common allergens include betaines (18%), propylene glycol (9%), lanolin (6%), and MCI/MI (3%).²⁰ Caregivers should be advised against the myth that natural products are safer and less allergenic and should be provided with resources such as the Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) for safe alternative personal care products.

Metal Allergens
Nickel, the American Contact Dermatitis Society 2008 Allergen of the Year, is another common allergen that affects children. Nickel allergy, commonly thought to affect the ears due to jewelry and ear piercing, may actually be found in a wide range of daily items such as braces, eyeglasses, keys, zippers, school chairs, electronics, toys, and even food.^3,6,21,22 With increased use of electronics in children of all ages, nickel found in mobile phones and other devices may be of particular concern. Caregivers can use a case or cover for metallic-appearing electronics.

Final Interpretation

Pediatric ACD is common. With limited surface area for patch testing in children, we recommend customized panels based on patient history and exposure. It is important for clinicians to recognize the unique causes of ACD in children and develop age-appropriate management plans.

The pediatric population has a unique product exposure profile due to the many care products specifically marketed for use in children. In fact, the prevalence of allergic contact dermatitis (ACD) in children may be as high as 24.5% in the United States.¹ In patch tested children, relevant positive reaction rates of 56.7% and 48% have been reported by the North American Contact Dermatitis Group and the Pediatric Contact Dermatitis Registry, respectively.^2,3 In this article, we provide an overview of current trends in pediatric patch testing as well as specific considerations in this patient population.

Patch Test Reactions in Children

Several publications have documented pediatric patch test reactions. The North American Contact Dermatitis Group reported patch test results in 883 children from the United States and Canada (2005-2012).² The most common reactions were nickel (28.1%), cobalt (12.3%), neomycin (7.1%), balsam of Peru (5.7%), lanolin (5.5%), and fragrance mix I (5.2%). When compared to adults, children were more likely to have relevant positive patch tests to nickel, cobalt, and compositae mix.² In comparison, data from the Pediatric Contact Dermatitis Registry showed that the most common reactions in 1142 children in the United States (2015-2016) were nickel (22%), fragrance mix I (11%), cobalt (9.1%), balsam of Peru (8.4%), neomycin (7.2%), and propylene glycol (6.8%).³

Allergen sensitivities may vary based on geographic region. In Spain, children showed the highest sensitivities to thiomersal (10.2%), cobalt (9.1%), colophony (9.1%), paraphenylenediamine (8.3%), mercury (7.9%), potassium dichromate (7.9%), and nickel (6.4%).⁴

Pediatric Patch Testing Pearls

History of Product Use
From diapers to drama club, pediatric exposures and sources of ACD are not the same as those seen in adults. Because obtaining a medical history from a toddler can be exasperating, the patient’s caregivers should be asked about potential exposures, ranging from personal care products and diapers to school activities, hobbies, and sports.^5,6 It is important to keep in mind that the patient’s primary caregiver may not be the only individual who applies products to the child.⁷

Application of Allergens
Children are not merely small adults, but they usually do have smaller backs than adult patients. This reduced surface area means that the patch tester must carefully select the allergens to be patch tested. For reference, the back of a typical 6-year-old child can fit 40 to 60 allergens during patch testing.⁸

Patch Test Chambers
In children, the use of plastic patch test chambers may be preferred over aluminum chambers. Children with persistent pruritic subcutaneous nodules induced by aluminum-based vaccines also may have delayed-type sensitivity reactions to aluminum.⁹ These patients could react to the aluminum present in some patch test chambers, making interpretation of the results difficult. The authors (A.R.A. and M.R.) typically use plastic chambers in the pediatric population.

Managing Expectations
As with other procedures in the pediatric population, patch testing can elicit emotions of fear, anxiety, and distrust. Video distraction and/or role-playing games may help capture the attention of children and can be particularly helpful during patch application. Children may be apprehensive about the term allergy testing if they are familiar with the term needle testing from previous allergies.⁵

Securing Patches
Young children can be quite active, posing another challenge for keeping patches in place. We recommend using extra tape to secure the patches in place on a child’s back. In addition, a large transparent film dressing (ie, 12×8 in) can be used if quick application is needed. For extra precaution, the use of a tight T-shirt or favorite onesie during the patch test process may be helpful, making it more difficult for little fingers to remove tape edges.

Duration of Patch Testing
Some authors have proposed application of patch tests for 24 hours in pediatric patients, as compared to 48 hours in adults.¹⁰ This recommendation is based on a theory that the reduced application period will decrease the risk for irritant reactions in pediatric patients.

Pediatric Patch Test Screening Series

A summary of the published screening series for patch testing in the pediatric population is provided (Table).

The T.R.U.E. Test (SmartPractice) is approved by the US Food and Drug Administration for use in patients 6 years and older¹¹; however, it may not adequately represent allergen exposures in the pediatric population. Brankov and Jacob¹⁴ found that 10 (40%) of their proposed top 25 pediatric allergens were not detected using the T.R.U.E. Test.

In 2014, the North American Pediatric Patch Test Series was proposed as a basic screening panel for children aged 6 to 12 years.¹² This series of 20 allergens was developed based on a literature review of pediatric patch test results and case reports as well as a database review. The authors proposed additional allergens to be considered based on patient history.¹²

More recently, a 2017 American Contact Dermatitis Society physician work group proposed the Pediatric Baseline Patch Test Series. This series of 38 allergens for children aged 6 to 18 years was developed based on expert consensus.⁸ Studies to determine the efficacy of this series have yet to be conducted, but it may have high sensitivity in detecting relevant allergens in children as demonstrated by a theoretical detection rate of 84%.¹⁴

There are 2 recommended patch test series for allergic diaper dermatitis.¹⁵ The first series focuses on 23 potential allergens found in wet wipes and topical diaper preparations. The second series contains 10 potential allergens found in diapers. These series contain common topical medications for children including corticosteroids, antimicrobials, and sensitizers specific to diapers such as rubbers and adhesives.¹⁵

Similar to adults, it may be difficult to designate one screening panel that can identify all relevant allergens in children; thus, it is always important to obtain a thorough exposure history and customize testing to suspected allergens and/or patient products based on history and clinical relevance.

Unique Pediatric Allergens

Hobbies
Sports gear such as shin guards and splints often contain allergens such as formaldehyde resin, thiuram mix, and dialkyl thioureas.¹⁶ Perioral dermatitis may be caused by musical instrument mouthpieces containing nickel.⁶

Preservatives
Commonly reported causes of ACD in children include methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI) found in wet wipes. A 2016 analysis of diaper wipes showed a low prevalence of MI (6.3%) and MCI (1.6%) in these products, which may reflect the industry’s awareness of these potential allergens and a subsequent change in the preservatives they utilize.¹⁷ However, the prevalence of MCI/MI contact allergy may be on the rise due to the popularity of homemade slime, which is made from common household products such as laundry detergent, dishwashing soap, and liquid glue. The Pediatric Baseline Patch Test Series captures most of the potential allergens in these homemade slime recipes and is recommended for use in pediatric patients suspected of having dermatitis secondary to playing with slime.^8,18

Toilet Seat Dermatitis
Toilet seat dermatitis presents as a pruritic dermatitis on the posterior upper thighs and buttocks. Although most cases of toilet seat dermatitis are irritant rather than allergic, potential allergens include plastics, fragrances, and components of cleaning products. Thus, physicians should maintain a high index of suspicion for ACD to toilet seats.¹⁹

Fragrance and Natural Ingredients
A 2018 study evaluating personal care products marketed specifically for infants and children found that 55% of products (294/533) contained at least 1 common allergen, with fragrance being the most common (48% [255/533]). Other common allergens include betaines (18%), propylene glycol (9%), lanolin (6%), and MCI/MI (3%).²⁰ Caregivers should be advised against the myth that natural products are safer and less allergenic and should be provided with resources such as the Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) for safe alternative personal care products.

Metal Allergens
Nickel, the American Contact Dermatitis Society 2008 Allergen of the Year, is another common allergen that affects children. Nickel allergy, commonly thought to affect the ears due to jewelry and ear piercing, may actually be found in a wide range of daily items such as braces, eyeglasses, keys, zippers, school chairs, electronics, toys, and even food.^3,6,21,22 With increased use of electronics in children of all ages, nickel found in mobile phones and other devices may be of particular concern. Caregivers can use a case or cover for metallic-appearing electronics.

Final Interpretation

Pediatric ACD is common. With limited surface area for patch testing in children, we recommend customized panels based on patient history and exposure. It is important for clinicians to recognize the unique causes of ACD in children and develop age-appropriate management plans.

BARCELONA – Disturbed HDL cholesterol metabolism is one of the earliest features that may predispose individuals to the development of type 2 diabetes, according to data from a genetics and metabolomics study conducted in the United Kingdom.

Sara Freeman/MDedge News

Changes in HDL cholesterol metabolism were seen in children as young as 8 years, decades before the clinical onset of disease, Joshua Bell, PhD, a research fellow at the University of Bristol (England), reported at the annual meeting of the European Association for the Study of Diabetes.

“We know that type 2 diabetes certainly doesn’t develop overnight,” Dr. Bell said. Indeed, data exist showing that there are changes in glucose metabolism several years before a formal diagnosis may be made in adults. “What we don’t know is what the very earliest features of diabetes look like,” he added.

“The main assumption is that type 2 diabetes is a metabolic disease, and so disease features are visible in systemic metabolism,” explained Dr. Bell. What was not clear, however, was that if any metabolic features – seen mainly in observational studies and in adults – were caused by the disease itself or perhaps were independent causes of type 2 diabetes.To investigate, Dr. Bell and associates performed a study linking genetic liability with metabolomic data collected at four time points from 4,761 offspring from participants in the Avon Longitudinal Study of Parents and Children cohort, which is also known as the Children of the 90s cohort. More than 200 metabolic traits were considered, and a genetic risk score comprising more than 162 single nucleotide polymorphisms previously linked to adult type 2 diabetes was used.

The metabolomic traits considered included lipoprotein subclass-specific cholesterol and triglyceride content, amino and fatty acids, and inflammatory glycoprotein acetyls, which had been measured in childhood at the age of 8 years, in adolescence at 16 years, in young adulthood at 18 years, and in adulthood at 25 years.

Early metabolic features of type 2 diabetes liability were grouped together and one feature that stood out was the sizes of lipid particles. In particular, it was the size of HDL cholesterol particle subtypes in children at the age of 8 years. Before other types of changes in lipid particles were being seen, there were reductions in the lipid content of HDL cholesterol particle subtypes, notably those that were very large.

By age 16 years, strong associations remained with lower lipids in HDL cholesterol particle subtypes and type 2 diabetes liability, which became stronger with preglycemic traits, such as citrate, and with glycoprotein acetyls. By age 18 years, elevations were seen in branched amino acids, and by age 25, association had strengthened for the lipid content of very low–density lipoprotein cholesterol.

“Linking genetic liability to adult disease with traits measured much earlier in life can tell you something about how the disease activity unfolds over a lifetime,” Dr. Bell said, adding that the feature that was “most consistently tracked” could be evaluated and could help reveal whether or not an individual might go on to develop type 2 diabetes.

In a press release issued by the EASD, Dr. Bell observed: “It’s remarkable that we can see signs of adult diabetes in the blood from such a young age. Knowing what early features of type 2 diabetes look like, could help us to intervene much earlier to halt progression to full-blown diabetes and its complications.”

The study was funded by Diabetes U.K., Cancer Research U.K., the Elizabeth Blackwell Institute for Health Research, the Wellcome Trust, the Medical Research Council, and the University of Bristol. Dr. Bell said he had no conflicts of interest to declare.

SOURCE: Bell J et al. bioRxiv. 2019 Sep 17. doi: 10.1101/767756.
 

BARCELONA – Disturbed HDL cholesterol metabolism is one of the earliest features that may predispose individuals to the development of type 2 diabetes, according to data from a genetics and metabolomics study conducted in the United Kingdom.

Sara Freeman/MDedge News

Changes in HDL cholesterol metabolism were seen in children as young as 8 years, decades before the clinical onset of disease, Joshua Bell, PhD, a research fellow at the University of Bristol (England), reported at the annual meeting of the European Association for the Study of Diabetes.

“We know that type 2 diabetes certainly doesn’t develop overnight,” Dr. Bell said. Indeed, data exist showing that there are changes in glucose metabolism several years before a formal diagnosis may be made in adults. “What we don’t know is what the very earliest features of diabetes look like,” he added.

“The main assumption is that type 2 diabetes is a metabolic disease, and so disease features are visible in systemic metabolism,” explained Dr. Bell. What was not clear, however, was that if any metabolic features – seen mainly in observational studies and in adults – were caused by the disease itself or perhaps were independent causes of type 2 diabetes.To investigate, Dr. Bell and associates performed a study linking genetic liability with metabolomic data collected at four time points from 4,761 offspring from participants in the Avon Longitudinal Study of Parents and Children cohort, which is also known as the Children of the 90s cohort. More than 200 metabolic traits were considered, and a genetic risk score comprising more than 162 single nucleotide polymorphisms previously linked to adult type 2 diabetes was used.

The metabolomic traits considered included lipoprotein subclass-specific cholesterol and triglyceride content, amino and fatty acids, and inflammatory glycoprotein acetyls, which had been measured in childhood at the age of 8 years, in adolescence at 16 years, in young adulthood at 18 years, and in adulthood at 25 years.

Early metabolic features of type 2 diabetes liability were grouped together and one feature that stood out was the sizes of lipid particles. In particular, it was the size of HDL cholesterol particle subtypes in children at the age of 8 years. Before other types of changes in lipid particles were being seen, there were reductions in the lipid content of HDL cholesterol particle subtypes, notably those that were very large.

By age 16 years, strong associations remained with lower lipids in HDL cholesterol particle subtypes and type 2 diabetes liability, which became stronger with preglycemic traits, such as citrate, and with glycoprotein acetyls. By age 18 years, elevations were seen in branched amino acids, and by age 25, association had strengthened for the lipid content of very low–density lipoprotein cholesterol.

“Linking genetic liability to adult disease with traits measured much earlier in life can tell you something about how the disease activity unfolds over a lifetime,” Dr. Bell said, adding that the feature that was “most consistently tracked” could be evaluated and could help reveal whether or not an individual might go on to develop type 2 diabetes.

In a press release issued by the EASD, Dr. Bell observed: “It’s remarkable that we can see signs of adult diabetes in the blood from such a young age. Knowing what early features of type 2 diabetes look like, could help us to intervene much earlier to halt progression to full-blown diabetes and its complications.”

The study was funded by Diabetes U.K., Cancer Research U.K., the Elizabeth Blackwell Institute for Health Research, the Wellcome Trust, the Medical Research Council, and the University of Bristol. Dr. Bell said he had no conflicts of interest to declare.

SOURCE: Bell J et al. bioRxiv. 2019 Sep 17. doi: 10.1101/767756.
 

BARCELONA – Disturbed HDL cholesterol metabolism is one of the earliest features that may predispose individuals to the development of type 2 diabetes, according to data from a genetics and metabolomics study conducted in the United Kingdom.

Sara Freeman/MDedge News

Changes in HDL cholesterol metabolism were seen in children as young as 8 years, decades before the clinical onset of disease, Joshua Bell, PhD, a research fellow at the University of Bristol (England), reported at the annual meeting of the European Association for the Study of Diabetes.

“We know that type 2 diabetes certainly doesn’t develop overnight,” Dr. Bell said. Indeed, data exist showing that there are changes in glucose metabolism several years before a formal diagnosis may be made in adults. “What we don’t know is what the very earliest features of diabetes look like,” he added.

“The main assumption is that type 2 diabetes is a metabolic disease, and so disease features are visible in systemic metabolism,” explained Dr. Bell. What was not clear, however, was that if any metabolic features – seen mainly in observational studies and in adults – were caused by the disease itself or perhaps were independent causes of type 2 diabetes.To investigate, Dr. Bell and associates performed a study linking genetic liability with metabolomic data collected at four time points from 4,761 offspring from participants in the Avon Longitudinal Study of Parents and Children cohort, which is also known as the Children of the 90s cohort. More than 200 metabolic traits were considered, and a genetic risk score comprising more than 162 single nucleotide polymorphisms previously linked to adult type 2 diabetes was used.

The metabolomic traits considered included lipoprotein subclass-specific cholesterol and triglyceride content, amino and fatty acids, and inflammatory glycoprotein acetyls, which had been measured in childhood at the age of 8 years, in adolescence at 16 years, in young adulthood at 18 years, and in adulthood at 25 years.

Early metabolic features of type 2 diabetes liability were grouped together and one feature that stood out was the sizes of lipid particles. In particular, it was the size of HDL cholesterol particle subtypes in children at the age of 8 years. Before other types of changes in lipid particles were being seen, there were reductions in the lipid content of HDL cholesterol particle subtypes, notably those that were very large.

By age 16 years, strong associations remained with lower lipids in HDL cholesterol particle subtypes and type 2 diabetes liability, which became stronger with preglycemic traits, such as citrate, and with glycoprotein acetyls. By age 18 years, elevations were seen in branched amino acids, and by age 25, association had strengthened for the lipid content of very low–density lipoprotein cholesterol.

“Linking genetic liability to adult disease with traits measured much earlier in life can tell you something about how the disease activity unfolds over a lifetime,” Dr. Bell said, adding that the feature that was “most consistently tracked” could be evaluated and could help reveal whether or not an individual might go on to develop type 2 diabetes.

In a press release issued by the EASD, Dr. Bell observed: “It’s remarkable that we can see signs of adult diabetes in the blood from such a young age. Knowing what early features of type 2 diabetes look like, could help us to intervene much earlier to halt progression to full-blown diabetes and its complications.”

The study was funded by Diabetes U.K., Cancer Research U.K., the Elizabeth Blackwell Institute for Health Research, the Wellcome Trust, the Medical Research Council, and the University of Bristol. Dr. Bell said he had no conflicts of interest to declare.

SOURCE: Bell J et al. bioRxiv. 2019 Sep 17. doi: 10.1101/767756.
 

WASHINGTON – Early diagnosis and intervention for genetic diseases using the latest carrier screening can allow families to be prepared and informed prior to pregnancy, said Aishwarya Arjunan, MS, MPH, a clinical product specialist for carrier screening at Myriad Women’s Health, part of a diagnostic testing company based in Salt Lake City, Utah.

Piolinfax/Wikimedia Commons/GNU Free Documentation License

“Rare diseases are responsible for 35% of deaths in the first year of life,” she said in a panel discussion at the Rare Diseases and Orphan Products Breakthrough Summit sponsored by the National Organization for Rare Disorders.

Most patients with rare diseases go through a “diagnostic odyssey” lasting an average of 8 years before they receive an accurate diagnosis, she said. During this time, data suggest that they have likely been misdiagnosed three times and have seen more than 10 specialists, she added.

Barriers to genetic screening include limited access to genetics professionals, lack of patient and provider education about screening, issues of insurance coverage and reimbursement, coding challenges, and misperceptions about the perceived impact of screening, noted Jodie Vento, manager of the Center for Rare Disease Therapy at the Children’s Hospital of Pittsburgh.

The genetic carrier screening options, often referred to as panethnic expanded carrier screening, represents a change from previous screening protocols based on ethnicity, said Ms. Arjunan. However, guidelines for screening based on ethnicity “misses a significant percentage of pregnancies affected by serious conditions and widens the health disparity gap,” she said.

By contrast, expanded carrier screening allows for standardization of care that gives couples and families information to make decisions and preparations.

Current genetic testing strategies include single gene testing, in which a single gene of interest is tested; multigene panel testing, in which a subset of clinically important genes are tested; whole-exome sequencing, in which the DNA responsible for coding proteins is tested; and whole-genome sequencing, in which the entire human genome is tested for genetic disorders.

Improving access to genetic testing involves a combination of provider education, changes in payer policies, action by advocacy groups, and adjustment of societal guidelines, said Ms. Arjunan. However, the advantages of expanded carrier screening are many and include guiding patients to expert care early and setting up plans for long-term care and follow-up, she noted. In addition, early identification through screening can help patients reduce or eliminate the diagnostic odyssey and connect with advocacy and community groups for support, she concluded.

The presenters had no financial conflicts to disclose.

WASHINGTON – Early diagnosis and intervention for genetic diseases using the latest carrier screening can allow families to be prepared and informed prior to pregnancy, said Aishwarya Arjunan, MS, MPH, a clinical product specialist for carrier screening at Myriad Women’s Health, part of a diagnostic testing company based in Salt Lake City, Utah.

Piolinfax/Wikimedia Commons/GNU Free Documentation License

“Rare diseases are responsible for 35% of deaths in the first year of life,” she said in a panel discussion at the Rare Diseases and Orphan Products Breakthrough Summit sponsored by the National Organization for Rare Disorders.

Most patients with rare diseases go through a “diagnostic odyssey” lasting an average of 8 years before they receive an accurate diagnosis, she said. During this time, data suggest that they have likely been misdiagnosed three times and have seen more than 10 specialists, she added.

Barriers to genetic screening include limited access to genetics professionals, lack of patient and provider education about screening, issues of insurance coverage and reimbursement, coding challenges, and misperceptions about the perceived impact of screening, noted Jodie Vento, manager of the Center for Rare Disease Therapy at the Children’s Hospital of Pittsburgh.

The genetic carrier screening options, often referred to as panethnic expanded carrier screening, represents a change from previous screening protocols based on ethnicity, said Ms. Arjunan. However, guidelines for screening based on ethnicity “misses a significant percentage of pregnancies affected by serious conditions and widens the health disparity gap,” she said.

By contrast, expanded carrier screening allows for standardization of care that gives couples and families information to make decisions and preparations.

Current genetic testing strategies include single gene testing, in which a single gene of interest is tested; multigene panel testing, in which a subset of clinically important genes are tested; whole-exome sequencing, in which the DNA responsible for coding proteins is tested; and whole-genome sequencing, in which the entire human genome is tested for genetic disorders.

Improving access to genetic testing involves a combination of provider education, changes in payer policies, action by advocacy groups, and adjustment of societal guidelines, said Ms. Arjunan. However, the advantages of expanded carrier screening are many and include guiding patients to expert care early and setting up plans for long-term care and follow-up, she noted. In addition, early identification through screening can help patients reduce or eliminate the diagnostic odyssey and connect with advocacy and community groups for support, she concluded.

The presenters had no financial conflicts to disclose.

WASHINGTON – Early diagnosis and intervention for genetic diseases using the latest carrier screening can allow families to be prepared and informed prior to pregnancy, said Aishwarya Arjunan, MS, MPH, a clinical product specialist for carrier screening at Myriad Women’s Health, part of a diagnostic testing company based in Salt Lake City, Utah.

Piolinfax/Wikimedia Commons/GNU Free Documentation License

“Rare diseases are responsible for 35% of deaths in the first year of life,” she said in a panel discussion at the Rare Diseases and Orphan Products Breakthrough Summit sponsored by the National Organization for Rare Disorders.

Most patients with rare diseases go through a “diagnostic odyssey” lasting an average of 8 years before they receive an accurate diagnosis, she said. During this time, data suggest that they have likely been misdiagnosed three times and have seen more than 10 specialists, she added.

Barriers to genetic screening include limited access to genetics professionals, lack of patient and provider education about screening, issues of insurance coverage and reimbursement, coding challenges, and misperceptions about the perceived impact of screening, noted Jodie Vento, manager of the Center for Rare Disease Therapy at the Children’s Hospital of Pittsburgh.

The genetic carrier screening options, often referred to as panethnic expanded carrier screening, represents a change from previous screening protocols based on ethnicity, said Ms. Arjunan. However, guidelines for screening based on ethnicity “misses a significant percentage of pregnancies affected by serious conditions and widens the health disparity gap,” she said.

By contrast, expanded carrier screening allows for standardization of care that gives couples and families information to make decisions and preparations.

Current genetic testing strategies include single gene testing, in which a single gene of interest is tested; multigene panel testing, in which a subset of clinically important genes are tested; whole-exome sequencing, in which the DNA responsible for coding proteins is tested; and whole-genome sequencing, in which the entire human genome is tested for genetic disorders.

Improving access to genetic testing involves a combination of provider education, changes in payer policies, action by advocacy groups, and adjustment of societal guidelines, said Ms. Arjunan. However, the advantages of expanded carrier screening are many and include guiding patients to expert care early and setting up plans for long-term care and follow-up, she noted. In addition, early identification through screening can help patients reduce or eliminate the diagnostic odyssey and connect with advocacy and community groups for support, she concluded.

The presenters had no financial conflicts to disclose.

A new study has uncovered how the measles virus (MeV) can induce immunosuppression by delaying the reconstitution of B cells.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Our findings provide a biological explanation for the observed increase in childhood mortality and secondary infections several years after an episode of measles,” said Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors. The study was published in Science Immunology.

To determine if B-cell impairment can lead to measles-associated immunosuppression, the researchers investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IGHV-J) gene frequencies across time periods (R² = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B cell frequencies in measles patients recovered to levels before infection, they had significant changes in IGHV-J gene frequencies (P = .01) and decreased correlation in gene expression (R² = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IGHV genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IGHV genes, Dr. Petrova and associates said.

Finally, the researchers confirmed a hypothesis about the depletion of B memory cell clones during measles and a repopulation of new cells with less clonal expansion. The frequency of individual IGHV-J gene combinations before infection was correlated with a reduction after infection, “with the most frequent combinations undergoing the most marked depletion” and the result being an increase in genetic diversity.

To further test their findings, the researchers vaccinated two groups of four ferrets with live-attenuated influenza vaccine (LAIV) and at 4 weeks infected one of the groups with canine distemper virus (CDV), a surrogate for MeV. At 14 weeks after vaccination, the uninfected group maintained high levels of influenza-specific neutralizing antibodies while the infected group saw impaired B cells and a subsequent reduction in neutralizing antibodies.
 

Understanding the impact of measles on the immune system

“How measles infection has such a long-lasting deleterious effect on the immune system while allowing robust immunity against itself has been a burning immunological question,” Duane R. Wesemann, MD, PhD, of Brigham and Women’s Hospital in Boston, said in an accompanying editorial. The research from Petrova et al. begins to answer that question.

Among the observations he found most interesting was how “post-measles memory cells were more diverse than the pre-measles memory pool,” despite expectations that measles immunity would be dominant. He speculated that the void in memory cells is filled by a set of clones binding to unidentified or nonnative antigens, which may bring polyclonal diversity into B memory cells.

More research is needed to determine just what these findings mean, including looking beyond memory cell depletion and focusing on the impact of immature immunoglobulin repertoires in naive cells. But his broad takeaway is that measles remains both a public health concern and an opportunity to understand how the human body counters disease.

“The unique relationship measles has with the human immune system,” he said, “can illuminate aspects of its inner workings.”

The study was funded by grants to the investigators the Indonesian Endowment Fund for Education, the Wellcome Trust, the German Centre for Infection Research, the Collaborative Research Centre of the German Research Foundation, the German Ministry of Health, and the Royal Society. The authors declared no conflicts of interest. Dr. Wesemann reported receiving support from National Institutes of Health grants and an award from the Burroughs Wellcome Fund; he also reports being a consultant for OpenBiome.

SOURCE: Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125; Wesemann DR. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aaz4195.

A new study has uncovered how the measles virus (MeV) can induce immunosuppression by delaying the reconstitution of B cells.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Our findings provide a biological explanation for the observed increase in childhood mortality and secondary infections several years after an episode of measles,” said Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors. The study was published in Science Immunology.

To determine if B-cell impairment can lead to measles-associated immunosuppression, the researchers investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IGHV-J) gene frequencies across time periods (R² = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B cell frequencies in measles patients recovered to levels before infection, they had significant changes in IGHV-J gene frequencies (P = .01) and decreased correlation in gene expression (R² = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IGHV genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IGHV genes, Dr. Petrova and associates said.

Finally, the researchers confirmed a hypothesis about the depletion of B memory cell clones during measles and a repopulation of new cells with less clonal expansion. The frequency of individual IGHV-J gene combinations before infection was correlated with a reduction after infection, “with the most frequent combinations undergoing the most marked depletion” and the result being an increase in genetic diversity.

To further test their findings, the researchers vaccinated two groups of four ferrets with live-attenuated influenza vaccine (LAIV) and at 4 weeks infected one of the groups with canine distemper virus (CDV), a surrogate for MeV. At 14 weeks after vaccination, the uninfected group maintained high levels of influenza-specific neutralizing antibodies while the infected group saw impaired B cells and a subsequent reduction in neutralizing antibodies.
 

Understanding the impact of measles on the immune system

“How measles infection has such a long-lasting deleterious effect on the immune system while allowing robust immunity against itself has been a burning immunological question,” Duane R. Wesemann, MD, PhD, of Brigham and Women’s Hospital in Boston, said in an accompanying editorial. The research from Petrova et al. begins to answer that question.

Among the observations he found most interesting was how “post-measles memory cells were more diverse than the pre-measles memory pool,” despite expectations that measles immunity would be dominant. He speculated that the void in memory cells is filled by a set of clones binding to unidentified or nonnative antigens, which may bring polyclonal diversity into B memory cells.

More research is needed to determine just what these findings mean, including looking beyond memory cell depletion and focusing on the impact of immature immunoglobulin repertoires in naive cells. But his broad takeaway is that measles remains both a public health concern and an opportunity to understand how the human body counters disease.

“The unique relationship measles has with the human immune system,” he said, “can illuminate aspects of its inner workings.”

The study was funded by grants to the investigators the Indonesian Endowment Fund for Education, the Wellcome Trust, the German Centre for Infection Research, the Collaborative Research Centre of the German Research Foundation, the German Ministry of Health, and the Royal Society. The authors declared no conflicts of interest. Dr. Wesemann reported receiving support from National Institutes of Health grants and an award from the Burroughs Wellcome Fund; he also reports being a consultant for OpenBiome.

SOURCE: Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125; Wesemann DR. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aaz4195.

A new study has uncovered how the measles virus (MeV) can induce immunosuppression by delaying the reconstitution of B cells.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Our findings provide a biological explanation for the observed increase in childhood mortality and secondary infections several years after an episode of measles,” said Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors. The study was published in Science Immunology.

To determine if B-cell impairment can lead to measles-associated immunosuppression, the researchers investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IGHV-J) gene frequencies across time periods (R² = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B cell frequencies in measles patients recovered to levels before infection, they had significant changes in IGHV-J gene frequencies (P = .01) and decreased correlation in gene expression (R² = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IGHV genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IGHV genes, Dr. Petrova and associates said.

Finally, the researchers confirmed a hypothesis about the depletion of B memory cell clones during measles and a repopulation of new cells with less clonal expansion. The frequency of individual IGHV-J gene combinations before infection was correlated with a reduction after infection, “with the most frequent combinations undergoing the most marked depletion” and the result being an increase in genetic diversity.

To further test their findings, the researchers vaccinated two groups of four ferrets with live-attenuated influenza vaccine (LAIV) and at 4 weeks infected one of the groups with canine distemper virus (CDV), a surrogate for MeV. At 14 weeks after vaccination, the uninfected group maintained high levels of influenza-specific neutralizing antibodies while the infected group saw impaired B cells and a subsequent reduction in neutralizing antibodies.
 

Understanding the impact of measles on the immune system

“How measles infection has such a long-lasting deleterious effect on the immune system while allowing robust immunity against itself has been a burning immunological question,” Duane R. Wesemann, MD, PhD, of Brigham and Women’s Hospital in Boston, said in an accompanying editorial. The research from Petrova et al. begins to answer that question.

Among the observations he found most interesting was how “post-measles memory cells were more diverse than the pre-measles memory pool,” despite expectations that measles immunity would be dominant. He speculated that the void in memory cells is filled by a set of clones binding to unidentified or nonnative antigens, which may bring polyclonal diversity into B memory cells.

More research is needed to determine just what these findings mean, including looking beyond memory cell depletion and focusing on the impact of immature immunoglobulin repertoires in naive cells. But his broad takeaway is that measles remains both a public health concern and an opportunity to understand how the human body counters disease.

“The unique relationship measles has with the human immune system,” he said, “can illuminate aspects of its inner workings.”

The study was funded by grants to the investigators the Indonesian Endowment Fund for Education, the Wellcome Trust, the German Centre for Infection Research, the Collaborative Research Centre of the German Research Foundation, the German Ministry of Health, and the Royal Society. The authors declared no conflicts of interest. Dr. Wesemann reported receiving support from National Institutes of Health grants and an award from the Burroughs Wellcome Fund; he also reports being a consultant for OpenBiome.

SOURCE: Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125; Wesemann DR. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aaz4195.

Religious exemptions for vaccination in kindergartners are lower in states with personal belief exemptions, and they appear to go up when personal belief exemptions go away, which might be caused by a replacement effect, researchers hypothesized in Pediatrics.

SDI Productions/Getty Images

“Put differently, state-level religious exemption rates appear to be a function of personal belief exemption availability, decreasing significantly when states offer a personal belief exemption alternative,” the researchers explained.

Led by Joshua T.B. Williams, MD, of the department of pediatrics at the Denver Health Medical Center, the researchers sought to update state-level analyses of vaccination exemption rates by performing a cross-sectional, retrospective investigation of publicly available aggregated yearly vaccine reports for kindergartners from the Centers for Disease Control and Prevention. They were specifically interested in the school years of 2011-2012 through 2017-2018 “to extend and provide meaningful comparisons to a previous study of exemption data” that had ended its study period in 2015-2016 (Open Forum Infect Dis. 2017 Nov 15. doi: 10.1093/ofid/ofx244). The researchers adjusted for heterogeneous exemption processes by coding for “difficulty” of obtaining such exemptions in accordance with that previous study’s methods because studies have suggested that nonmedical exemption rates are lower in states with more difficult exemption policies. They also looked at how rates of religious exemptions changed in Vermont after the state eliminated personal, or philosophical, exemptions in 2016. The final analysis included 295 state-years from among the 45 states and the District of Columbia that all allow religious exemptions and the 15 states that permit personal belief exemptions.

The unadjusted analysis showed that the mean proportion of kindergartners with religious exemptions was lower where personal belief exemptions were available (0.41%; 95% confidence interval, 0.28%-0.53%) than they were where only religious exemptions were an option (1.63%; 95% CI, 1.30%-1.97%). In the adjusted analysis, states with both religious and personal belief exemptions were only a quarter as likely to have kindergartners with religious exemptions than those without personal belief exemptions (adjusted risk ratio, 0.25; 95% CI, 0.16-0.38). Furthermore, the proportion of kindergartners in Vermont with religious exemptions went from 0.5% in the years 2011-2012 through 2015-2016 when personal belief exemptions were still an option, to 3.7% in 2016-2017 through 2017-2018, after they went away.

One of the study’s limitations is that not all states used the same methods of data collection; however, the authors felt that, given about three-quarters of states included performed censuses with at least 80% of children counted, the effects on the study’s results should be minimal.

After discussing the role of religious exemptions and some of their history, as well as citing the seemingly paradoxical reported decline in religiosity and rise in religious exemptions, the researchers wrote in their conclusion that these “may be an increasingly problematic or outdated exemption category, and researchers and policy makers must work together to determine how best to balance a respect for religious liberty and the need to protect public health.”

[email protected]

SOURCE: Williams JTB et al. Pediatrics. 2019 Nov. doi: 10.1542/peds.2019-2710.

Religious exemptions for vaccination in kindergartners are lower in states with personal belief exemptions, and they appear to go up when personal belief exemptions go away, which might be caused by a replacement effect, researchers hypothesized in Pediatrics.

SDI Productions/Getty Images

“Put differently, state-level religious exemption rates appear to be a function of personal belief exemption availability, decreasing significantly when states offer a personal belief exemption alternative,” the researchers explained.

Led by Joshua T.B. Williams, MD, of the department of pediatrics at the Denver Health Medical Center, the researchers sought to update state-level analyses of vaccination exemption rates by performing a cross-sectional, retrospective investigation of publicly available aggregated yearly vaccine reports for kindergartners from the Centers for Disease Control and Prevention. They were specifically interested in the school years of 2011-2012 through 2017-2018 “to extend and provide meaningful comparisons to a previous study of exemption data” that had ended its study period in 2015-2016 (Open Forum Infect Dis. 2017 Nov 15. doi: 10.1093/ofid/ofx244). The researchers adjusted for heterogeneous exemption processes by coding for “difficulty” of obtaining such exemptions in accordance with that previous study’s methods because studies have suggested that nonmedical exemption rates are lower in states with more difficult exemption policies. They also looked at how rates of religious exemptions changed in Vermont after the state eliminated personal, or philosophical, exemptions in 2016. The final analysis included 295 state-years from among the 45 states and the District of Columbia that all allow religious exemptions and the 15 states that permit personal belief exemptions.

The unadjusted analysis showed that the mean proportion of kindergartners with religious exemptions was lower where personal belief exemptions were available (0.41%; 95% confidence interval, 0.28%-0.53%) than they were where only religious exemptions were an option (1.63%; 95% CI, 1.30%-1.97%). In the adjusted analysis, states with both religious and personal belief exemptions were only a quarter as likely to have kindergartners with religious exemptions than those without personal belief exemptions (adjusted risk ratio, 0.25; 95% CI, 0.16-0.38). Furthermore, the proportion of kindergartners in Vermont with religious exemptions went from 0.5% in the years 2011-2012 through 2015-2016 when personal belief exemptions were still an option, to 3.7% in 2016-2017 through 2017-2018, after they went away.

One of the study’s limitations is that not all states used the same methods of data collection; however, the authors felt that, given about three-quarters of states included performed censuses with at least 80% of children counted, the effects on the study’s results should be minimal.

After discussing the role of religious exemptions and some of their history, as well as citing the seemingly paradoxical reported decline in religiosity and rise in religious exemptions, the researchers wrote in their conclusion that these “may be an increasingly problematic or outdated exemption category, and researchers and policy makers must work together to determine how best to balance a respect for religious liberty and the need to protect public health.”

[email protected]

SOURCE: Williams JTB et al. Pediatrics. 2019 Nov. doi: 10.1542/peds.2019-2710.

Religious exemptions for vaccination in kindergartners are lower in states with personal belief exemptions, and they appear to go up when personal belief exemptions go away, which might be caused by a replacement effect, researchers hypothesized in Pediatrics.

SDI Productions/Getty Images

“Put differently, state-level religious exemption rates appear to be a function of personal belief exemption availability, decreasing significantly when states offer a personal belief exemption alternative,” the researchers explained.

Led by Joshua T.B. Williams, MD, of the department of pediatrics at the Denver Health Medical Center, the researchers sought to update state-level analyses of vaccination exemption rates by performing a cross-sectional, retrospective investigation of publicly available aggregated yearly vaccine reports for kindergartners from the Centers for Disease Control and Prevention. They were specifically interested in the school years of 2011-2012 through 2017-2018 “to extend and provide meaningful comparisons to a previous study of exemption data” that had ended its study period in 2015-2016 (Open Forum Infect Dis. 2017 Nov 15. doi: 10.1093/ofid/ofx244). The researchers adjusted for heterogeneous exemption processes by coding for “difficulty” of obtaining such exemptions in accordance with that previous study’s methods because studies have suggested that nonmedical exemption rates are lower in states with more difficult exemption policies. They also looked at how rates of religious exemptions changed in Vermont after the state eliminated personal, or philosophical, exemptions in 2016. The final analysis included 295 state-years from among the 45 states and the District of Columbia that all allow religious exemptions and the 15 states that permit personal belief exemptions.

The unadjusted analysis showed that the mean proportion of kindergartners with religious exemptions was lower where personal belief exemptions were available (0.41%; 95% confidence interval, 0.28%-0.53%) than they were where only religious exemptions were an option (1.63%; 95% CI, 1.30%-1.97%). In the adjusted analysis, states with both religious and personal belief exemptions were only a quarter as likely to have kindergartners with religious exemptions than those without personal belief exemptions (adjusted risk ratio, 0.25; 95% CI, 0.16-0.38). Furthermore, the proportion of kindergartners in Vermont with religious exemptions went from 0.5% in the years 2011-2012 through 2015-2016 when personal belief exemptions were still an option, to 3.7% in 2016-2017 through 2017-2018, after they went away.

One of the study’s limitations is that not all states used the same methods of data collection; however, the authors felt that, given about three-quarters of states included performed censuses with at least 80% of children counted, the effects on the study’s results should be minimal.

After discussing the role of religious exemptions and some of their history, as well as citing the seemingly paradoxical reported decline in religiosity and rise in religious exemptions, the researchers wrote in their conclusion that these “may be an increasingly problematic or outdated exemption category, and researchers and policy makers must work together to determine how best to balance a respect for religious liberty and the need to protect public health.”

[email protected]

SOURCE: Williams JTB et al. Pediatrics. 2019 Nov. doi: 10.1542/peds.2019-2710.

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020

Here are 5 articles from the November issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Poor response to statins hikes risk of cardiovascular events

To take the posttest, go to: https://bit.ly/2MVHlDR
Expires April 17, 2020

2. Postvaccination febrile seizures are no more severe than other febrile seizures

To take the posttest, go to: https://bit.ly/2VUJzaE
Expires April 19, 2020

3. Hydroxychloroquine adherence in SLE: worse than you thought

To take the posttest, go to: https://bit.ly/2oT00Z9
Expires April 22, 2020

4. Long-term antibiotic use may heighten stroke, CHD risk

To take the posttest, go to: https://bit.ly/2OUUVu5
Expires April 28, 2020

5. Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large

To take the posttest, go to: https://bit.ly/2Msgqkb
Expires May 1, 2020

PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

[email protected]

PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

[email protected]

PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

[email protected]

SAN ANTONIO – Fresh red cells were no better than conventional stored red cells when transfused into critically ill children, and there was some evidence in the ABC PICU trial suggesting that fresh red cells could be associated with a higher incidence of posttransfusion organ dysfunction.

Among 1,461 children randomly assigned to receive RBC transfusions with either fresh cells (stored for 7 days or less) or standard-issue cells (stored anywhere from 2-42 days), there were no differences in the primary endpoint of new or progressive multiple organ dysfunction syndrome (NPMODS), reported Philip Spinella, MD from Washington University, St. Louis.

“Our results do not support current blood management policies that recommend providing fresh red cell units to certain populations of children,” he said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The study findings support those of a systematic review (Transfus Med Rev. 2018;32:77-88), whose authors found that “transfusion of fresher RBCs is not associated with decreased risk of death but is associated with higher rates of transfusion reactions and possibly infection.” The authors of the review concluded that “the current evidence does not support a change from current usual transfusion practice.”

Is fresh really better?

The launch of the ABC PICU trial was motivated by laboratory and observational evidence suggesting that older RBCs may be less safe or efficacious than fresh RBCs, especially in vulnerable populations such as critically ill children.

Although physician and institutional practice has been to transfuse fresh RBCs to some pediatric patients, the standard practice among blood banks has been to deliver the oldest stored units first, in an effort to prevent product wastage.

Dr. Spinella and colleagues across 50 centers in the United States, Canada, France, Italy, and Israel enrolled patients who were admitted to a pediatric ICU who received their first RBC transfusion within 7 days of admission and had an expected length of stay after transfusion of more than 24 hours.

The median patient age was 1.8 years for those who received fresh cells, and 1.9 years for those who received usual care.

There were 1,630 transfusions of fresh RBCs stored for a median of 5 days and 1,533 transfusions of standard RBCs stored for a median of 18 days. The median volume of red cell units transfused was 17.5 mL/kg in the fresh group and 16.6 mL/kg in the standard group.

The incidence of NPMODS was 20.2% for fresh-RBC recipients and 18.2% for standard-product recipients. The absolute difference of 2.0% was not statistically significant.

There were also no significant differences in the timing of NPMODS occurrence between the groups, and no significant differences by patient age (28 days or younger, 29-365 days old, or older than 1 year).

Similarly, there were no differences in NPMODS incidence between the groups by country, although in Canada there was a trend toward a higher incidence of organ dysfunction in the group that received fresh RBCs, Dr. Spinella noted.

Additionally, there were no significant differences between the groups by admission to the ICU by medical, surgical, cardiac, or trauma services; no differences by quartile of red cell volume transfused; and no differences in mortality rates either in the ICU or the main hospital, or at 28 or 90 days after discharge.

Why no difference?

Seeking explanations for why fresh RBCs did not perform better than older stored cells, Dr. Spinella suggested that changes such as storage lesions that occur over time may not be as clinically relevant as previously supposed.

“Another possibility is that these study patients didn’t need red cells to begin with to improve oxygen delivery,” he said.

Other potential explanations include the possibility that exposure to fresh red cells may be associated with immune suppression because viable white cells may also be present in the product, and that the chronological age of a stored red cell unit may not equate to its biologic or metabolic age or performance, he added.

ABC PICU was supported by Washington University; the National Heart, Lung, and Blood Institute; the Canadian and French governments; and other groups. Dr. Spinella reported having no relevant conflicts of interest.

SAN ANTONIO – Fresh red cells were no better than conventional stored red cells when transfused into critically ill children, and there was some evidence in the ABC PICU trial suggesting that fresh red cells could be associated with a higher incidence of posttransfusion organ dysfunction.

Among 1,461 children randomly assigned to receive RBC transfusions with either fresh cells (stored for 7 days or less) or standard-issue cells (stored anywhere from 2-42 days), there were no differences in the primary endpoint of new or progressive multiple organ dysfunction syndrome (NPMODS), reported Philip Spinella, MD from Washington University, St. Louis.

“Our results do not support current blood management policies that recommend providing fresh red cell units to certain populations of children,” he said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The study findings support those of a systematic review (Transfus Med Rev. 2018;32:77-88), whose authors found that “transfusion of fresher RBCs is not associated with decreased risk of death but is associated with higher rates of transfusion reactions and possibly infection.” The authors of the review concluded that “the current evidence does not support a change from current usual transfusion practice.”

Is fresh really better?

The launch of the ABC PICU trial was motivated by laboratory and observational evidence suggesting that older RBCs may be less safe or efficacious than fresh RBCs, especially in vulnerable populations such as critically ill children.

Although physician and institutional practice has been to transfuse fresh RBCs to some pediatric patients, the standard practice among blood banks has been to deliver the oldest stored units first, in an effort to prevent product wastage.

Dr. Spinella and colleagues across 50 centers in the United States, Canada, France, Italy, and Israel enrolled patients who were admitted to a pediatric ICU who received their first RBC transfusion within 7 days of admission and had an expected length of stay after transfusion of more than 24 hours.

The median patient age was 1.8 years for those who received fresh cells, and 1.9 years for those who received usual care.

There were 1,630 transfusions of fresh RBCs stored for a median of 5 days and 1,533 transfusions of standard RBCs stored for a median of 18 days. The median volume of red cell units transfused was 17.5 mL/kg in the fresh group and 16.6 mL/kg in the standard group.

The incidence of NPMODS was 20.2% for fresh-RBC recipients and 18.2% for standard-product recipients. The absolute difference of 2.0% was not statistically significant.

There were also no significant differences in the timing of NPMODS occurrence between the groups, and no significant differences by patient age (28 days or younger, 29-365 days old, or older than 1 year).

Similarly, there were no differences in NPMODS incidence between the groups by country, although in Canada there was a trend toward a higher incidence of organ dysfunction in the group that received fresh RBCs, Dr. Spinella noted.

Additionally, there were no significant differences between the groups by admission to the ICU by medical, surgical, cardiac, or trauma services; no differences by quartile of red cell volume transfused; and no differences in mortality rates either in the ICU or the main hospital, or at 28 or 90 days after discharge.

Why no difference?

Seeking explanations for why fresh RBCs did not perform better than older stored cells, Dr. Spinella suggested that changes such as storage lesions that occur over time may not be as clinically relevant as previously supposed.

“Another possibility is that these study patients didn’t need red cells to begin with to improve oxygen delivery,” he said.

Other potential explanations include the possibility that exposure to fresh red cells may be associated with immune suppression because viable white cells may also be present in the product, and that the chronological age of a stored red cell unit may not equate to its biologic or metabolic age or performance, he added.

ABC PICU was supported by Washington University; the National Heart, Lung, and Blood Institute; the Canadian and French governments; and other groups. Dr. Spinella reported having no relevant conflicts of interest.

SAN ANTONIO – Fresh red cells were no better than conventional stored red cells when transfused into critically ill children, and there was some evidence in the ABC PICU trial suggesting that fresh red cells could be associated with a higher incidence of posttransfusion organ dysfunction.

Among 1,461 children randomly assigned to receive RBC transfusions with either fresh cells (stored for 7 days or less) or standard-issue cells (stored anywhere from 2-42 days), there were no differences in the primary endpoint of new or progressive multiple organ dysfunction syndrome (NPMODS), reported Philip Spinella, MD from Washington University, St. Louis.

“Our results do not support current blood management policies that recommend providing fresh red cell units to certain populations of children,” he said at the annual meeting of AABB, the group formerly known as the American Association of Blood Banks.

The study findings support those of a systematic review (Transfus Med Rev. 2018;32:77-88), whose authors found that “transfusion of fresher RBCs is not associated with decreased risk of death but is associated with higher rates of transfusion reactions and possibly infection.” The authors of the review concluded that “the current evidence does not support a change from current usual transfusion practice.”

Is fresh really better?

The launch of the ABC PICU trial was motivated by laboratory and observational evidence suggesting that older RBCs may be less safe or efficacious than fresh RBCs, especially in vulnerable populations such as critically ill children.

Although physician and institutional practice has been to transfuse fresh RBCs to some pediatric patients, the standard practice among blood banks has been to deliver the oldest stored units first, in an effort to prevent product wastage.

Dr. Spinella and colleagues across 50 centers in the United States, Canada, France, Italy, and Israel enrolled patients who were admitted to a pediatric ICU who received their first RBC transfusion within 7 days of admission and had an expected length of stay after transfusion of more than 24 hours.

The median patient age was 1.8 years for those who received fresh cells, and 1.9 years for those who received usual care.

There were 1,630 transfusions of fresh RBCs stored for a median of 5 days and 1,533 transfusions of standard RBCs stored for a median of 18 days. The median volume of red cell units transfused was 17.5 mL/kg in the fresh group and 16.6 mL/kg in the standard group.

The incidence of NPMODS was 20.2% for fresh-RBC recipients and 18.2% for standard-product recipients. The absolute difference of 2.0% was not statistically significant.

There were also no significant differences in the timing of NPMODS occurrence between the groups, and no significant differences by patient age (28 days or younger, 29-365 days old, or older than 1 year).

Similarly, there were no differences in NPMODS incidence between the groups by country, although in Canada there was a trend toward a higher incidence of organ dysfunction in the group that received fresh RBCs, Dr. Spinella noted.

Additionally, there were no significant differences between the groups by admission to the ICU by medical, surgical, cardiac, or trauma services; no differences by quartile of red cell volume transfused; and no differences in mortality rates either in the ICU or the main hospital, or at 28 or 90 days after discharge.

Why no difference?

Seeking explanations for why fresh RBCs did not perform better than older stored cells, Dr. Spinella suggested that changes such as storage lesions that occur over time may not be as clinically relevant as previously supposed.

“Another possibility is that these study patients didn’t need red cells to begin with to improve oxygen delivery,” he said.

Other potential explanations include the possibility that exposure to fresh red cells may be associated with immune suppression because viable white cells may also be present in the product, and that the chronological age of a stored red cell unit may not equate to its biologic or metabolic age or performance, he added.

ABC PICU was supported by Washington University; the National Heart, Lung, and Blood Institute; the Canadian and French governments; and other groups. Dr. Spinella reported having no relevant conflicts of interest.

Although most neonatal vascular lumps, bumps, and tumors are benign, proper diagnosis is important for prognosis and management. Therefore, knowledge of both common and rare conditions is important when evaluating a neonatal nodule. Differential diagnosis of neonatal vascular nodules must focus on important diagnostic clues that should prompt consideration and evaluation for less common and/or potentially threatening conditions. Infantile hemangioma (IH), congenital hemangioma (CH), venous malformation (VM), lymphatic malformation (LM), kaposiform hemangioendothelioma (KHE) and tufted angioma, and malignant tumors are reviewed here.

Infantile Hemangioma

Infantile hemangioma, a benign proliferation of capillaries, is the most common tumor of infancy with reported incidence of up to 5% in neonates.¹ As such, suspicion for less common lesions is often predicated on identifying features that would be atypical for an IH. A superficial IH presents as a bright red papule, nodule, or plaque, while a deep IH presents as a flesh-colored to bluish nodule. Mixed IHs combine features of both superficial and deep lesions. The distribution may be focal or segmental, with segmental lesions encompassing a larger territory–like distribution and frequently displaying a thin, coarsely telangiectatic appearance.

Knowledge of the natural history of IH generally is crucial in differentiating it from other neonatal lesions. Infantile hemangiomas display a natural history that is distinct and predictable. They typically manifest within the first few weeks of life, though up to 30% present at birth with a premonitory mark, which may be a light red, pink, bluish, or vasoconstricted patch. Thus, mere presence of a lesion at birth is not the feature that distinguishes other congenital lesions from an IH. After initial appearance, IHs undergo a period of proliferation that occurs over 4 to 6 months in most patients. In some cases, areas of proliferation may be subtle, but nonetheless the presence of some areas of increased redness and/or volumetric growth generally is required to firmly establish the diagnosis of IH. Thereafter, IH will involute, a process that begins before 1 year of age in most cases and continues over years. Although IHs undergo involution, complete clearance may not occur, as nearly 70% will leave permanent residua such as fibrofatty masses or anetodermic skin.² Nevertheless, the presence of a proliferative phase followed by a slower period of involution is a hallmark feature of the IH.

Biopsy and imaging rarely are required for establishing diagnosis of an IH. Histopathology showing a proliferation of capillaries with positive glucose transporter 1 (GLUT-1) staining is characteristic. Imaging with ultrasound reveals a fast-flow lesion. Apart from exceptionally rare cases, a cutaneous IH typically does not cross muscle fascia, and thus alternative diagnoses should be considered for a cutaneous lesion that demonstrates infiltration into nerve, bone, joint, or other deeper tissues. Most IHs do not require treatment; however, a small subset may be associated with complications and thus require intervention. Complications of IH may include impairment of function (eg, vision, feeding, respiratory), ulceration, and risk for permanent disfigurement. When treatment is indicated, the most commonly employed options during the proliferative phase are the topical beta-blocker timolol and the oral beta-blocker propranolol. In addition, certain IHs may be associated with either syndromic presentations and/or visceral involvement, thus requiring further workup (Table).

Congenital Hemangioma

A CH is an uncommon benign neonatal tumor that is distinct from an IH in behavior, biology, and treatment. Congenital hemangiomas may have a rapidly involuting course, referred to as RICH (rapidly involuting congenital hemangioma), or a noninvoluting course, referred to as NICH (noninvoluting congenital hemangioma). Partially involuting types also have been described.³ A RICH typically presents as a highly vascular, red-violaceous or bluish plaque, nodule, or large mass at birth. An NICH presents as a red-violaceous or bluish, coarsely telangiectatic patch, plaque, or nodule. A characteristic feature of the CH is the rim of vasoconstriction around the lesion, which is an important diagnostic clue (Figure 1). In contrast to IH, multifocal lesions are highly unlikely in CH, though it rarely has been reported.⁴

Regardless of subtype, CHs are fully developed at birth. Infantile hemangiomas, on the other hand, are either minimally present or not present at birth and thereafter proliferate. After birth, a RICH rapidly involutes over the first 9 to 12 months of life. This process generally is evident even in the first few weeks of life, which would not be expected of an IH and is therefore a major distinguishing factor. A NICH, on the other hand, is expected to be persistent, for the most part neither showing signs of proliferation nor involution.

Complications of CHs may include ulceration, functional impairment, or risk for permanent disfigurement depending on location. In addition, due to their fast-flow state and potential large size, some CHs may be complicated by high-output heart failure in the neonate. Distinguishing an IH from a CH is important not only for prognosis but also treatment. Beta-blocker therapy generally is not useful for CHs, and management usually is supportive in the neonatal period.

In the majority of cases, diagnosis can be achieved solely on clinical features. Biopsy with immunohistochemistry shows negative GLUT-1 staining, which will distinguish this lesion from an IH. At times, the highly vascular nature and/or striking size of a CH may lead some to consider the potential diagnosis of an arteriovenous malformation. However, soft-tissue arteriovenous malformations involving the skin are almost never fully developed in the neonatal period and generally take years to evolve from a quiescent state to a destructive lesion.

Venous Malformation

Venous malformations are congenital malformations of veins that may be apparent at birth or later. They appear as bluish to flesh-colored, compressible nodules or plaques. They tend to increase in size when the affected body part is in a dependent position, and this maneuver can be a helpful distinguishing clue. Although the majority of patients have a single lesion, multifocal involvement may occur uncommonly (Table). The diagnosis of VM usually is clinical, though at times, a VM may be difficult to distinguish from a purely deep IH. However, a VM will persist over time, growing in proportion to the patient. In addition, a VM displays low flow on ultrasound, a distinguishing feature from the fast-flow IH. Magnetic resonance imaging with and without contrast is the imaging study of choice. At times, cutaneous VMs will demonstrate infiltration into other tissue planes such as muscle and joint. Pain may occur secondary to thrombus formation within the malformation. In extensive lesions, intravascular coagulation may be notable, as reflected in elevated D-dimer and decreased fibrinogen levels. Treatment with sclerotherapy or surgery may be considered in select cases during infancy; however, in general, an asymptomatic VM may be observed early on in life.

Lymphatic Malformation

A lymphatic malformation (LM) is a congenital malformation of lymphatic vessels and may be further differentiated into microcystic, macrocystic, or mixed types depending on the size of the channels. An LM may present at birth or later and persists over time. Superficial microcystic LMs, synonymous with the term lymphangioma circumscriptum, characteristically appear as a group of clear and violaceous hemorrhagic vesicles on the skin. Deeper LMs appear as a tense or spongy, flesh-colored nodule or mass. Involvement of the head and neck is common. Complications frequently occur in LMs. Cutaneous LMs may ooze or bleed. Infection and hemorrhage into cysts may occur, which will cause acute pain, redness, swelling, and induration. Cervicofacial lesions may result in respiratory distress. Thus, the majority of LMs require treatment, though asymptomatic lesions may be observed in the neonate. An ultrasound will demonstrate a low-flow lesion, and magnetic resonance imaging is the diagnostic modality of choice for diagnosis and definition of extent.

KHE and Tufted Angioma

Kaposiform hemangioendothelioma is a rare, locally aggressive, vascular tumor that is frequently associated with a potentially life-threatening coagulopathy, Kasabach-Merritt phenomenon. Tufted angiomas are now understood to belong on a spectrum with KHEs, which usually present in the neonatal period or infancy as firm, red-violaceous plaques, nodules, or large tumors. Infiltration into nerve, muscle, and bone may occur. The firm/hard nature and deep violaceous appearance generally are initial clues that it is not an IH. Kasabach-Merritt phenomenon manifests as thrombocytopenia as well as low fibrinogen and elevated D-dimer levels. Thrombocytopenia is generally profound in Kasabach-Merritt phenomenon and results from platelet trapping within the vascular tumor. Given these potential complications, KHEs generally require immediate medical attention, and various treatment protocols including prednisone, vincristine, and sirolimus are utilized for complicated cases.⁵ The diagnosis may require biopsy to distinguish it from malignant tumors, particularly sarcomas.

Malignant Tumors

Various malignancies, including congenital leukemia, neuroblastoma, Langerhans cell histiocytosis, infantile fibrosarcoma, and rhabdomyosarcoma, rarely may present as cutaneous nodules or masses in a neonate mimicking hemangiomas or other vascular lesions (Figure 2). Neonates may present with multiple bluish papules and nodules resembling a blueberry muffin baby; multiple violaceous-red nodules; or a single red-violaceous, highly vascular–appearing mass mimicking hemangiomas. Malignant tumors may display vascularity on imaging, and thus the presence of vascular flow on ultrasound should not dissuade one from the possibility of a malignancy if other clinical features are atypical or unusual for a hemangioma. When a neonatal malignancy is suspected, a large punch biopsy or incisional biopsy is required for workup.

Final Thoughts

Although IHs are the most common vascular nodules in neonates and young infants, other conditions such as VMs, LMs, CHs, KHEs, and malignancy may occur less commonly. Identifying features that would be considered atypical for IH is crucial to recognize these less common possibilities.

Although most neonatal vascular lumps, bumps, and tumors are benign, proper diagnosis is important for prognosis and management. Therefore, knowledge of both common and rare conditions is important when evaluating a neonatal nodule. Differential diagnosis of neonatal vascular nodules must focus on important diagnostic clues that should prompt consideration and evaluation for less common and/or potentially threatening conditions. Infantile hemangioma (IH), congenital hemangioma (CH), venous malformation (VM), lymphatic malformation (LM), kaposiform hemangioendothelioma (KHE) and tufted angioma, and malignant tumors are reviewed here.

Infantile Hemangioma

Infantile hemangioma, a benign proliferation of capillaries, is the most common tumor of infancy with reported incidence of up to 5% in neonates.¹ As such, suspicion for less common lesions is often predicated on identifying features that would be atypical for an IH. A superficial IH presents as a bright red papule, nodule, or plaque, while a deep IH presents as a flesh-colored to bluish nodule. Mixed IHs combine features of both superficial and deep lesions. The distribution may be focal or segmental, with segmental lesions encompassing a larger territory–like distribution and frequently displaying a thin, coarsely telangiectatic appearance.

Knowledge of the natural history of IH generally is crucial in differentiating it from other neonatal lesions. Infantile hemangiomas display a natural history that is distinct and predictable. They typically manifest within the first few weeks of life, though up to 30% present at birth with a premonitory mark, which may be a light red, pink, bluish, or vasoconstricted patch. Thus, mere presence of a lesion at birth is not the feature that distinguishes other congenital lesions from an IH. After initial appearance, IHs undergo a period of proliferation that occurs over 4 to 6 months in most patients. In some cases, areas of proliferation may be subtle, but nonetheless the presence of some areas of increased redness and/or volumetric growth generally is required to firmly establish the diagnosis of IH. Thereafter, IH will involute, a process that begins before 1 year of age in most cases and continues over years. Although IHs undergo involution, complete clearance may not occur, as nearly 70% will leave permanent residua such as fibrofatty masses or anetodermic skin.² Nevertheless, the presence of a proliferative phase followed by a slower period of involution is a hallmark feature of the IH.

Biopsy and imaging rarely are required for establishing diagnosis of an IH. Histopathology showing a proliferation of capillaries with positive glucose transporter 1 (GLUT-1) staining is characteristic. Imaging with ultrasound reveals a fast-flow lesion. Apart from exceptionally rare cases, a cutaneous IH typically does not cross muscle fascia, and thus alternative diagnoses should be considered for a cutaneous lesion that demonstrates infiltration into nerve, bone, joint, or other deeper tissues. Most IHs do not require treatment; however, a small subset may be associated with complications and thus require intervention. Complications of IH may include impairment of function (eg, vision, feeding, respiratory), ulceration, and risk for permanent disfigurement. When treatment is indicated, the most commonly employed options during the proliferative phase are the topical beta-blocker timolol and the oral beta-blocker propranolol. In addition, certain IHs may be associated with either syndromic presentations and/or visceral involvement, thus requiring further workup (Table).

Congenital Hemangioma

A CH is an uncommon benign neonatal tumor that is distinct from an IH in behavior, biology, and treatment. Congenital hemangiomas may have a rapidly involuting course, referred to as RICH (rapidly involuting congenital hemangioma), or a noninvoluting course, referred to as NICH (noninvoluting congenital hemangioma). Partially involuting types also have been described.³ A RICH typically presents as a highly vascular, red-violaceous or bluish plaque, nodule, or large mass at birth. An NICH presents as a red-violaceous or bluish, coarsely telangiectatic patch, plaque, or nodule. A characteristic feature of the CH is the rim of vasoconstriction around the lesion, which is an important diagnostic clue (Figure 1). In contrast to IH, multifocal lesions are highly unlikely in CH, though it rarely has been reported.⁴

Regardless of subtype, CHs are fully developed at birth. Infantile hemangiomas, on the other hand, are either minimally present or not present at birth and thereafter proliferate. After birth, a RICH rapidly involutes over the first 9 to 12 months of life. This process generally is evident even in the first few weeks of life, which would not be expected of an IH and is therefore a major distinguishing factor. A NICH, on the other hand, is expected to be persistent, for the most part neither showing signs of proliferation nor involution.

Complications of CHs may include ulceration, functional impairment, or risk for permanent disfigurement depending on location. In addition, due to their fast-flow state and potential large size, some CHs may be complicated by high-output heart failure in the neonate. Distinguishing an IH from a CH is important not only for prognosis but also treatment. Beta-blocker therapy generally is not useful for CHs, and management usually is supportive in the neonatal period.

In the majority of cases, diagnosis can be achieved solely on clinical features. Biopsy with immunohistochemistry shows negative GLUT-1 staining, which will distinguish this lesion from an IH. At times, the highly vascular nature and/or striking size of a CH may lead some to consider the potential diagnosis of an arteriovenous malformation. However, soft-tissue arteriovenous malformations involving the skin are almost never fully developed in the neonatal period and generally take years to evolve from a quiescent state to a destructive lesion.

Venous Malformation

Venous malformations are congenital malformations of veins that may be apparent at birth or later. They appear as bluish to flesh-colored, compressible nodules or plaques. They tend to increase in size when the affected body part is in a dependent position, and this maneuver can be a helpful distinguishing clue. Although the majority of patients have a single lesion, multifocal involvement may occur uncommonly (Table). The diagnosis of VM usually is clinical, though at times, a VM may be difficult to distinguish from a purely deep IH. However, a VM will persist over time, growing in proportion to the patient. In addition, a VM displays low flow on ultrasound, a distinguishing feature from the fast-flow IH. Magnetic resonance imaging with and without contrast is the imaging study of choice. At times, cutaneous VMs will demonstrate infiltration into other tissue planes such as muscle and joint. Pain may occur secondary to thrombus formation within the malformation. In extensive lesions, intravascular coagulation may be notable, as reflected in elevated D-dimer and decreased fibrinogen levels. Treatment with sclerotherapy or surgery may be considered in select cases during infancy; however, in general, an asymptomatic VM may be observed early on in life.

Lymphatic Malformation

A lymphatic malformation (LM) is a congenital malformation of lymphatic vessels and may be further differentiated into microcystic, macrocystic, or mixed types depending on the size of the channels. An LM may present at birth or later and persists over time. Superficial microcystic LMs, synonymous with the term lymphangioma circumscriptum, characteristically appear as a group of clear and violaceous hemorrhagic vesicles on the skin. Deeper LMs appear as a tense or spongy, flesh-colored nodule or mass. Involvement of the head and neck is common. Complications frequently occur in LMs. Cutaneous LMs may ooze or bleed. Infection and hemorrhage into cysts may occur, which will cause acute pain, redness, swelling, and induration. Cervicofacial lesions may result in respiratory distress. Thus, the majority of LMs require treatment, though asymptomatic lesions may be observed in the neonate. An ultrasound will demonstrate a low-flow lesion, and magnetic resonance imaging is the diagnostic modality of choice for diagnosis and definition of extent.

KHE and Tufted Angioma

Kaposiform hemangioendothelioma is a rare, locally aggressive, vascular tumor that is frequently associated with a potentially life-threatening coagulopathy, Kasabach-Merritt phenomenon. Tufted angiomas are now understood to belong on a spectrum with KHEs, which usually present in the neonatal period or infancy as firm, red-violaceous plaques, nodules, or large tumors. Infiltration into nerve, muscle, and bone may occur. The firm/hard nature and deep violaceous appearance generally are initial clues that it is not an IH. Kasabach-Merritt phenomenon manifests as thrombocytopenia as well as low fibrinogen and elevated D-dimer levels. Thrombocytopenia is generally profound in Kasabach-Merritt phenomenon and results from platelet trapping within the vascular tumor. Given these potential complications, KHEs generally require immediate medical attention, and various treatment protocols including prednisone, vincristine, and sirolimus are utilized for complicated cases.⁵ The diagnosis may require biopsy to distinguish it from malignant tumors, particularly sarcomas.

Malignant Tumors

Various malignancies, including congenital leukemia, neuroblastoma, Langerhans cell histiocytosis, infantile fibrosarcoma, and rhabdomyosarcoma, rarely may present as cutaneous nodules or masses in a neonate mimicking hemangiomas or other vascular lesions (Figure 2). Neonates may present with multiple bluish papules and nodules resembling a blueberry muffin baby; multiple violaceous-red nodules; or a single red-violaceous, highly vascular–appearing mass mimicking hemangiomas. Malignant tumors may display vascularity on imaging, and thus the presence of vascular flow on ultrasound should not dissuade one from the possibility of a malignancy if other clinical features are atypical or unusual for a hemangioma. When a neonatal malignancy is suspected, a large punch biopsy or incisional biopsy is required for workup.

Final Thoughts

Although IHs are the most common vascular nodules in neonates and young infants, other conditions such as VMs, LMs, CHs, KHEs, and malignancy may occur less commonly. Identifying features that would be considered atypical for IH is crucial to recognize these less common possibilities.

Although most neonatal vascular lumps, bumps, and tumors are benign, proper diagnosis is important for prognosis and management. Therefore, knowledge of both common and rare conditions is important when evaluating a neonatal nodule. Differential diagnosis of neonatal vascular nodules must focus on important diagnostic clues that should prompt consideration and evaluation for less common and/or potentially threatening conditions. Infantile hemangioma (IH), congenital hemangioma (CH), venous malformation (VM), lymphatic malformation (LM), kaposiform hemangioendothelioma (KHE) and tufted angioma, and malignant tumors are reviewed here.

Infantile Hemangioma

Infantile hemangioma, a benign proliferation of capillaries, is the most common tumor of infancy with reported incidence of up to 5% in neonates.¹ As such, suspicion for less common lesions is often predicated on identifying features that would be atypical for an IH. A superficial IH presents as a bright red papule, nodule, or plaque, while a deep IH presents as a flesh-colored to bluish nodule. Mixed IHs combine features of both superficial and deep lesions. The distribution may be focal or segmental, with segmental lesions encompassing a larger territory–like distribution and frequently displaying a thin, coarsely telangiectatic appearance.

Knowledge of the natural history of IH generally is crucial in differentiating it from other neonatal lesions. Infantile hemangiomas display a natural history that is distinct and predictable. They typically manifest within the first few weeks of life, though up to 30% present at birth with a premonitory mark, which may be a light red, pink, bluish, or vasoconstricted patch. Thus, mere presence of a lesion at birth is not the feature that distinguishes other congenital lesions from an IH. After initial appearance, IHs undergo a period of proliferation that occurs over 4 to 6 months in most patients. In some cases, areas of proliferation may be subtle, but nonetheless the presence of some areas of increased redness and/or volumetric growth generally is required to firmly establish the diagnosis of IH. Thereafter, IH will involute, a process that begins before 1 year of age in most cases and continues over years. Although IHs undergo involution, complete clearance may not occur, as nearly 70% will leave permanent residua such as fibrofatty masses or anetodermic skin.² Nevertheless, the presence of a proliferative phase followed by a slower period of involution is a hallmark feature of the IH.

Biopsy and imaging rarely are required for establishing diagnosis of an IH. Histopathology showing a proliferation of capillaries with positive glucose transporter 1 (GLUT-1) staining is characteristic. Imaging with ultrasound reveals a fast-flow lesion. Apart from exceptionally rare cases, a cutaneous IH typically does not cross muscle fascia, and thus alternative diagnoses should be considered for a cutaneous lesion that demonstrates infiltration into nerve, bone, joint, or other deeper tissues. Most IHs do not require treatment; however, a small subset may be associated with complications and thus require intervention. Complications of IH may include impairment of function (eg, vision, feeding, respiratory), ulceration, and risk for permanent disfigurement. When treatment is indicated, the most commonly employed options during the proliferative phase are the topical beta-blocker timolol and the oral beta-blocker propranolol. In addition, certain IHs may be associated with either syndromic presentations and/or visceral involvement, thus requiring further workup (Table).

Congenital Hemangioma

A CH is an uncommon benign neonatal tumor that is distinct from an IH in behavior, biology, and treatment. Congenital hemangiomas may have a rapidly involuting course, referred to as RICH (rapidly involuting congenital hemangioma), or a noninvoluting course, referred to as NICH (noninvoluting congenital hemangioma). Partially involuting types also have been described.³ A RICH typically presents as a highly vascular, red-violaceous or bluish plaque, nodule, or large mass at birth. An NICH presents as a red-violaceous or bluish, coarsely telangiectatic patch, plaque, or nodule. A characteristic feature of the CH is the rim of vasoconstriction around the lesion, which is an important diagnostic clue (Figure 1). In contrast to IH, multifocal lesions are highly unlikely in CH, though it rarely has been reported.⁴

Regardless of subtype, CHs are fully developed at birth. Infantile hemangiomas, on the other hand, are either minimally present or not present at birth and thereafter proliferate. After birth, a RICH rapidly involutes over the first 9 to 12 months of life. This process generally is evident even in the first few weeks of life, which would not be expected of an IH and is therefore a major distinguishing factor. A NICH, on the other hand, is expected to be persistent, for the most part neither showing signs of proliferation nor involution.

Complications of CHs may include ulceration, functional impairment, or risk for permanent disfigurement depending on location. In addition, due to their fast-flow state and potential large size, some CHs may be complicated by high-output heart failure in the neonate. Distinguishing an IH from a CH is important not only for prognosis but also treatment. Beta-blocker therapy generally is not useful for CHs, and management usually is supportive in the neonatal period.

In the majority of cases, diagnosis can be achieved solely on clinical features. Biopsy with immunohistochemistry shows negative GLUT-1 staining, which will distinguish this lesion from an IH. At times, the highly vascular nature and/or striking size of a CH may lead some to consider the potential diagnosis of an arteriovenous malformation. However, soft-tissue arteriovenous malformations involving the skin are almost never fully developed in the neonatal period and generally take years to evolve from a quiescent state to a destructive lesion.

Venous Malformation

Venous malformations are congenital malformations of veins that may be apparent at birth or later. They appear as bluish to flesh-colored, compressible nodules or plaques. They tend to increase in size when the affected body part is in a dependent position, and this maneuver can be a helpful distinguishing clue. Although the majority of patients have a single lesion, multifocal involvement may occur uncommonly (Table). The diagnosis of VM usually is clinical, though at times, a VM may be difficult to distinguish from a purely deep IH. However, a VM will persist over time, growing in proportion to the patient. In addition, a VM displays low flow on ultrasound, a distinguishing feature from the fast-flow IH. Magnetic resonance imaging with and without contrast is the imaging study of choice. At times, cutaneous VMs will demonstrate infiltration into other tissue planes such as muscle and joint. Pain may occur secondary to thrombus formation within the malformation. In extensive lesions, intravascular coagulation may be notable, as reflected in elevated D-dimer and decreased fibrinogen levels. Treatment with sclerotherapy or surgery may be considered in select cases during infancy; however, in general, an asymptomatic VM may be observed early on in life.

Lymphatic Malformation

A lymphatic malformation (LM) is a congenital malformation of lymphatic vessels and may be further differentiated into microcystic, macrocystic, or mixed types depending on the size of the channels. An LM may present at birth or later and persists over time. Superficial microcystic LMs, synonymous with the term lymphangioma circumscriptum, characteristically appear as a group of clear and violaceous hemorrhagic vesicles on the skin. Deeper LMs appear as a tense or spongy, flesh-colored nodule or mass. Involvement of the head and neck is common. Complications frequently occur in LMs. Cutaneous LMs may ooze or bleed. Infection and hemorrhage into cysts may occur, which will cause acute pain, redness, swelling, and induration. Cervicofacial lesions may result in respiratory distress. Thus, the majority of LMs require treatment, though asymptomatic lesions may be observed in the neonate. An ultrasound will demonstrate a low-flow lesion, and magnetic resonance imaging is the diagnostic modality of choice for diagnosis and definition of extent.

KHE and Tufted Angioma

Kaposiform hemangioendothelioma is a rare, locally aggressive, vascular tumor that is frequently associated with a potentially life-threatening coagulopathy, Kasabach-Merritt phenomenon. Tufted angiomas are now understood to belong on a spectrum with KHEs, which usually present in the neonatal period or infancy as firm, red-violaceous plaques, nodules, or large tumors. Infiltration into nerve, muscle, and bone may occur. The firm/hard nature and deep violaceous appearance generally are initial clues that it is not an IH. Kasabach-Merritt phenomenon manifests as thrombocytopenia as well as low fibrinogen and elevated D-dimer levels. Thrombocytopenia is generally profound in Kasabach-Merritt phenomenon and results from platelet trapping within the vascular tumor. Given these potential complications, KHEs generally require immediate medical attention, and various treatment protocols including prednisone, vincristine, and sirolimus are utilized for complicated cases.⁵ The diagnosis may require biopsy to distinguish it from malignant tumors, particularly sarcomas.

Malignant Tumors

Various malignancies, including congenital leukemia, neuroblastoma, Langerhans cell histiocytosis, infantile fibrosarcoma, and rhabdomyosarcoma, rarely may present as cutaneous nodules or masses in a neonate mimicking hemangiomas or other vascular lesions (Figure 2). Neonates may present with multiple bluish papules and nodules resembling a blueberry muffin baby; multiple violaceous-red nodules; or a single red-violaceous, highly vascular–appearing mass mimicking hemangiomas. Malignant tumors may display vascularity on imaging, and thus the presence of vascular flow on ultrasound should not dissuade one from the possibility of a malignancy if other clinical features are atypical or unusual for a hemangioma. When a neonatal malignancy is suspected, a large punch biopsy or incisional biopsy is required for workup.

Final Thoughts

Although IHs are the most common vascular nodules in neonates and young infants, other conditions such as VMs, LMs, CHs, KHEs, and malignancy may occur less commonly. Identifying features that would be considered atypical for IH is crucial to recognize these less common possibilities.