Infectious Diseases

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.

Treating Clostridioides difficile infection with fecal microbiota transplantation is associated with a lower risk of bloodstream infection and recurrence than treatment with antibiotics, new research has found.

A paper published in Annals of Internal Medicine presents outcomes of a prospective cohort study in 290 inpatients with recurrent C. difficile infection, 109 of whom were treated with fecal microbiota transplantation (FMT); the remainder were treated with antibiotics including metronidazole, vancomycin, and fidaxomicin.

While the FMT group had a higher mean number of previous C. difficile infections than the antibiotics group (2.82 vs. 1.23, respectively), a sustained cure was achieved in 97% of the FMT group, compared with 38% in the antibiotics group.

Blood cultures were done if patients developed a temperature above 30° C or showed symptoms that might be attributable to sepsis. Bloodstream infections were diagnosed in 5% (5 patients) of those treated with FMT, and 22% (40 patients) in the antibiotics group.

The patients in the FMT group with bloodstream infections all had bacterial infections – one of which was polymicrobial – and there were no cases of fungal bloodstream infections. In the antibiotics group, 28 patients (15%) had bacterial bloodstream infections – 11 of which were polymicrobial – and 12 (7%) had fungal bloodstream infections.

Bloodstream infections were particularly evident among the 11 patients whose C. difficile infection was treated with fidaxomicin, 4 of whom developed a bloodstream infection.

Overall, 27% of patients died during the 90-day follow-up, with 7% dying because of bloodstream infections, all of whom were in the antibiotic-treated cohort. Three patients in the FMT group died because of overwhelming C. difficile infection, compared with 12 in the antibiotic cohort.

Nearly three-quarters of deaths occurred within 30 days of the end of treatment; 5 of these deaths were in the FMT group, and 53 were in the antibiotics group.

“These findings suggest that the longer 90-day [overall survival] of patients in the FMT group is attributable to cure of [C. difficile infection] leading to an improvement in clinical condition,” wrote Gianluca Ianiro, MD, from the Catholic University of the Sacred Heart in Rome, and coauthors.

The 90-day overall survival rate was 92% in the FMT group and 61% in the antibiotic group. Patients treated with FMT also showed significantly shorter mean duration of hospital stay at 13.3 days, compared with 29.7 days in patients treated with antibiotics.

The authors noted the results should be interpreted with caution because of baseline differences between the two groups that were not entirely accounted for by using propensity matching. However, even in the propensity-matched cohort of 57 patients from each group, there was still a significantly higher overall survival at 90 days among patients treated with FMT.

One author declared grants from the pharmaceutical sector outside the submitted work. No funding or other conflicts of interest were reported.

SOURCE: Ianiro G et al. Ann Intern Med. 2019 Nov 4. doi: 10.7326/M18-3635.

Treating Clostridioides difficile infection with fecal microbiota transplantation is associated with a lower risk of bloodstream infection and recurrence than treatment with antibiotics, new research has found.

A paper published in Annals of Internal Medicine presents outcomes of a prospective cohort study in 290 inpatients with recurrent C. difficile infection, 109 of whom were treated with fecal microbiota transplantation (FMT); the remainder were treated with antibiotics including metronidazole, vancomycin, and fidaxomicin.

While the FMT group had a higher mean number of previous C. difficile infections than the antibiotics group (2.82 vs. 1.23, respectively), a sustained cure was achieved in 97% of the FMT group, compared with 38% in the antibiotics group.

Blood cultures were done if patients developed a temperature above 30° C or showed symptoms that might be attributable to sepsis. Bloodstream infections were diagnosed in 5% (5 patients) of those treated with FMT, and 22% (40 patients) in the antibiotics group.

The patients in the FMT group with bloodstream infections all had bacterial infections – one of which was polymicrobial – and there were no cases of fungal bloodstream infections. In the antibiotics group, 28 patients (15%) had bacterial bloodstream infections – 11 of which were polymicrobial – and 12 (7%) had fungal bloodstream infections.

Bloodstream infections were particularly evident among the 11 patients whose C. difficile infection was treated with fidaxomicin, 4 of whom developed a bloodstream infection.

Overall, 27% of patients died during the 90-day follow-up, with 7% dying because of bloodstream infections, all of whom were in the antibiotic-treated cohort. Three patients in the FMT group died because of overwhelming C. difficile infection, compared with 12 in the antibiotic cohort.

Nearly three-quarters of deaths occurred within 30 days of the end of treatment; 5 of these deaths were in the FMT group, and 53 were in the antibiotics group.

“These findings suggest that the longer 90-day [overall survival] of patients in the FMT group is attributable to cure of [C. difficile infection] leading to an improvement in clinical condition,” wrote Gianluca Ianiro, MD, from the Catholic University of the Sacred Heart in Rome, and coauthors.

The 90-day overall survival rate was 92% in the FMT group and 61% in the antibiotic group. Patients treated with FMT also showed significantly shorter mean duration of hospital stay at 13.3 days, compared with 29.7 days in patients treated with antibiotics.

The authors noted the results should be interpreted with caution because of baseline differences between the two groups that were not entirely accounted for by using propensity matching. However, even in the propensity-matched cohort of 57 patients from each group, there was still a significantly higher overall survival at 90 days among patients treated with FMT.

One author declared grants from the pharmaceutical sector outside the submitted work. No funding or other conflicts of interest were reported.

SOURCE: Ianiro G et al. Ann Intern Med. 2019 Nov 4. doi: 10.7326/M18-3635.

Treating Clostridioides difficile infection with fecal microbiota transplantation is associated with a lower risk of bloodstream infection and recurrence than treatment with antibiotics, new research has found.

A paper published in Annals of Internal Medicine presents outcomes of a prospective cohort study in 290 inpatients with recurrent C. difficile infection, 109 of whom were treated with fecal microbiota transplantation (FMT); the remainder were treated with antibiotics including metronidazole, vancomycin, and fidaxomicin.

While the FMT group had a higher mean number of previous C. difficile infections than the antibiotics group (2.82 vs. 1.23, respectively), a sustained cure was achieved in 97% of the FMT group, compared with 38% in the antibiotics group.

Blood cultures were done if patients developed a temperature above 30° C or showed symptoms that might be attributable to sepsis. Bloodstream infections were diagnosed in 5% (5 patients) of those treated with FMT, and 22% (40 patients) in the antibiotics group.

The patients in the FMT group with bloodstream infections all had bacterial infections – one of which was polymicrobial – and there were no cases of fungal bloodstream infections. In the antibiotics group, 28 patients (15%) had bacterial bloodstream infections – 11 of which were polymicrobial – and 12 (7%) had fungal bloodstream infections.

Bloodstream infections were particularly evident among the 11 patients whose C. difficile infection was treated with fidaxomicin, 4 of whom developed a bloodstream infection.

Overall, 27% of patients died during the 90-day follow-up, with 7% dying because of bloodstream infections, all of whom were in the antibiotic-treated cohort. Three patients in the FMT group died because of overwhelming C. difficile infection, compared with 12 in the antibiotic cohort.

Nearly three-quarters of deaths occurred within 30 days of the end of treatment; 5 of these deaths were in the FMT group, and 53 were in the antibiotics group.

“These findings suggest that the longer 90-day [overall survival] of patients in the FMT group is attributable to cure of [C. difficile infection] leading to an improvement in clinical condition,” wrote Gianluca Ianiro, MD, from the Catholic University of the Sacred Heart in Rome, and coauthors.

The 90-day overall survival rate was 92% in the FMT group and 61% in the antibiotic group. Patients treated with FMT also showed significantly shorter mean duration of hospital stay at 13.3 days, compared with 29.7 days in patients treated with antibiotics.

The authors noted the results should be interpreted with caution because of baseline differences between the two groups that were not entirely accounted for by using propensity matching. However, even in the propensity-matched cohort of 57 patients from each group, there was still a significantly higher overall survival at 90 days among patients treated with FMT.

One author declared grants from the pharmaceutical sector outside the submitted work. No funding or other conflicts of interest were reported.

SOURCE: Ianiro G et al. Ann Intern Med. 2019 Nov 4. doi: 10.7326/M18-3635.

Background: Despite the rise in utilization of PICC lines, few studies have addressed complications experienced by patients following PICC placement, especially subsequent to discharge from the inpatient setting.

Dr. Cooke is a hospitalist at Beth Israel Deaconess Medical Center.

Background: Despite the rise in utilization of PICC lines, few studies have addressed complications experienced by patients following PICC placement, especially subsequent to discharge from the inpatient setting.

Dr. Cooke is a hospitalist at Beth Israel Deaconess Medical Center.

Background: Despite the rise in utilization of PICC lines, few studies have addressed complications experienced by patients following PICC placement, especially subsequent to discharge from the inpatient setting.

Dr. Cooke is a hospitalist at Beth Israel Deaconess Medical Center.

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

Sexually transmitted infections (STIs) such as gonorrhea, chlamydia, and syphilis are still increasing in incidence and probably will continue to do so in the near future. Moreover, drug-resistant strains of Neisseria gonorrhoeae are emerging, as are less-known organisms such as Mycoplasma genitalium.

Now the good news: new tests for STIs are available or are coming! Based on nucleic acid amplification, these tests can be performed at the point of care, so that patients can leave the clinic with an accurate diagnosis and proper treatment for themselves and their sexual partners. Also, the tests can be run on samples collected by the patients themselves, either swabs or urine collections, eliminating the need for invasive sampling and making doctor-shy patients more likely to come in to be treated.¹ We hope that by using these sensitive and accurate tests we can begin to bend the upward curve of STIs and be better antimicrobial stewards.²

This article reviews current issues surrounding STI control, and provides detailed guidance on recognizing, testing for, and treating gonorrhea, chlamydia, trichomoniasis, and M genitalium infection.

STI RATES ARE HIGH AND RISING

STIs are among the most common acute infectious diseases worldwide, with an estimated 1 million new curable cases every day.³ Further, STIs have major impacts on sexual, reproductive, and psychological health.

In the United States, rates of reportable STIs (chlamydia, gonorrhea, and syphilis) are rising.⁴ In addition, more-sensitive tests for trichomoniasis, which is not a reportable infection in any state, have revealed it to be more prevalent than previously thought.⁵

BARRIERS AND CHALLENGES TO DIAGNOSIS

The medical system does not fully meet the needs of some populations, including young people and men who have sex with men, regarding their sexual and reproductive health. 

Ongoing barriers among young people include reluctance to use available health services, limited access to STI testing, worries about confidentiality, and the shame and stigma associated with STIs.⁶

Men who have sex with men have a higher incidence of STIs than other groups. Since STIs are associated with a higher risk of human immunodeficiency virus (HIV) infection, it is important to detect, diagnose, and manage STIs in this group—and in all high-risk groups. Rectal STIs are an independent risk factor for incident HIV infection.⁷ In addition, many men who have sex with men face challenges navigating the emotional, physical, and cognitive aspects of adolescence, a voyage further complicated by mental health issues, unprotected sexual encounters, and substance abuse in many, especially among minority youth.⁸ These same factors also impair their ability to access resources for preventing and treating HIV and other STIs.

STI diagnosis is often missed

Most people who have STIs feel no symptoms, which increases the importance of risk-based screening to detect these infections.^9,10 In many other cases, STIs manifest with nonspecific genitourinary symptoms that are mistaken for urinary tract infection. Tomas et al¹¹ found that of 264 women who presented to an emergency department with genitourinary symptoms or were being treated for urinary tract infection, 175 were given a diagnosis of a urinary tract infection. Of these, 100 (57%) were treated without performing a urine culture; 60 (23%) of the 264 women had 1 or more positive STI tests, 22 (37%) of whom did not receive treatment for an STI.

Poor follow-up of patients and partners

Patients with STIs need to be retested 3 months after treatment to make sure the treatment was effective. Another reason for follow-up is that these patients are at higher risk of another infection within a year.¹²

Although treating patients’ partners has been shown to reduce reinfection rates, fewer than one-third of STIs (including HIV infections) were recognized through partner notification between 2010 and 2012 in a Dutch study, in men who have sex with men and in women.¹³ Challenges included partners who could not be identified among men who have sex with men, failure of heterosexual men to notify their partners, and lower rates of partner notification for HIV.  

In the United States, “expedited partner therapy” allows healthcare providers to provide a prescription or medications to partners of patients diagnosed with chlamydia or gonorrhea without examining the partner.¹⁴ While this approach is legal in most states, implementation can be challenging.¹⁵

STI EVALUATION

History and physical examination

A complete sexual history helps in estimating the patient’s risk of an STI and applying appropriate risk-based screening. Factors such as sexual practices, use of barrier protection, and history of STIs should be discussed.

Physical examination is also important. Although some patients may experience discomfort during a genital or pelvic examination, omitting this step may lead to missed diagnoses in women with STIs.¹⁶

Laboratory testing

Laboratory testing for STIs helps ensure accurate diagnosis and treatment. Empiric treatment without testing could give a patient a false sense of health by missing an infection that is not currently causing symptoms but that could later worsen or have lasting complications. Failure to test patients also misses the opportunity for partner notification, linkage to services, and follow-up testing.

Many of the most common STIs, including gonorrhea, chlamydia, and trichomoniasis, can be detected using vaginal, cervical, or urethral swabs or first-catch urine (from the initial urine stream). In studies that compared various sampling methods,¹⁷ self-collected urine samples for gonorrhea in men were nearly as good as clinician-collected swabs of the urethra. In women, self-collected vaginal swabs for gonorrhea and chlamydia were nearly as good as clinician-collected vaginal swabs. While urine specimens are acceptable for chlamydia testing in women, their sensitivity may be slightly lower than with vaginal and endocervical swab specimens.^18,19

A major advantage of urine specimens for STI testing is that collection is noninvasive and is therefore more likely to be acceptable to patients. Urine testing can also be conducted in a variety of nonclinical settings such as health fairs, pharmacy-based screening programs, and express STI testing sites, thus increasing availability.

To prevent further transmission and morbidity and to aid in public health efforts, it is critical to recognize the cause of infectious cervicitis and urethritis and to screen for STIs according to guidelines.¹² Table 1 summarizes current screening and laboratory testing recommendations.

 

 

GONORRHEA AND CHLAMYDIA

Gonorrhea and chlamydia are the 2 most frequently reported STIs in the United States, with more than 550,000 cases of gonorrhea and 1.7 million cases of chlamydia reported in 2017.⁴

Both infections present similarly: cervicitis or urethritis characterized by discharge (mucopurulent discharge with gonorrhea) and dysuria. Untreated, they can lead to pelvic inflammatory disease, inflammation, and infertility.

Extragenital infections can be asymptomatic or cause exudative pharyngitis or proctitis. Most people in whom chlamydia is detected from pharyngeal specimens are asymptomatic. When pharyngeal symptoms exist secondary to gonorrheal infection, they typically include sore throat and pharyngeal exudates. However, Komaroff et al,²⁰ in a study of 192 men and women who presented with sore throat, found that only 2 (1%) tested positive for N gonorrhoeae.

Screening for gonorrhea and chlamydia

Best practices include screening for gonorrhea and chlamydia as follows^21–23:

• Every year in sexually active women through age 25 (including during pregnancy) and in older women who have risk factors for infection¹²
• At least every year in men who have sex with men, at all sites of sexual contact (urethra, pharynx, rectum), along with testing for HIV and syphilis
• Every 3 to 6 months in men who have sex with men who have multiple or anonymous partners, who are sexually active and use illicit drugs, or who have partners who use illicit drugs
• Possibly every year in young men who live in high-prevalence areas or who are seen in certain clinical settings, such as STI and adolescent clinics.

Specimens. A vaginal swab is preferred for screening in women. Several studies have shown that self-collected swabs have clinical sensitivity and specificity comparable to that of provider-collected samples.^17,24 First-catch urine or endocervical swabs have similar performance characteristics and are also acceptable. In men, urethral swabs or first-catch urine samples are appropriate for screening for urogenital infections.

Testing methods. Testing for both pathogens should be done simultaneously with a nucleic acid amplification test (NAAT). Commercially available NAATs are more sensitive than culture and antigen testing for detecting gonorrhea and chlamydia.^25–27

Most assays are approved by the US Food and Drug Administration (FDA) for testing vaginal, urethral, cervical, and urine specimens. Until recently, no commercial assay was cleared for testing extragenital sites, but recommendations for screening extragenital sites prompted many clinical laboratories to validate throat and rectal swabs for use with NAATs, which are more sensitive than culture at these sites.^25,28 The recent FDA approval of extragenital specimen types for 2 commercially available assays may increase the availability of testing for these sites.

Data on the utility of NAATs for detecting chlamydia and gonorrhea in children are limited, and many clinical laboratories have not validated molecular methods for testing in children. Current guidelines specific to this population should be followed regarding test methods and preferred specimen types.^12,29,30

Although gonococcal infection is usually diagnosed with culture-independent molecular methods, antimicrobial resistance is emerging. Thus, failure of the combination of ceftriaxone and azithromycin should prompt culture-based follow-up testing to determine antimicrobial susceptibility.

Strategies for treatment and control

Historically, people treated for gonorrhea have been treated for chlamydia at the same time, as these diseases tend to go together. This can be with a single intramuscular dose of ceftriaxone for the gonorrhea plus a single oral dose of azithromycin for the chlamydia.¹² For patients who have only gonorrhea, this double regimen may help prevent the development of resistant gonorrhea strains.

All the patient’s sexual partners in the previous 60 days should be tested and treated, and expedited partner therapy should be offered if possible. Patients should be advised to have no sexual contact until they complete the treatment, or 7 days after single-dose treatment. Testing should be repeated 3 months after treatment.

 

 

M GENITALIUM IS EMERGING

A member of the Mycoplasmataceae family, M genitalium was originally identified as a pathogen in the early 1980s but has only recently emerged as an important cause of STI. Studies indicate that it is responsible for 10% to 20% of cases of nongonococcal urethritis and 10% to 30% of cases of cervicitis.^31–33 Additionally, 2% to 22% of cases of pelvic inflammatory disease have evidence of M genitalium.^34,35

However, data on M genitalium prevalence are suspect because the organism is hard to identify—lacking a cell wall, it is undetectable by Gram stain.³⁶ Although it has been isolated in respiratory and synovial fluids, it has so far been recognized to be clinically important only in the urogenital tract. It can persist for years in infected patients by exploiting specialized cell-surface structures to invade cells.³⁶ Once inside a cell, it triggers secretion of mycoplasmal toxins and destructive metabolites such as hydrogen peroxide, evading the host immune system as it does so.³⁷

Testing guidelines for M genitalium

Current guidelines do not recommend routine screening for M genitalium, and no commercial test was available until recently.¹² Although evidence suggests that M genitalium is independently associated with preterm birth and miscarriages,³⁸ routine screening of pregnant women is not recommended.¹²

Testing for M genitalium should be considered in cases of persistent or recurrent nongonococcal urethritis in patients who test negative for gonorrhea and chlamydia or for whom treatment has failed.¹² Many isolates exhibit genotypic resistance to macrolide antibiotics, which are often the first-line therapy for nongonococcal urethritis.³⁹

Further study is needed to evaluate the potential impact of routine screening for M genitalium on the reproductive and sexual health of at-risk populations.

Diagnostic tests for M genitalium

Awareness of M genitalium as a cause of nongonococcal urethritis has been hampered by a dearth of diagnostic tests.⁴⁰ The organism’s fastidious requirements and extremely slow growth preclude culture as a practical method of diagnosis.⁴¹ Serologic assays are dogged by cross-reactivity and poor sensitivity.^42,43 Thus, molecular assays for detecting M genitalium and associated resistance markers are preferred for diagnosis.¹²

Several molecular tests are approved, available, and in use in Europe for diagnosing M genitalium infection,⁴⁰ and in January 2019 the FDA approved a molecular test that can detect M genitalium in urine specimens and vaginal, endocervical, urethral, and penile meatal swabs. Although vaginal swabs are preferred for this assay because they have higher sensitivity (92% for provider-collected and 99% for patient-collected swabs), urine specimens are acceptable, with a sensitivity of 78%.⁴⁴

At least 1 company is seeking FDA clearance for another molecular diagnostic assay for detecting M genitalium and markers of macrolide resistance in urine and genital swab specimens. Such assays may facilitate appropriate treatment.

Clinicians should stay abreast of diagnostic testing options, which are likely to become more readily available soon.

A high rate of macrolide resistance

Because M genitalium lacks a cell wall, antibiotics such as beta-lactams that target cell wall synthesis are ineffective.

Regimens for treating M genitalium are outlined in Table 2.¹² Azithromycin is more effective than doxycycline. However, as many as 50% of strains were macrolide-resistant in a cohort of US female patients.⁴⁵ Given the high incidence of treatment failure with azithromycin 1 g, it is thought that this regimen might select for resistance. For cases in which symptoms persist, a 1- to 2-week course of moxifloxacin is recommended.¹² However, this has not been validated by clinical trials, and failures of the 7-day regimen have been reported.⁴⁶

Partners of patients who test positive for M genitalium should also be tested and undergo clinically applicable screening for nongonococcal urethritis, cervicitis, and pelvic inflammatory disease.¹²

TRICHOMONIASIS

Trichomoniasis, caused by the parasite Trichomonas vaginalis, is the most prevalent nonviral STI in the United States. It disproportionately affects black women, in whom the prevalence is 13%, compared with 1% in non-Hispanic white women.⁴⁷ It is also present in 26% of women with symptoms who are seen in STI clinics and is highly prevalent in incarcerated populations. It is uncommon in men who have sex with men.⁴⁸

In men, trichomoniasis manifests as urethritis, epididymitis, or prostatitis. While most infected women have no symptoms, they may experience vaginitis with discharge that is diffuse, frothy, pruritic, malodorous, or yellow-green. Vaginal and cervical erythema (“strawberry cervix”) can also occur.

Screening for trichomoniasis

Current guidelines of the US Centers for Disease Control and Prevention (CDC) recommend testing for T vaginalis in women who have symptoms and routinely screening in women who are HIV-positive, regardless of symptoms. There is no evidence to support routine screening of pregnant women without symptoms, and pregnant women who do have symptoms should be evaluated according to the same guidelines as for nonpregnant women.¹² Testing can be considered in patients who have no symptoms but who engage in high-risk behaviors and in areas of high prevalence.

A lack of studies using sensitive methods for T vaginalis detection has hampered a true estimation of disease burden and at-risk populations. Screening recommendations may evolve in upcoming clinical guidelines as the field advances.

As infection can recur, women should be retested 3 months after initial diagnosis.¹²

NAAT is the preferred test for trichomoniasis

Commercially available diagnostic tests for trichomoniasis include culture, antigen testing, and NAAT.⁴⁹ While many clinicians do their own wet-mount microscopy for a rapid result, this method has low sensitivity.⁵⁰ Similarly, antigen testing and culture perform poorly compared with NAATs, which are the gold standard for detection.^51,52 A major advantage of NAATs for T vaginalis detection is that they combine high sensitivity and fast results, facilitating diagnosis and appropriate treatment of patients and their partners.

In spite of these benefits, adoption of molecular diagnostic testing for T vaginalis has lagged behind that for chlamydia and gonorrhea.⁵³ FDA-cleared NAATs are available for testing vaginal, cervical, or urine specimens from women, but until recently, there were no approved assays for testing in men. The Cepheid Xpert TV assay, which is valid for male urine specimens to diagnose other sexually transmitted diseases, has demonstrated excellent diagnostic sensitivity for T vaginalis in men and women.⁵⁴ Interestingly, a large proportion of male patients in this study had no symptoms, suggesting that screening of men in high-risk groups may be warranted.

7-day metronidazole treatment beats single-dose treatment

The first-line treatment for trichomoniasis has been a single dose of metronidazole 2 g by mouth, but in a recent randomized controlled trial,⁵⁵ a course of 500 mg by mouth twice a day for 7 days was 45% more effective at 4 weeks than a single dose, and it should now be the preferred regimen.

In clinical trials,⁵⁶ a single dose of tinidazole 2 g orally was equivalent or superior to metronidazole 2 g and had fewer gastrointestinal side effects, but it is more expensive.

Sexually transmitted infections (STIs) such as gonorrhea, chlamydia, and syphilis are still increasing in incidence and probably will continue to do so in the near future. Moreover, drug-resistant strains of Neisseria gonorrhoeae are emerging, as are less-known organisms such as Mycoplasma genitalium.

Now the good news: new tests for STIs are available or are coming! Based on nucleic acid amplification, these tests can be performed at the point of care, so that patients can leave the clinic with an accurate diagnosis and proper treatment for themselves and their sexual partners. Also, the tests can be run on samples collected by the patients themselves, either swabs or urine collections, eliminating the need for invasive sampling and making doctor-shy patients more likely to come in to be treated.¹ We hope that by using these sensitive and accurate tests we can begin to bend the upward curve of STIs and be better antimicrobial stewards.²

This article reviews current issues surrounding STI control, and provides detailed guidance on recognizing, testing for, and treating gonorrhea, chlamydia, trichomoniasis, and M genitalium infection.

STI RATES ARE HIGH AND RISING

STIs are among the most common acute infectious diseases worldwide, with an estimated 1 million new curable cases every day.³ Further, STIs have major impacts on sexual, reproductive, and psychological health.

In the United States, rates of reportable STIs (chlamydia, gonorrhea, and syphilis) are rising.⁴ In addition, more-sensitive tests for trichomoniasis, which is not a reportable infection in any state, have revealed it to be more prevalent than previously thought.⁵

BARRIERS AND CHALLENGES TO DIAGNOSIS

The medical system does not fully meet the needs of some populations, including young people and men who have sex with men, regarding their sexual and reproductive health. 

Ongoing barriers among young people include reluctance to use available health services, limited access to STI testing, worries about confidentiality, and the shame and stigma associated with STIs.⁶

Men who have sex with men have a higher incidence of STIs than other groups. Since STIs are associated with a higher risk of human immunodeficiency virus (HIV) infection, it is important to detect, diagnose, and manage STIs in this group—and in all high-risk groups. Rectal STIs are an independent risk factor for incident HIV infection.⁷ In addition, many men who have sex with men face challenges navigating the emotional, physical, and cognitive aspects of adolescence, a voyage further complicated by mental health issues, unprotected sexual encounters, and substance abuse in many, especially among minority youth.⁸ These same factors also impair their ability to access resources for preventing and treating HIV and other STIs.

STI diagnosis is often missed

Most people who have STIs feel no symptoms, which increases the importance of risk-based screening to detect these infections.^9,10 In many other cases, STIs manifest with nonspecific genitourinary symptoms that are mistaken for urinary tract infection. Tomas et al¹¹ found that of 264 women who presented to an emergency department with genitourinary symptoms or were being treated for urinary tract infection, 175 were given a diagnosis of a urinary tract infection. Of these, 100 (57%) were treated without performing a urine culture; 60 (23%) of the 264 women had 1 or more positive STI tests, 22 (37%) of whom did not receive treatment for an STI.

Poor follow-up of patients and partners

Patients with STIs need to be retested 3 months after treatment to make sure the treatment was effective. Another reason for follow-up is that these patients are at higher risk of another infection within a year.¹²

Although treating patients’ partners has been shown to reduce reinfection rates, fewer than one-third of STIs (including HIV infections) were recognized through partner notification between 2010 and 2012 in a Dutch study, in men who have sex with men and in women.¹³ Challenges included partners who could not be identified among men who have sex with men, failure of heterosexual men to notify their partners, and lower rates of partner notification for HIV.  

In the United States, “expedited partner therapy” allows healthcare providers to provide a prescription or medications to partners of patients diagnosed with chlamydia or gonorrhea without examining the partner.¹⁴ While this approach is legal in most states, implementation can be challenging.¹⁵

STI EVALUATION

History and physical examination

A complete sexual history helps in estimating the patient’s risk of an STI and applying appropriate risk-based screening. Factors such as sexual practices, use of barrier protection, and history of STIs should be discussed.

Physical examination is also important. Although some patients may experience discomfort during a genital or pelvic examination, omitting this step may lead to missed diagnoses in women with STIs.¹⁶

Laboratory testing

Laboratory testing for STIs helps ensure accurate diagnosis and treatment. Empiric treatment without testing could give a patient a false sense of health by missing an infection that is not currently causing symptoms but that could later worsen or have lasting complications. Failure to test patients also misses the opportunity for partner notification, linkage to services, and follow-up testing.

Many of the most common STIs, including gonorrhea, chlamydia, and trichomoniasis, can be detected using vaginal, cervical, or urethral swabs or first-catch urine (from the initial urine stream). In studies that compared various sampling methods,¹⁷ self-collected urine samples for gonorrhea in men were nearly as good as clinician-collected swabs of the urethra. In women, self-collected vaginal swabs for gonorrhea and chlamydia were nearly as good as clinician-collected vaginal swabs. While urine specimens are acceptable for chlamydia testing in women, their sensitivity may be slightly lower than with vaginal and endocervical swab specimens.^18,19

A major advantage of urine specimens for STI testing is that collection is noninvasive and is therefore more likely to be acceptable to patients. Urine testing can also be conducted in a variety of nonclinical settings such as health fairs, pharmacy-based screening programs, and express STI testing sites, thus increasing availability.

To prevent further transmission and morbidity and to aid in public health efforts, it is critical to recognize the cause of infectious cervicitis and urethritis and to screen for STIs according to guidelines.¹² Table 1 summarizes current screening and laboratory testing recommendations.

 

 

GONORRHEA AND CHLAMYDIA

Gonorrhea and chlamydia are the 2 most frequently reported STIs in the United States, with more than 550,000 cases of gonorrhea and 1.7 million cases of chlamydia reported in 2017.⁴

Both infections present similarly: cervicitis or urethritis characterized by discharge (mucopurulent discharge with gonorrhea) and dysuria. Untreated, they can lead to pelvic inflammatory disease, inflammation, and infertility.

Extragenital infections can be asymptomatic or cause exudative pharyngitis or proctitis. Most people in whom chlamydia is detected from pharyngeal specimens are asymptomatic. When pharyngeal symptoms exist secondary to gonorrheal infection, they typically include sore throat and pharyngeal exudates. However, Komaroff et al,²⁰ in a study of 192 men and women who presented with sore throat, found that only 2 (1%) tested positive for N gonorrhoeae.

Screening for gonorrhea and chlamydia

Best practices include screening for gonorrhea and chlamydia as follows^21–23:

• Every year in sexually active women through age 25 (including during pregnancy) and in older women who have risk factors for infection¹²
• At least every year in men who have sex with men, at all sites of sexual contact (urethra, pharynx, rectum), along with testing for HIV and syphilis
• Every 3 to 6 months in men who have sex with men who have multiple or anonymous partners, who are sexually active and use illicit drugs, or who have partners who use illicit drugs
• Possibly every year in young men who live in high-prevalence areas or who are seen in certain clinical settings, such as STI and adolescent clinics.

Specimens. A vaginal swab is preferred for screening in women. Several studies have shown that self-collected swabs have clinical sensitivity and specificity comparable to that of provider-collected samples.^17,24 First-catch urine or endocervical swabs have similar performance characteristics and are also acceptable. In men, urethral swabs or first-catch urine samples are appropriate for screening for urogenital infections.

Testing methods. Testing for both pathogens should be done simultaneously with a nucleic acid amplification test (NAAT). Commercially available NAATs are more sensitive than culture and antigen testing for detecting gonorrhea and chlamydia.^25–27

Most assays are approved by the US Food and Drug Administration (FDA) for testing vaginal, urethral, cervical, and urine specimens. Until recently, no commercial assay was cleared for testing extragenital sites, but recommendations for screening extragenital sites prompted many clinical laboratories to validate throat and rectal swabs for use with NAATs, which are more sensitive than culture at these sites.^25,28 The recent FDA approval of extragenital specimen types for 2 commercially available assays may increase the availability of testing for these sites.

Data on the utility of NAATs for detecting chlamydia and gonorrhea in children are limited, and many clinical laboratories have not validated molecular methods for testing in children. Current guidelines specific to this population should be followed regarding test methods and preferred specimen types.^12,29,30

Although gonococcal infection is usually diagnosed with culture-independent molecular methods, antimicrobial resistance is emerging. Thus, failure of the combination of ceftriaxone and azithromycin should prompt culture-based follow-up testing to determine antimicrobial susceptibility.

Strategies for treatment and control

Historically, people treated for gonorrhea have been treated for chlamydia at the same time, as these diseases tend to go together. This can be with a single intramuscular dose of ceftriaxone for the gonorrhea plus a single oral dose of azithromycin for the chlamydia.¹² For patients who have only gonorrhea, this double regimen may help prevent the development of resistant gonorrhea strains.

All the patient’s sexual partners in the previous 60 days should be tested and treated, and expedited partner therapy should be offered if possible. Patients should be advised to have no sexual contact until they complete the treatment, or 7 days after single-dose treatment. Testing should be repeated 3 months after treatment.

 

 

M GENITALIUM IS EMERGING

A member of the Mycoplasmataceae family, M genitalium was originally identified as a pathogen in the early 1980s but has only recently emerged as an important cause of STI. Studies indicate that it is responsible for 10% to 20% of cases of nongonococcal urethritis and 10% to 30% of cases of cervicitis.^31–33 Additionally, 2% to 22% of cases of pelvic inflammatory disease have evidence of M genitalium.^34,35

However, data on M genitalium prevalence are suspect because the organism is hard to identify—lacking a cell wall, it is undetectable by Gram stain.³⁶ Although it has been isolated in respiratory and synovial fluids, it has so far been recognized to be clinically important only in the urogenital tract. It can persist for years in infected patients by exploiting specialized cell-surface structures to invade cells.³⁶ Once inside a cell, it triggers secretion of mycoplasmal toxins and destructive metabolites such as hydrogen peroxide, evading the host immune system as it does so.³⁷

Testing guidelines for M genitalium

Current guidelines do not recommend routine screening for M genitalium, and no commercial test was available until recently.¹² Although evidence suggests that M genitalium is independently associated with preterm birth and miscarriages,³⁸ routine screening of pregnant women is not recommended.¹²

Testing for M genitalium should be considered in cases of persistent or recurrent nongonococcal urethritis in patients who test negative for gonorrhea and chlamydia or for whom treatment has failed.¹² Many isolates exhibit genotypic resistance to macrolide antibiotics, which are often the first-line therapy for nongonococcal urethritis.³⁹

Further study is needed to evaluate the potential impact of routine screening for M genitalium on the reproductive and sexual health of at-risk populations.

Diagnostic tests for M genitalium

Awareness of M genitalium as a cause of nongonococcal urethritis has been hampered by a dearth of diagnostic tests.⁴⁰ The organism’s fastidious requirements and extremely slow growth preclude culture as a practical method of diagnosis.⁴¹ Serologic assays are dogged by cross-reactivity and poor sensitivity.^42,43 Thus, molecular assays for detecting M genitalium and associated resistance markers are preferred for diagnosis.¹²

Several molecular tests are approved, available, and in use in Europe for diagnosing M genitalium infection,⁴⁰ and in January 2019 the FDA approved a molecular test that can detect M genitalium in urine specimens and vaginal, endocervical, urethral, and penile meatal swabs. Although vaginal swabs are preferred for this assay because they have higher sensitivity (92% for provider-collected and 99% for patient-collected swabs), urine specimens are acceptable, with a sensitivity of 78%.⁴⁴

At least 1 company is seeking FDA clearance for another molecular diagnostic assay for detecting M genitalium and markers of macrolide resistance in urine and genital swab specimens. Such assays may facilitate appropriate treatment.

Clinicians should stay abreast of diagnostic testing options, which are likely to become more readily available soon.

A high rate of macrolide resistance

Because M genitalium lacks a cell wall, antibiotics such as beta-lactams that target cell wall synthesis are ineffective.

Regimens for treating M genitalium are outlined in Table 2.¹² Azithromycin is more effective than doxycycline. However, as many as 50% of strains were macrolide-resistant in a cohort of US female patients.⁴⁵ Given the high incidence of treatment failure with azithromycin 1 g, it is thought that this regimen might select for resistance. For cases in which symptoms persist, a 1- to 2-week course of moxifloxacin is recommended.¹² However, this has not been validated by clinical trials, and failures of the 7-day regimen have been reported.⁴⁶

Partners of patients who test positive for M genitalium should also be tested and undergo clinically applicable screening for nongonococcal urethritis, cervicitis, and pelvic inflammatory disease.¹²

TRICHOMONIASIS

Trichomoniasis, caused by the parasite Trichomonas vaginalis, is the most prevalent nonviral STI in the United States. It disproportionately affects black women, in whom the prevalence is 13%, compared with 1% in non-Hispanic white women.⁴⁷ It is also present in 26% of women with symptoms who are seen in STI clinics and is highly prevalent in incarcerated populations. It is uncommon in men who have sex with men.⁴⁸

In men, trichomoniasis manifests as urethritis, epididymitis, or prostatitis. While most infected women have no symptoms, they may experience vaginitis with discharge that is diffuse, frothy, pruritic, malodorous, or yellow-green. Vaginal and cervical erythema (“strawberry cervix”) can also occur.

Screening for trichomoniasis

Current guidelines of the US Centers for Disease Control and Prevention (CDC) recommend testing for T vaginalis in women who have symptoms and routinely screening in women who are HIV-positive, regardless of symptoms. There is no evidence to support routine screening of pregnant women without symptoms, and pregnant women who do have symptoms should be evaluated according to the same guidelines as for nonpregnant women.¹² Testing can be considered in patients who have no symptoms but who engage in high-risk behaviors and in areas of high prevalence.

A lack of studies using sensitive methods for T vaginalis detection has hampered a true estimation of disease burden and at-risk populations. Screening recommendations may evolve in upcoming clinical guidelines as the field advances.

As infection can recur, women should be retested 3 months after initial diagnosis.¹²

NAAT is the preferred test for trichomoniasis

Commercially available diagnostic tests for trichomoniasis include culture, antigen testing, and NAAT.⁴⁹ While many clinicians do their own wet-mount microscopy for a rapid result, this method has low sensitivity.⁵⁰ Similarly, antigen testing and culture perform poorly compared with NAATs, which are the gold standard for detection.^51,52 A major advantage of NAATs for T vaginalis detection is that they combine high sensitivity and fast results, facilitating diagnosis and appropriate treatment of patients and their partners.

In spite of these benefits, adoption of molecular diagnostic testing for T vaginalis has lagged behind that for chlamydia and gonorrhea.⁵³ FDA-cleared NAATs are available for testing vaginal, cervical, or urine specimens from women, but until recently, there were no approved assays for testing in men. The Cepheid Xpert TV assay, which is valid for male urine specimens to diagnose other sexually transmitted diseases, has demonstrated excellent diagnostic sensitivity for T vaginalis in men and women.⁵⁴ Interestingly, a large proportion of male patients in this study had no symptoms, suggesting that screening of men in high-risk groups may be warranted.

7-day metronidazole treatment beats single-dose treatment

The first-line treatment for trichomoniasis has been a single dose of metronidazole 2 g by mouth, but in a recent randomized controlled trial,⁵⁵ a course of 500 mg by mouth twice a day for 7 days was 45% more effective at 4 weeks than a single dose, and it should now be the preferred regimen.

In clinical trials,⁵⁶ a single dose of tinidazole 2 g orally was equivalent or superior to metronidazole 2 g and had fewer gastrointestinal side effects, but it is more expensive.

Sexually transmitted infections (STIs) such as gonorrhea, chlamydia, and syphilis are still increasing in incidence and probably will continue to do so in the near future. Moreover, drug-resistant strains of Neisseria gonorrhoeae are emerging, as are less-known organisms such as Mycoplasma genitalium.

Now the good news: new tests for STIs are available or are coming! Based on nucleic acid amplification, these tests can be performed at the point of care, so that patients can leave the clinic with an accurate diagnosis and proper treatment for themselves and their sexual partners. Also, the tests can be run on samples collected by the patients themselves, either swabs or urine collections, eliminating the need for invasive sampling and making doctor-shy patients more likely to come in to be treated.¹ We hope that by using these sensitive and accurate tests we can begin to bend the upward curve of STIs and be better antimicrobial stewards.²

This article reviews current issues surrounding STI control, and provides detailed guidance on recognizing, testing for, and treating gonorrhea, chlamydia, trichomoniasis, and M genitalium infection.

STI RATES ARE HIGH AND RISING

STIs are among the most common acute infectious diseases worldwide, with an estimated 1 million new curable cases every day.³ Further, STIs have major impacts on sexual, reproductive, and psychological health.

In the United States, rates of reportable STIs (chlamydia, gonorrhea, and syphilis) are rising.⁴ In addition, more-sensitive tests for trichomoniasis, which is not a reportable infection in any state, have revealed it to be more prevalent than previously thought.⁵

BARRIERS AND CHALLENGES TO DIAGNOSIS

The medical system does not fully meet the needs of some populations, including young people and men who have sex with men, regarding their sexual and reproductive health. 

Ongoing barriers among young people include reluctance to use available health services, limited access to STI testing, worries about confidentiality, and the shame and stigma associated with STIs.⁶

Men who have sex with men have a higher incidence of STIs than other groups. Since STIs are associated with a higher risk of human immunodeficiency virus (HIV) infection, it is important to detect, diagnose, and manage STIs in this group—and in all high-risk groups. Rectal STIs are an independent risk factor for incident HIV infection.⁷ In addition, many men who have sex with men face challenges navigating the emotional, physical, and cognitive aspects of adolescence, a voyage further complicated by mental health issues, unprotected sexual encounters, and substance abuse in many, especially among minority youth.⁸ These same factors also impair their ability to access resources for preventing and treating HIV and other STIs.

STI diagnosis is often missed

Most people who have STIs feel no symptoms, which increases the importance of risk-based screening to detect these infections.^9,10 In many other cases, STIs manifest with nonspecific genitourinary symptoms that are mistaken for urinary tract infection. Tomas et al¹¹ found that of 264 women who presented to an emergency department with genitourinary symptoms or were being treated for urinary tract infection, 175 were given a diagnosis of a urinary tract infection. Of these, 100 (57%) were treated without performing a urine culture; 60 (23%) of the 264 women had 1 or more positive STI tests, 22 (37%) of whom did not receive treatment for an STI.

Poor follow-up of patients and partners

Patients with STIs need to be retested 3 months after treatment to make sure the treatment was effective. Another reason for follow-up is that these patients are at higher risk of another infection within a year.¹²

Although treating patients’ partners has been shown to reduce reinfection rates, fewer than one-third of STIs (including HIV infections) were recognized through partner notification between 2010 and 2012 in a Dutch study, in men who have sex with men and in women.¹³ Challenges included partners who could not be identified among men who have sex with men, failure of heterosexual men to notify their partners, and lower rates of partner notification for HIV.  

In the United States, “expedited partner therapy” allows healthcare providers to provide a prescription or medications to partners of patients diagnosed with chlamydia or gonorrhea without examining the partner.¹⁴ While this approach is legal in most states, implementation can be challenging.¹⁵

STI EVALUATION

History and physical examination

A complete sexual history helps in estimating the patient’s risk of an STI and applying appropriate risk-based screening. Factors such as sexual practices, use of barrier protection, and history of STIs should be discussed.

Physical examination is also important. Although some patients may experience discomfort during a genital or pelvic examination, omitting this step may lead to missed diagnoses in women with STIs.¹⁶

Laboratory testing

Laboratory testing for STIs helps ensure accurate diagnosis and treatment. Empiric treatment without testing could give a patient a false sense of health by missing an infection that is not currently causing symptoms but that could later worsen or have lasting complications. Failure to test patients also misses the opportunity for partner notification, linkage to services, and follow-up testing.

Many of the most common STIs, including gonorrhea, chlamydia, and trichomoniasis, can be detected using vaginal, cervical, or urethral swabs or first-catch urine (from the initial urine stream). In studies that compared various sampling methods,¹⁷ self-collected urine samples for gonorrhea in men were nearly as good as clinician-collected swabs of the urethra. In women, self-collected vaginal swabs for gonorrhea and chlamydia were nearly as good as clinician-collected vaginal swabs. While urine specimens are acceptable for chlamydia testing in women, their sensitivity may be slightly lower than with vaginal and endocervical swab specimens.^18,19

A major advantage of urine specimens for STI testing is that collection is noninvasive and is therefore more likely to be acceptable to patients. Urine testing can also be conducted in a variety of nonclinical settings such as health fairs, pharmacy-based screening programs, and express STI testing sites, thus increasing availability.

To prevent further transmission and morbidity and to aid in public health efforts, it is critical to recognize the cause of infectious cervicitis and urethritis and to screen for STIs according to guidelines.¹² Table 1 summarizes current screening and laboratory testing recommendations.

 

 

GONORRHEA AND CHLAMYDIA

Gonorrhea and chlamydia are the 2 most frequently reported STIs in the United States, with more than 550,000 cases of gonorrhea and 1.7 million cases of chlamydia reported in 2017.⁴

Both infections present similarly: cervicitis or urethritis characterized by discharge (mucopurulent discharge with gonorrhea) and dysuria. Untreated, they can lead to pelvic inflammatory disease, inflammation, and infertility.

Extragenital infections can be asymptomatic or cause exudative pharyngitis or proctitis. Most people in whom chlamydia is detected from pharyngeal specimens are asymptomatic. When pharyngeal symptoms exist secondary to gonorrheal infection, they typically include sore throat and pharyngeal exudates. However, Komaroff et al,²⁰ in a study of 192 men and women who presented with sore throat, found that only 2 (1%) tested positive for N gonorrhoeae.

Screening for gonorrhea and chlamydia

Best practices include screening for gonorrhea and chlamydia as follows^21–23:

• Every year in sexually active women through age 25 (including during pregnancy) and in older women who have risk factors for infection¹²
• At least every year in men who have sex with men, at all sites of sexual contact (urethra, pharynx, rectum), along with testing for HIV and syphilis
• Every 3 to 6 months in men who have sex with men who have multiple or anonymous partners, who are sexually active and use illicit drugs, or who have partners who use illicit drugs
• Possibly every year in young men who live in high-prevalence areas or who are seen in certain clinical settings, such as STI and adolescent clinics.

Specimens. A vaginal swab is preferred for screening in women. Several studies have shown that self-collected swabs have clinical sensitivity and specificity comparable to that of provider-collected samples.^17,24 First-catch urine or endocervical swabs have similar performance characteristics and are also acceptable. In men, urethral swabs or first-catch urine samples are appropriate for screening for urogenital infections.

Testing methods. Testing for both pathogens should be done simultaneously with a nucleic acid amplification test (NAAT). Commercially available NAATs are more sensitive than culture and antigen testing for detecting gonorrhea and chlamydia.^25–27

Most assays are approved by the US Food and Drug Administration (FDA) for testing vaginal, urethral, cervical, and urine specimens. Until recently, no commercial assay was cleared for testing extragenital sites, but recommendations for screening extragenital sites prompted many clinical laboratories to validate throat and rectal swabs for use with NAATs, which are more sensitive than culture at these sites.^25,28 The recent FDA approval of extragenital specimen types for 2 commercially available assays may increase the availability of testing for these sites.

Data on the utility of NAATs for detecting chlamydia and gonorrhea in children are limited, and many clinical laboratories have not validated molecular methods for testing in children. Current guidelines specific to this population should be followed regarding test methods and preferred specimen types.^12,29,30

Although gonococcal infection is usually diagnosed with culture-independent molecular methods, antimicrobial resistance is emerging. Thus, failure of the combination of ceftriaxone and azithromycin should prompt culture-based follow-up testing to determine antimicrobial susceptibility.

Strategies for treatment and control

Historically, people treated for gonorrhea have been treated for chlamydia at the same time, as these diseases tend to go together. This can be with a single intramuscular dose of ceftriaxone for the gonorrhea plus a single oral dose of azithromycin for the chlamydia.¹² For patients who have only gonorrhea, this double regimen may help prevent the development of resistant gonorrhea strains.

All the patient’s sexual partners in the previous 60 days should be tested and treated, and expedited partner therapy should be offered if possible. Patients should be advised to have no sexual contact until they complete the treatment, or 7 days after single-dose treatment. Testing should be repeated 3 months after treatment.

 

 

M GENITALIUM IS EMERGING

A member of the Mycoplasmataceae family, M genitalium was originally identified as a pathogen in the early 1980s but has only recently emerged as an important cause of STI. Studies indicate that it is responsible for 10% to 20% of cases of nongonococcal urethritis and 10% to 30% of cases of cervicitis.^31–33 Additionally, 2% to 22% of cases of pelvic inflammatory disease have evidence of M genitalium.^34,35

However, data on M genitalium prevalence are suspect because the organism is hard to identify—lacking a cell wall, it is undetectable by Gram stain.³⁶ Although it has been isolated in respiratory and synovial fluids, it has so far been recognized to be clinically important only in the urogenital tract. It can persist for years in infected patients by exploiting specialized cell-surface structures to invade cells.³⁶ Once inside a cell, it triggers secretion of mycoplasmal toxins and destructive metabolites such as hydrogen peroxide, evading the host immune system as it does so.³⁷

Testing guidelines for M genitalium

Current guidelines do not recommend routine screening for M genitalium, and no commercial test was available until recently.¹² Although evidence suggests that M genitalium is independently associated with preterm birth and miscarriages,³⁸ routine screening of pregnant women is not recommended.¹²

Testing for M genitalium should be considered in cases of persistent or recurrent nongonococcal urethritis in patients who test negative for gonorrhea and chlamydia or for whom treatment has failed.¹² Many isolates exhibit genotypic resistance to macrolide antibiotics, which are often the first-line therapy for nongonococcal urethritis.³⁹

Further study is needed to evaluate the potential impact of routine screening for M genitalium on the reproductive and sexual health of at-risk populations.

Diagnostic tests for M genitalium

Awareness of M genitalium as a cause of nongonococcal urethritis has been hampered by a dearth of diagnostic tests.⁴⁰ The organism’s fastidious requirements and extremely slow growth preclude culture as a practical method of diagnosis.⁴¹ Serologic assays are dogged by cross-reactivity and poor sensitivity.^42,43 Thus, molecular assays for detecting M genitalium and associated resistance markers are preferred for diagnosis.¹²

Several molecular tests are approved, available, and in use in Europe for diagnosing M genitalium infection,⁴⁰ and in January 2019 the FDA approved a molecular test that can detect M genitalium in urine specimens and vaginal, endocervical, urethral, and penile meatal swabs. Although vaginal swabs are preferred for this assay because they have higher sensitivity (92% for provider-collected and 99% for patient-collected swabs), urine specimens are acceptable, with a sensitivity of 78%.⁴⁴

At least 1 company is seeking FDA clearance for another molecular diagnostic assay for detecting M genitalium and markers of macrolide resistance in urine and genital swab specimens. Such assays may facilitate appropriate treatment.

Clinicians should stay abreast of diagnostic testing options, which are likely to become more readily available soon.

A high rate of macrolide resistance

Because M genitalium lacks a cell wall, antibiotics such as beta-lactams that target cell wall synthesis are ineffective.

Regimens for treating M genitalium are outlined in Table 2.¹² Azithromycin is more effective than doxycycline. However, as many as 50% of strains were macrolide-resistant in a cohort of US female patients.⁴⁵ Given the high incidence of treatment failure with azithromycin 1 g, it is thought that this regimen might select for resistance. For cases in which symptoms persist, a 1- to 2-week course of moxifloxacin is recommended.¹² However, this has not been validated by clinical trials, and failures of the 7-day regimen have been reported.⁴⁶

Partners of patients who test positive for M genitalium should also be tested and undergo clinically applicable screening for nongonococcal urethritis, cervicitis, and pelvic inflammatory disease.¹²

TRICHOMONIASIS

Trichomoniasis, caused by the parasite Trichomonas vaginalis, is the most prevalent nonviral STI in the United States. It disproportionately affects black women, in whom the prevalence is 13%, compared with 1% in non-Hispanic white women.⁴⁷ It is also present in 26% of women with symptoms who are seen in STI clinics and is highly prevalent in incarcerated populations. It is uncommon in men who have sex with men.⁴⁸

In men, trichomoniasis manifests as urethritis, epididymitis, or prostatitis. While most infected women have no symptoms, they may experience vaginitis with discharge that is diffuse, frothy, pruritic, malodorous, or yellow-green. Vaginal and cervical erythema (“strawberry cervix”) can also occur.

Screening for trichomoniasis

Current guidelines of the US Centers for Disease Control and Prevention (CDC) recommend testing for T vaginalis in women who have symptoms and routinely screening in women who are HIV-positive, regardless of symptoms. There is no evidence to support routine screening of pregnant women without symptoms, and pregnant women who do have symptoms should be evaluated according to the same guidelines as for nonpregnant women.¹² Testing can be considered in patients who have no symptoms but who engage in high-risk behaviors and in areas of high prevalence.

A lack of studies using sensitive methods for T vaginalis detection has hampered a true estimation of disease burden and at-risk populations. Screening recommendations may evolve in upcoming clinical guidelines as the field advances.

As infection can recur, women should be retested 3 months after initial diagnosis.¹²

NAAT is the preferred test for trichomoniasis

Commercially available diagnostic tests for trichomoniasis include culture, antigen testing, and NAAT.⁴⁹ While many clinicians do their own wet-mount microscopy for a rapid result, this method has low sensitivity.⁵⁰ Similarly, antigen testing and culture perform poorly compared with NAATs, which are the gold standard for detection.^51,52 A major advantage of NAATs for T vaginalis detection is that they combine high sensitivity and fast results, facilitating diagnosis and appropriate treatment of patients and their partners.

In spite of these benefits, adoption of molecular diagnostic testing for T vaginalis has lagged behind that for chlamydia and gonorrhea.⁵³ FDA-cleared NAATs are available for testing vaginal, cervical, or urine specimens from women, but until recently, there were no approved assays for testing in men. The Cepheid Xpert TV assay, which is valid for male urine specimens to diagnose other sexually transmitted diseases, has demonstrated excellent diagnostic sensitivity for T vaginalis in men and women.⁵⁴ Interestingly, a large proportion of male patients in this study had no symptoms, suggesting that screening of men in high-risk groups may be warranted.

7-day metronidazole treatment beats single-dose treatment

The first-line treatment for trichomoniasis has been a single dose of metronidazole 2 g by mouth, but in a recent randomized controlled trial,⁵⁵ a course of 500 mg by mouth twice a day for 7 days was 45% more effective at 4 weeks than a single dose, and it should now be the preferred regimen.

In clinical trials,⁵⁶ a single dose of tinidazole 2 g orally was equivalent or superior to metronidazole 2 g and had fewer gastrointestinal side effects, but it is more expensive.

Lyme disease is a complex multisystem bacterial infection affecting the skin, joints, heart, and nervous system. The full spectrum of disease was first recognized and the disease was named in the 1970s during an outbreak of arthritis in children in the town of Lyme, Connecticut.¹

This review describes the epidemiology and pathogenesis of Lyme disease, the advantages and disadvantages of current diagnostic methods, and diagnostic algorithms.

THE MOST COMMON TICK-BORNE INFECTION IN NORTH AMERICA

Lyme disease is the most common tick-borne infection in North America.^2,3 In the United States, more than 30,000 cases are reported annually. In fact, in 2017, the number of cases was about 42,000, a 16% increase from the previous year, according to the US Centers for Disease Control and Prevention (CDC).

From Sigal LH. Myths and facts about Lyme disease. Cleve Clin J Med 1997; 64(4):203–209.

The infection is caused by Borrelia burgdorferi, a particularly arthritogenic spirochete transmitted by Ixodes scapularis (the black-legged deer tick, (Figure 1) and Ixodes pacificus (the Western black-legged tick). Although the infection can occur at any time of the year, its peak incidence is in May to late September, coinciding with increased outdoor recreational activity in areas where ticks live.^3,4 The typical tick habitat consists of deciduous woodland with sufficient humidity provided by a good layer of decaying vegetation. However, people can contract Lyme disease in their own backyard.³

Most cases of Lyme disease are seen in the northeastern United States, mainly in suburban and rural areas.^2,3 Other areas affected include the midwestern states of Minnesota, Wisconsin, and Michigan, as well as northern California.⁴ Fourteen states and the District of Columbia report a high average incidence (> 10 cases per 100,000 persons) (Table 1).²

FIRST COMES IgM, THEN IgG

The pathogenesis and the different stages of infection should inform laboratory testing in Lyme disease.

It is estimated that only 5% of infected ticks that bite people actually transmit their spirochetes to the human host.⁵ However, once infected, the patient’s innate immune system mounts a response that results in the classic erythema migrans rash at the bite site. A rash develops in only about 85% of patients who are infected and can appear at any time between 3 and 30 days, but most commonly after 7 days. Hence, a rash occurring within the first few hours of tick contact is not erythema migrans and does not indicate infection, but rather an early reaction to tick salivary antigens.⁵

Antibody levels remain below the detection limits of currently available serologic tests in the first 7 days after exposure. Immunoglobulin M (IgM) antibody titers peak between 8 and 14 days after tick contact, but IgM antibodies may never develop if the patient is started on early appropriate antimicrobial therapy.⁵

If the infection is not treated, the spirochete may disseminate through the blood from the bite site to different tissues.³ Both cell-mediated and antibody-mediated immunity swing into action to kill the spirochetes at this stage. The IgM antibody response occurs in 1 to 2 weeks, followed by a robust IgG response in 2 to 4 weeks.⁶

Because IgM can also cross-react with antigens other than those associated with B burgdorferi, the IgM test is less specific than the IgG test for Lyme disease.

Once a patient is exposed and mounts an antibody-mediated response to the spirochete, the antibody profile may persist for months to years, even after successful antibiotic treatment and cure of the disease.⁵

Despite the immune system’s robust series of defenses, untreated B burgdorferi infection can persist, as the organism has a bag of tricks to evade destruction. It can decrease its expression of specific immunogenic surface-exposed proteins, change its antigenic properties through recombination, and bind to the patient’s extracellular matrix proteins to facilitate further dissemination.³

Certain host-genetic factors also play a role in the pathogenesis of Lyme disease, such as the HLA-DR4 allele, which has been associated with antibiotic-refractory Lyme-related arthritis.³

LYME DISEASE EVOLVES THROUGH STAGES

Lyme disease evolves through stages broadly classified as early and late infection, with significant variability in its presentation.⁷

Early infection

Early disease is further subdivided into “localized” infection (stage 1), characterized by a single erythema migrans lesion and local lymphadenopathy, and “disseminated” infection (stage 2), associated with multiple erythema migrans lesions distant from the bite site, facial nerve palsy, radiculoneuritis, meningitis, carditis, or migratory arthritis or arthralgia.⁸

Highly specific physical findings include erythema migrans, cranial nerve palsy, high-grade or progressive conduction block, and recurrent migratory polyarthritis. Less specific symptoms and signs of Lyme disease include arthralgia, myalgia, neck stiffness, palpitations, and myocarditis.⁵

Erythema migrans lesions are evident in at least 85% of patients with early disease.⁹ If they are not apparent on physical examination, they may be located at hidden sites and may be atypical in appearance or transient.⁵

If treatment is not started in the initial stage of the disease, 60% of infected patients may develop disseminated infection.⁵ Progressive, untreated infection can manifest with Lyme arthritis and neuroborreliosis.⁷

Noncutaneous manifestations are less common now than in the past due to increased awareness of the disease and early initiation of treatment.¹⁰

Late infection

Manifestations of late (stage 3) infection include oligoarthritis (affecting any joint but often the knee) and neuroborreliosis. Clinical signs and symptoms of Lyme disease may take months to resolve even after appropriate antimicrobial therapy is completed. This should not be interpreted as ongoing, persistent infection, but as related to host immune-mediated activity.⁵

 

 

INTERPRET LABORATORY RESULTS BASED ON PRETEST PROBABILITY

The usefulness of a laboratory test depends on the individual patient’s pretest probability of infection, which in turn depends on the patient’s epidemiologic risk of exposure and clinical features of Lyme disease. Patients with a high pretest probability—eg, a history of a tick bite followed by the classic erythema migrans rash—do not need testing and can start antimicrobial therapy right away.¹¹

Serologic tests are the gold standard

Prompt diagnosis is important, as early Lyme disease is easily treatable without any future sequelae.¹¹

Tests for Lyme disease can be divided into direct methods, which detect the spirochete itself by culture or by polymerase chain reaction (PCR), and indirect methods, which detect antibodies (Table 2). Direct tests lack sensitivity for Lyme disease; hence, serologic tests remain the gold standard. Currently recommended is a standard 2-tier testing strategy using an enzyme-linked immunosorbent assay (ELISA) followed by Western blot for confirmation.

DIRECT METHODS

Culture lacks sensitivity

A number of factors limit the sensitivity of direct culture for diagnosing Lyme disease. B burgdorferi does not grow easily in culture, requiring special media, low temperatures, and long periods of incubation. Only a relatively few spirochetes are present in human tissues and body fluids to begin with, and bacterial counts are further reduced with duration and dissemination of infection.⁵ All of these limit the possibility of detecting this organism.

Polymerase chain reaction may help in some situations

Molecular assays are not part of the standard evaluation and should be used only in conjunction with serologic testing.⁷ These tests have high specificity but lack consistent sensitivity.

That said, PCR testing may be useful:

• In early infection, before antibody responses develop
• In reinfection, when serologic tests are not reliable because the antibodies persist for many years after an infection in many patients
• In endemic areas where serologic testing has high false-positive rates due to high baseline population seropositivity for anti-Borrelia antibodies caused by subclinical infection.³

PCR assays that target plasmid-borne genes encoding outer surface proteins A and C (OspA and OspC) and VisE (variable major protein-like sequence, expressed) are more sensitive than those that detect chromosomal 16s ribosomal ribonucleic acid (rRNA) genes, as plasmid-rich “blebs” are shed in larger concentrations than chromosomal DNA during active infection.⁷ However, these plasmid-contained genes persist in body tissues and fluids even after the infection is cleared, and their detection may not necessarily correlate with ongoing disease.⁸ Detection of chromosomal 16s rRNA genes is a better predictor of true organism viability.

The sensitivity of PCR for borrelial DNA depends on the type of sample. If a skin biopsy sample is taken of the leading edge of an erythema migrans lesion, the sensitivity is 69% and the specificity is 100%. In patients with Lyme arthritis, PCR of the synovial fluid has a sensitivity of up to 80%. However, the sensitivity of PCR of the cerebrospinal fluid of patients with neurologic manifestations of Lyme disease is only 19%.⁷ PCR of other clinical samples, including blood and urine, is not recommended, as spirochetes are primarily confined to tissues, and very few are present in these body fluids.^3,12

The disadvantage of PCR is that a positive result does not always mean active infection, as the DNA of the dead microbe persists for several months even after successful treatment.⁸

INDIRECT METHODS

Enzyme-linked immunosorbent assay

ELISAs detect anti-Borrelia antibodies. Early-generation ELISAs, still used in many laboratories, use whole-cell extracts of B burgdorferi. Examples are the Vidas Lyme screen (Biomérieux, biomerieux-usa.com) and the Wampole B burgdorferi IgG/M EIA II assay (Alere, www.alere.com). Newer ELISAs use recombinant proteins.¹³

Three major targets for ELISA antibodies are flagellin (Fla), outer surface protein C (OspC), and VisE, especially the invariable region 6 (IR6). Among these, VisE-IR6 is the most conserved region in B burgdorferi.

Early-generation assays have a sensitivity of 89% and specificity of 72%.¹¹ However, the patient’s serum may have antibodies that cross-react with unrelated bacterial antigens, leading to false-positive results (Table 3). Whole-cell sonicate assays are not recommended as an independent test and must be confirmed with Western blot testing when assay results are indeterminate or positive.¹¹

Newer-generation ELISAs detect antibodies targeting recombinant proteins of VisE, especially a synthetic peptide C6, within IR6.¹³ VisE-IR6 is the most conserved region of the B burgdorferi complex, and its detection is a highly specific finding, supporting the diagnosis of Lyme disease. Antibodies against VisE-IR6 antigen are the earliest to develop.⁵ An example of a newer-generation serologic test is the VisE C6 Lyme EIA kit, approved as a first-tier test by the US Food and Drug Administration in 2001. This test has a specificity of 99%,^14,15 and its specificity is further increased when used in conjunction with Western blot (99.5%).¹⁵ The advantage of the C6 antibody test is that it is more sensitive than 2-tier testing during early infection (sensitivity 29%–74% vs 17%–40% in early localized infection, and 56%–90% vs 27%–78% in early disseminated infection).⁶

During early infection, older and newer ELISAs are less sensitive because of the limited number of antigens expressed at this stage.¹³ All patients suspected of having early Lyme disease who are seronegative at initial testing should have follow-up testing to look for seroconversion.¹³

Western blot

Western blot (immunoblot) testing identifies IgM and IgG antibodies against specific B burgdorferi antigens. It is considered positive if it detects at least 2 of a possible 3 specific IgM bands in the first 4 weeks of disease or at least 5 of 10 specific IgG bands after 4 weeks of disease (Table 4 and Figure 2).¹⁶

The nature of the bands indicates the duration of infection: Western blot bands against 23-kD OspC and 41-kD FlaB are seen in early localized infection, whereas bands against all 3 B burgdorferi proteins will be seen after several weeks of disease.¹⁷ The IgM result should be interpreted carefully, as only 2 bands are required for the test to be positive, and IgM binds to antigen less specifically than IgG.¹²

 

 

Interpreting the IgM Western blot test: The ‘1-month rule’

If clinical symptoms and signs of Lyme disease have been present for more than 1 month, IgM reactivity alone should not be used to support the diagnosis, in view of the likelihood of a false-positive test result in this situation.¹⁸ This is called the “1-month rule” in the diagnosis of Lyme disease.¹³

In early localized infection, Western blot is only half as sensitive as ELISA testing. Since the overall sensitivity of a 2-step algorithm is equal to that of its least sensitive component, 2-tiered testing is not useful in early disease.¹³

Although currently considered the most specific test for confirmation of Lyme disease, Western blot has limitations. It is technically and interpretively complex and is thus not universally available.¹³ The blots are scored by visual examination, compromising the reproducibility of the test, although densitometric blot analysis techniques and automated scanning and scoring attempt to address some of these limitations.¹³ Like the ELISA, Western blot can have false-positive results in healthy individuals without tick exposure, as nonspecific IgM immunoblots develop faint bands. This is because of cross-reaction between B burgdorferi antigens and antigens from other microorganisms. Around 50% of healthy adults show low-level serum IgG reactivity against the FlaB antigen, leading to false-positive results as well. In cases in which the Western blot result is indeterminate, other etiologies must be considered.

False-positive IgM Western blots are a significant problem. In a 5-year retrospective study done at 63 US Air Force healthcare facilities, 113 (53.3%) of 212 IgM Western blots were falsely positive.¹⁹ A false-positive test was defined as one that failed to meet seropositivity (a first-tier test omitted or negative, > 30 days of symptoms with negative IgG blot), lack of exposure including residing in areas without documented tick habitats, patients having atypical or no symptoms, and negative serology within 30 days of a positive test.

In a similar study done in a highly endemic area, 50 (27.5%) of 182 patients had a false-positive test.²⁰ Physicians need to be careful when interpreting IgM Western blots. It is always important to consider locale, epidemiology, and symptoms when interpreting the test.

Limitations of serologic tests for Lyme disease

Currently available serologic tests have inherent limitations:

• Antibodies against B burgdorferi take at least 1 week to develop
• The background rate of seropositivity in endemic areas can be up to 4%, affecting the utility of a positive test result
• Serologic tests cannot be used as tests of cure because antibodies can persist for months to years even after appropriate antimicrobial therapy and cure of disease; thus, a positive serologic result could represent active infection or remote exposure²¹
• Antibodies can cross-react with related bacteria, including other borrelial or treponemal spirochetes
• False-positive serologic test results can also occur in association with other medical conditions such as polyclonal gammopathies and systemic lupus erythematosus.¹²

RECOMMENDATIONS FOR TESTING

Standard 2-tier testing

The CDC released recommendations for diagnosing Lyme disease after a second national conference of serologic diagnosis of Lyme disease in October 1994.¹⁸ The 2-tiered testing method, involving a sensitive ELISA followed by the Western blot to confirm positive and indeterminate ELISA results, was suggested as the gold standard for diagnosis (Figure 3). Of note, negative ELISA results do not require further testing.¹¹

The sensitivity of 2-tiered testing depends on the stage of the disease. Unfortunately, this method has a wide range of sensitivity (17% to 78%) in stage 1 disease. In the same stage, the sensitivity increases from 14.1% in patients with a single erythema migrans lesion and early localized infection to 65.4% in those with multiple lesions. The algorithm has excellent sensitivity in late stage 3 infection (96% to 100%).⁵

A 2-step ELISA algorithm

A 2-step ELISA algorithm (without the Western blot) that includes the whole-cell sonicate assay followed by the VisE C6 peptide assay actually showed higher sensitivity and comparable specificity compared with 2-tiered testing in early localized disease (sensitivity 61%–74% vs 29%–48%, respectively; specificity 99.5% for both methods).²² This higher sensitivity was even more pronounced in early disseminated infection (sensitivity 100% vs 40%, respectively). By late infection, the sensitivities of both testing strategies reached 100%. Compared with the Western blot, the 2-step ELISA algorithm was simpler to execute in a reproducible fashion.⁵

The Infectious Diseases Society of America is revising its current guidelines, with an update expected late this year, which may shift the recommendation from 2-tiered testing to the 2-step ELISA algorithm.

Multiplex testing

To overcome the intrinsic problems of protein-based assays, a multiplexed, array-based assay for the diagnosis of tick-borne infections called Tick-Borne Disease Serochip (TBD-Serochip) was established using recombinant antigens that identify key immunodominant epitopes.⁸ More studies are needed to establish the validity and usefulness of these tests in clinical practice.

Who should not be tested?

The American College of Physicians⁶ recommends against testing in patients:

• Presenting with nonspecific symptoms (eg, headache, myalgia, fatigue, arthralgia) without objective signs of Lyme disease
• With low pretest probability of infection based on epidemiologic exposures and clinical features
• Living in Lyme-endemic areas with no history of tick exposure⁶
• Presenting less than 1 week after tick exposure⁵
• Seeking a test of cure for treated Lyme disease.

DIAGNOSIS IN SPECIAL SITUATIONS

Early Lyme disease

The classic erythema migrans lesion on physical examination of a patient with suspected Lyme disease is diagnostic and does not require laboratory confirmation.¹⁰

In ambiguous cases, 2-tiered testing of a serum sample during the acute presentation and again 4 to 6 weeks later can be useful. In patients who remain seronegative on paired serum samples despite symptoms lasting longer than 6 weeks and no antibiotic treatment in the interim, the diagnosis of Lyme disease is unlikely, and another diagnosis should be sought.³

Antimicrobial therapy may block the serologic response; hence, negative serologic testing in patients started on empiric antibiotics should not rule out Lyme disease.⁶

PCR or bacterial culture testing is not recommended in the evaluation of suspected early Lyme disease.

Central nervous system Lyme disease

Central nervous system Lyme disease is diagnosed by 2-tiered testing using peripheral blood samples because all patients with this infectious manifestation should have mounted an adequate IgG response in the blood.¹¹

B cells migrate to and proliferate inside the central nervous system, leading to intrathecal production of anti-Borrelia antibodies. An index of cerebrospinal fluid to serum antibody greater than 1 is thus also indicative of neuroborreliosis.¹² Thus, performing lumbar puncture to detect intrathecal production of antibodies may support the diagnosis of central nervous system Lyme disease; however, it is not necessary.¹¹

Antibodies persist in the central nervous system for many years after appropriate antimicrobial treatment.

Lyme arthritis

Articular involvement in Lyme disease is characterized by a robust humoral response such that a negative IgG serologic test virtually rules out Lyme arthritis.²³ PCR testing of synovial fluid for borrelial DNA has a sensitivity of 80% but may become falsely negative after 1 to 2 months of antibiotic treatment.^24,25 In an algorithm suggested by Puius et al,²³ PCR testing of synovial fluid should be done in patients who have minimal to no response after 2 months of appropriate oral antimicrobial therapy to determine whether intravenous antibiotics are merited.

Table 5 summarizes the tests of choice in different clinical stages of infection.

Acknowledgment: The authors would like to acknowledge Anita Modi, MD, and Ceena N. Jacob, MD, for reviewing the manuscript and providing valuable suggestions, and Belinda Yen-Lieberman, PhD, for contributing pictures of the Western blot test results.

Lyme disease is a complex multisystem bacterial infection affecting the skin, joints, heart, and nervous system. The full spectrum of disease was first recognized and the disease was named in the 1970s during an outbreak of arthritis in children in the town of Lyme, Connecticut.¹

This review describes the epidemiology and pathogenesis of Lyme disease, the advantages and disadvantages of current diagnostic methods, and diagnostic algorithms.

THE MOST COMMON TICK-BORNE INFECTION IN NORTH AMERICA

Lyme disease is the most common tick-borne infection in North America.^2,3 In the United States, more than 30,000 cases are reported annually. In fact, in 2017, the number of cases was about 42,000, a 16% increase from the previous year, according to the US Centers for Disease Control and Prevention (CDC).

From Sigal LH. Myths and facts about Lyme disease. Cleve Clin J Med 1997; 64(4):203–209.

The infection is caused by Borrelia burgdorferi, a particularly arthritogenic spirochete transmitted by Ixodes scapularis (the black-legged deer tick, (Figure 1) and Ixodes pacificus (the Western black-legged tick). Although the infection can occur at any time of the year, its peak incidence is in May to late September, coinciding with increased outdoor recreational activity in areas where ticks live.^3,4 The typical tick habitat consists of deciduous woodland with sufficient humidity provided by a good layer of decaying vegetation. However, people can contract Lyme disease in their own backyard.³

Most cases of Lyme disease are seen in the northeastern United States, mainly in suburban and rural areas.^2,3 Other areas affected include the midwestern states of Minnesota, Wisconsin, and Michigan, as well as northern California.⁴ Fourteen states and the District of Columbia report a high average incidence (> 10 cases per 100,000 persons) (Table 1).²

FIRST COMES IgM, THEN IgG

The pathogenesis and the different stages of infection should inform laboratory testing in Lyme disease.

It is estimated that only 5% of infected ticks that bite people actually transmit their spirochetes to the human host.⁵ However, once infected, the patient’s innate immune system mounts a response that results in the classic erythema migrans rash at the bite site. A rash develops in only about 85% of patients who are infected and can appear at any time between 3 and 30 days, but most commonly after 7 days. Hence, a rash occurring within the first few hours of tick contact is not erythema migrans and does not indicate infection, but rather an early reaction to tick salivary antigens.⁵

Antibody levels remain below the detection limits of currently available serologic tests in the first 7 days after exposure. Immunoglobulin M (IgM) antibody titers peak between 8 and 14 days after tick contact, but IgM antibodies may never develop if the patient is started on early appropriate antimicrobial therapy.⁵

If the infection is not treated, the spirochete may disseminate through the blood from the bite site to different tissues.³ Both cell-mediated and antibody-mediated immunity swing into action to kill the spirochetes at this stage. The IgM antibody response occurs in 1 to 2 weeks, followed by a robust IgG response in 2 to 4 weeks.⁶

Because IgM can also cross-react with antigens other than those associated with B burgdorferi, the IgM test is less specific than the IgG test for Lyme disease.

Once a patient is exposed and mounts an antibody-mediated response to the spirochete, the antibody profile may persist for months to years, even after successful antibiotic treatment and cure of the disease.⁵

Despite the immune system’s robust series of defenses, untreated B burgdorferi infection can persist, as the organism has a bag of tricks to evade destruction. It can decrease its expression of specific immunogenic surface-exposed proteins, change its antigenic properties through recombination, and bind to the patient’s extracellular matrix proteins to facilitate further dissemination.³

Certain host-genetic factors also play a role in the pathogenesis of Lyme disease, such as the HLA-DR4 allele, which has been associated with antibiotic-refractory Lyme-related arthritis.³

LYME DISEASE EVOLVES THROUGH STAGES

Lyme disease evolves through stages broadly classified as early and late infection, with significant variability in its presentation.⁷

Early infection

Early disease is further subdivided into “localized” infection (stage 1), characterized by a single erythema migrans lesion and local lymphadenopathy, and “disseminated” infection (stage 2), associated with multiple erythema migrans lesions distant from the bite site, facial nerve palsy, radiculoneuritis, meningitis, carditis, or migratory arthritis or arthralgia.⁸

Highly specific physical findings include erythema migrans, cranial nerve palsy, high-grade or progressive conduction block, and recurrent migratory polyarthritis. Less specific symptoms and signs of Lyme disease include arthralgia, myalgia, neck stiffness, palpitations, and myocarditis.⁵

Erythema migrans lesions are evident in at least 85% of patients with early disease.⁹ If they are not apparent on physical examination, they may be located at hidden sites and may be atypical in appearance or transient.⁵

If treatment is not started in the initial stage of the disease, 60% of infected patients may develop disseminated infection.⁵ Progressive, untreated infection can manifest with Lyme arthritis and neuroborreliosis.⁷

Noncutaneous manifestations are less common now than in the past due to increased awareness of the disease and early initiation of treatment.¹⁰

Late infection

Manifestations of late (stage 3) infection include oligoarthritis (affecting any joint but often the knee) and neuroborreliosis. Clinical signs and symptoms of Lyme disease may take months to resolve even after appropriate antimicrobial therapy is completed. This should not be interpreted as ongoing, persistent infection, but as related to host immune-mediated activity.⁵

 

 

INTERPRET LABORATORY RESULTS BASED ON PRETEST PROBABILITY

The usefulness of a laboratory test depends on the individual patient’s pretest probability of infection, which in turn depends on the patient’s epidemiologic risk of exposure and clinical features of Lyme disease. Patients with a high pretest probability—eg, a history of a tick bite followed by the classic erythema migrans rash—do not need testing and can start antimicrobial therapy right away.¹¹

Serologic tests are the gold standard

Prompt diagnosis is important, as early Lyme disease is easily treatable without any future sequelae.¹¹

Tests for Lyme disease can be divided into direct methods, which detect the spirochete itself by culture or by polymerase chain reaction (PCR), and indirect methods, which detect antibodies (Table 2). Direct tests lack sensitivity for Lyme disease; hence, serologic tests remain the gold standard. Currently recommended is a standard 2-tier testing strategy using an enzyme-linked immunosorbent assay (ELISA) followed by Western blot for confirmation.

DIRECT METHODS

Culture lacks sensitivity

A number of factors limit the sensitivity of direct culture for diagnosing Lyme disease. B burgdorferi does not grow easily in culture, requiring special media, low temperatures, and long periods of incubation. Only a relatively few spirochetes are present in human tissues and body fluids to begin with, and bacterial counts are further reduced with duration and dissemination of infection.⁵ All of these limit the possibility of detecting this organism.

Polymerase chain reaction may help in some situations

Molecular assays are not part of the standard evaluation and should be used only in conjunction with serologic testing.⁷ These tests have high specificity but lack consistent sensitivity.

That said, PCR testing may be useful:

• In early infection, before antibody responses develop
• In reinfection, when serologic tests are not reliable because the antibodies persist for many years after an infection in many patients
• In endemic areas where serologic testing has high false-positive rates due to high baseline population seropositivity for anti-Borrelia antibodies caused by subclinical infection.³

PCR assays that target plasmid-borne genes encoding outer surface proteins A and C (OspA and OspC) and VisE (variable major protein-like sequence, expressed) are more sensitive than those that detect chromosomal 16s ribosomal ribonucleic acid (rRNA) genes, as plasmid-rich “blebs” are shed in larger concentrations than chromosomal DNA during active infection.⁷ However, these plasmid-contained genes persist in body tissues and fluids even after the infection is cleared, and their detection may not necessarily correlate with ongoing disease.⁸ Detection of chromosomal 16s rRNA genes is a better predictor of true organism viability.

The sensitivity of PCR for borrelial DNA depends on the type of sample. If a skin biopsy sample is taken of the leading edge of an erythema migrans lesion, the sensitivity is 69% and the specificity is 100%. In patients with Lyme arthritis, PCR of the synovial fluid has a sensitivity of up to 80%. However, the sensitivity of PCR of the cerebrospinal fluid of patients with neurologic manifestations of Lyme disease is only 19%.⁷ PCR of other clinical samples, including blood and urine, is not recommended, as spirochetes are primarily confined to tissues, and very few are present in these body fluids.^3,12

The disadvantage of PCR is that a positive result does not always mean active infection, as the DNA of the dead microbe persists for several months even after successful treatment.⁸

INDIRECT METHODS

Enzyme-linked immunosorbent assay

ELISAs detect anti-Borrelia antibodies. Early-generation ELISAs, still used in many laboratories, use whole-cell extracts of B burgdorferi. Examples are the Vidas Lyme screen (Biomérieux, biomerieux-usa.com) and the Wampole B burgdorferi IgG/M EIA II assay (Alere, www.alere.com). Newer ELISAs use recombinant proteins.¹³

Three major targets for ELISA antibodies are flagellin (Fla), outer surface protein C (OspC), and VisE, especially the invariable region 6 (IR6). Among these, VisE-IR6 is the most conserved region in B burgdorferi.

Early-generation assays have a sensitivity of 89% and specificity of 72%.¹¹ However, the patient’s serum may have antibodies that cross-react with unrelated bacterial antigens, leading to false-positive results (Table 3). Whole-cell sonicate assays are not recommended as an independent test and must be confirmed with Western blot testing when assay results are indeterminate or positive.¹¹

Newer-generation ELISAs detect antibodies targeting recombinant proteins of VisE, especially a synthetic peptide C6, within IR6.¹³ VisE-IR6 is the most conserved region of the B burgdorferi complex, and its detection is a highly specific finding, supporting the diagnosis of Lyme disease. Antibodies against VisE-IR6 antigen are the earliest to develop.⁵ An example of a newer-generation serologic test is the VisE C6 Lyme EIA kit, approved as a first-tier test by the US Food and Drug Administration in 2001. This test has a specificity of 99%,^14,15 and its specificity is further increased when used in conjunction with Western blot (99.5%).¹⁵ The advantage of the C6 antibody test is that it is more sensitive than 2-tier testing during early infection (sensitivity 29%–74% vs 17%–40% in early localized infection, and 56%–90% vs 27%–78% in early disseminated infection).⁶

During early infection, older and newer ELISAs are less sensitive because of the limited number of antigens expressed at this stage.¹³ All patients suspected of having early Lyme disease who are seronegative at initial testing should have follow-up testing to look for seroconversion.¹³

Western blot

Western blot (immunoblot) testing identifies IgM and IgG antibodies against specific B burgdorferi antigens. It is considered positive if it detects at least 2 of a possible 3 specific IgM bands in the first 4 weeks of disease or at least 5 of 10 specific IgG bands after 4 weeks of disease (Table 4 and Figure 2).¹⁶

The nature of the bands indicates the duration of infection: Western blot bands against 23-kD OspC and 41-kD FlaB are seen in early localized infection, whereas bands against all 3 B burgdorferi proteins will be seen after several weeks of disease.¹⁷ The IgM result should be interpreted carefully, as only 2 bands are required for the test to be positive, and IgM binds to antigen less specifically than IgG.¹²

 

 

Interpreting the IgM Western blot test: The ‘1-month rule’

If clinical symptoms and signs of Lyme disease have been present for more than 1 month, IgM reactivity alone should not be used to support the diagnosis, in view of the likelihood of a false-positive test result in this situation.¹⁸ This is called the “1-month rule” in the diagnosis of Lyme disease.¹³

In early localized infection, Western blot is only half as sensitive as ELISA testing. Since the overall sensitivity of a 2-step algorithm is equal to that of its least sensitive component, 2-tiered testing is not useful in early disease.¹³

Although currently considered the most specific test for confirmation of Lyme disease, Western blot has limitations. It is technically and interpretively complex and is thus not universally available.¹³ The blots are scored by visual examination, compromising the reproducibility of the test, although densitometric blot analysis techniques and automated scanning and scoring attempt to address some of these limitations.¹³ Like the ELISA, Western blot can have false-positive results in healthy individuals without tick exposure, as nonspecific IgM immunoblots develop faint bands. This is because of cross-reaction between B burgdorferi antigens and antigens from other microorganisms. Around 50% of healthy adults show low-level serum IgG reactivity against the FlaB antigen, leading to false-positive results as well. In cases in which the Western blot result is indeterminate, other etiologies must be considered.

False-positive IgM Western blots are a significant problem. In a 5-year retrospective study done at 63 US Air Force healthcare facilities, 113 (53.3%) of 212 IgM Western blots were falsely positive.¹⁹ A false-positive test was defined as one that failed to meet seropositivity (a first-tier test omitted or negative, > 30 days of symptoms with negative IgG blot), lack of exposure including residing in areas without documented tick habitats, patients having atypical or no symptoms, and negative serology within 30 days of a positive test.

In a similar study done in a highly endemic area, 50 (27.5%) of 182 patients had a false-positive test.²⁰ Physicians need to be careful when interpreting IgM Western blots. It is always important to consider locale, epidemiology, and symptoms when interpreting the test.

Limitations of serologic tests for Lyme disease

Currently available serologic tests have inherent limitations:

• Antibodies against B burgdorferi take at least 1 week to develop
• The background rate of seropositivity in endemic areas can be up to 4%, affecting the utility of a positive test result
• Serologic tests cannot be used as tests of cure because antibodies can persist for months to years even after appropriate antimicrobial therapy and cure of disease; thus, a positive serologic result could represent active infection or remote exposure²¹
• Antibodies can cross-react with related bacteria, including other borrelial or treponemal spirochetes
• False-positive serologic test results can also occur in association with other medical conditions such as polyclonal gammopathies and systemic lupus erythematosus.¹²

RECOMMENDATIONS FOR TESTING

Standard 2-tier testing

The CDC released recommendations for diagnosing Lyme disease after a second national conference of serologic diagnosis of Lyme disease in October 1994.¹⁸ The 2-tiered testing method, involving a sensitive ELISA followed by the Western blot to confirm positive and indeterminate ELISA results, was suggested as the gold standard for diagnosis (Figure 3). Of note, negative ELISA results do not require further testing.¹¹

The sensitivity of 2-tiered testing depends on the stage of the disease. Unfortunately, this method has a wide range of sensitivity (17% to 78%) in stage 1 disease. In the same stage, the sensitivity increases from 14.1% in patients with a single erythema migrans lesion and early localized infection to 65.4% in those with multiple lesions. The algorithm has excellent sensitivity in late stage 3 infection (96% to 100%).⁵

A 2-step ELISA algorithm

A 2-step ELISA algorithm (without the Western blot) that includes the whole-cell sonicate assay followed by the VisE C6 peptide assay actually showed higher sensitivity and comparable specificity compared with 2-tiered testing in early localized disease (sensitivity 61%–74% vs 29%–48%, respectively; specificity 99.5% for both methods).²² This higher sensitivity was even more pronounced in early disseminated infection (sensitivity 100% vs 40%, respectively). By late infection, the sensitivities of both testing strategies reached 100%. Compared with the Western blot, the 2-step ELISA algorithm was simpler to execute in a reproducible fashion.⁵

The Infectious Diseases Society of America is revising its current guidelines, with an update expected late this year, which may shift the recommendation from 2-tiered testing to the 2-step ELISA algorithm.

Multiplex testing

To overcome the intrinsic problems of protein-based assays, a multiplexed, array-based assay for the diagnosis of tick-borne infections called Tick-Borne Disease Serochip (TBD-Serochip) was established using recombinant antigens that identify key immunodominant epitopes.⁸ More studies are needed to establish the validity and usefulness of these tests in clinical practice.

Who should not be tested?

The American College of Physicians⁶ recommends against testing in patients:

• Presenting with nonspecific symptoms (eg, headache, myalgia, fatigue, arthralgia) without objective signs of Lyme disease
• With low pretest probability of infection based on epidemiologic exposures and clinical features
• Living in Lyme-endemic areas with no history of tick exposure⁶
• Presenting less than 1 week after tick exposure⁵
• Seeking a test of cure for treated Lyme disease.

DIAGNOSIS IN SPECIAL SITUATIONS

Early Lyme disease

The classic erythema migrans lesion on physical examination of a patient with suspected Lyme disease is diagnostic and does not require laboratory confirmation.¹⁰

In ambiguous cases, 2-tiered testing of a serum sample during the acute presentation and again 4 to 6 weeks later can be useful. In patients who remain seronegative on paired serum samples despite symptoms lasting longer than 6 weeks and no antibiotic treatment in the interim, the diagnosis of Lyme disease is unlikely, and another diagnosis should be sought.³

Antimicrobial therapy may block the serologic response; hence, negative serologic testing in patients started on empiric antibiotics should not rule out Lyme disease.⁶

PCR or bacterial culture testing is not recommended in the evaluation of suspected early Lyme disease.

Central nervous system Lyme disease

Central nervous system Lyme disease is diagnosed by 2-tiered testing using peripheral blood samples because all patients with this infectious manifestation should have mounted an adequate IgG response in the blood.¹¹

B cells migrate to and proliferate inside the central nervous system, leading to intrathecal production of anti-Borrelia antibodies. An index of cerebrospinal fluid to serum antibody greater than 1 is thus also indicative of neuroborreliosis.¹² Thus, performing lumbar puncture to detect intrathecal production of antibodies may support the diagnosis of central nervous system Lyme disease; however, it is not necessary.¹¹

Antibodies persist in the central nervous system for many years after appropriate antimicrobial treatment.

Lyme arthritis

Articular involvement in Lyme disease is characterized by a robust humoral response such that a negative IgG serologic test virtually rules out Lyme arthritis.²³ PCR testing of synovial fluid for borrelial DNA has a sensitivity of 80% but may become falsely negative after 1 to 2 months of antibiotic treatment.^24,25 In an algorithm suggested by Puius et al,²³ PCR testing of synovial fluid should be done in patients who have minimal to no response after 2 months of appropriate oral antimicrobial therapy to determine whether intravenous antibiotics are merited.

Table 5 summarizes the tests of choice in different clinical stages of infection.

Acknowledgment: The authors would like to acknowledge Anita Modi, MD, and Ceena N. Jacob, MD, for reviewing the manuscript and providing valuable suggestions, and Belinda Yen-Lieberman, PhD, for contributing pictures of the Western blot test results.

Lyme disease is a complex multisystem bacterial infection affecting the skin, joints, heart, and nervous system. The full spectrum of disease was first recognized and the disease was named in the 1970s during an outbreak of arthritis in children in the town of Lyme, Connecticut.¹

This review describes the epidemiology and pathogenesis of Lyme disease, the advantages and disadvantages of current diagnostic methods, and diagnostic algorithms.

THE MOST COMMON TICK-BORNE INFECTION IN NORTH AMERICA

Lyme disease is the most common tick-borne infection in North America.^2,3 In the United States, more than 30,000 cases are reported annually. In fact, in 2017, the number of cases was about 42,000, a 16% increase from the previous year, according to the US Centers for Disease Control and Prevention (CDC).

From Sigal LH. Myths and facts about Lyme disease. Cleve Clin J Med 1997; 64(4):203–209.

The infection is caused by Borrelia burgdorferi, a particularly arthritogenic spirochete transmitted by Ixodes scapularis (the black-legged deer tick, (Figure 1) and Ixodes pacificus (the Western black-legged tick). Although the infection can occur at any time of the year, its peak incidence is in May to late September, coinciding with increased outdoor recreational activity in areas where ticks live.^3,4 The typical tick habitat consists of deciduous woodland with sufficient humidity provided by a good layer of decaying vegetation. However, people can contract Lyme disease in their own backyard.³

Most cases of Lyme disease are seen in the northeastern United States, mainly in suburban and rural areas.^2,3 Other areas affected include the midwestern states of Minnesota, Wisconsin, and Michigan, as well as northern California.⁴ Fourteen states and the District of Columbia report a high average incidence (> 10 cases per 100,000 persons) (Table 1).²

FIRST COMES IgM, THEN IgG

The pathogenesis and the different stages of infection should inform laboratory testing in Lyme disease.

It is estimated that only 5% of infected ticks that bite people actually transmit their spirochetes to the human host.⁵ However, once infected, the patient’s innate immune system mounts a response that results in the classic erythema migrans rash at the bite site. A rash develops in only about 85% of patients who are infected and can appear at any time between 3 and 30 days, but most commonly after 7 days. Hence, a rash occurring within the first few hours of tick contact is not erythema migrans and does not indicate infection, but rather an early reaction to tick salivary antigens.⁵

Antibody levels remain below the detection limits of currently available serologic tests in the first 7 days after exposure. Immunoglobulin M (IgM) antibody titers peak between 8 and 14 days after tick contact, but IgM antibodies may never develop if the patient is started on early appropriate antimicrobial therapy.⁵

If the infection is not treated, the spirochete may disseminate through the blood from the bite site to different tissues.³ Both cell-mediated and antibody-mediated immunity swing into action to kill the spirochetes at this stage. The IgM antibody response occurs in 1 to 2 weeks, followed by a robust IgG response in 2 to 4 weeks.⁶

Because IgM can also cross-react with antigens other than those associated with B burgdorferi, the IgM test is less specific than the IgG test for Lyme disease.

Once a patient is exposed and mounts an antibody-mediated response to the spirochete, the antibody profile may persist for months to years, even after successful antibiotic treatment and cure of the disease.⁵

Despite the immune system’s robust series of defenses, untreated B burgdorferi infection can persist, as the organism has a bag of tricks to evade destruction. It can decrease its expression of specific immunogenic surface-exposed proteins, change its antigenic properties through recombination, and bind to the patient’s extracellular matrix proteins to facilitate further dissemination.³

Certain host-genetic factors also play a role in the pathogenesis of Lyme disease, such as the HLA-DR4 allele, which has been associated with antibiotic-refractory Lyme-related arthritis.³

LYME DISEASE EVOLVES THROUGH STAGES

Lyme disease evolves through stages broadly classified as early and late infection, with significant variability in its presentation.⁷

Early infection

Early disease is further subdivided into “localized” infection (stage 1), characterized by a single erythema migrans lesion and local lymphadenopathy, and “disseminated” infection (stage 2), associated with multiple erythema migrans lesions distant from the bite site, facial nerve palsy, radiculoneuritis, meningitis, carditis, or migratory arthritis or arthralgia.⁸

Highly specific physical findings include erythema migrans, cranial nerve palsy, high-grade or progressive conduction block, and recurrent migratory polyarthritis. Less specific symptoms and signs of Lyme disease include arthralgia, myalgia, neck stiffness, palpitations, and myocarditis.⁵

Erythema migrans lesions are evident in at least 85% of patients with early disease.⁹ If they are not apparent on physical examination, they may be located at hidden sites and may be atypical in appearance or transient.⁵

If treatment is not started in the initial stage of the disease, 60% of infected patients may develop disseminated infection.⁵ Progressive, untreated infection can manifest with Lyme arthritis and neuroborreliosis.⁷

Noncutaneous manifestations are less common now than in the past due to increased awareness of the disease and early initiation of treatment.¹⁰

Late infection

Manifestations of late (stage 3) infection include oligoarthritis (affecting any joint but often the knee) and neuroborreliosis. Clinical signs and symptoms of Lyme disease may take months to resolve even after appropriate antimicrobial therapy is completed. This should not be interpreted as ongoing, persistent infection, but as related to host immune-mediated activity.⁵

 

 

INTERPRET LABORATORY RESULTS BASED ON PRETEST PROBABILITY

The usefulness of a laboratory test depends on the individual patient’s pretest probability of infection, which in turn depends on the patient’s epidemiologic risk of exposure and clinical features of Lyme disease. Patients with a high pretest probability—eg, a history of a tick bite followed by the classic erythema migrans rash—do not need testing and can start antimicrobial therapy right away.¹¹

Serologic tests are the gold standard

Prompt diagnosis is important, as early Lyme disease is easily treatable without any future sequelae.¹¹

Tests for Lyme disease can be divided into direct methods, which detect the spirochete itself by culture or by polymerase chain reaction (PCR), and indirect methods, which detect antibodies (Table 2). Direct tests lack sensitivity for Lyme disease; hence, serologic tests remain the gold standard. Currently recommended is a standard 2-tier testing strategy using an enzyme-linked immunosorbent assay (ELISA) followed by Western blot for confirmation.

DIRECT METHODS

Culture lacks sensitivity

A number of factors limit the sensitivity of direct culture for diagnosing Lyme disease. B burgdorferi does not grow easily in culture, requiring special media, low temperatures, and long periods of incubation. Only a relatively few spirochetes are present in human tissues and body fluids to begin with, and bacterial counts are further reduced with duration and dissemination of infection.⁵ All of these limit the possibility of detecting this organism.

Polymerase chain reaction may help in some situations

Molecular assays are not part of the standard evaluation and should be used only in conjunction with serologic testing.⁷ These tests have high specificity but lack consistent sensitivity.

That said, PCR testing may be useful:

• In early infection, before antibody responses develop
• In reinfection, when serologic tests are not reliable because the antibodies persist for many years after an infection in many patients
• In endemic areas where serologic testing has high false-positive rates due to high baseline population seropositivity for anti-Borrelia antibodies caused by subclinical infection.³

PCR assays that target plasmid-borne genes encoding outer surface proteins A and C (OspA and OspC) and VisE (variable major protein-like sequence, expressed) are more sensitive than those that detect chromosomal 16s ribosomal ribonucleic acid (rRNA) genes, as plasmid-rich “blebs” are shed in larger concentrations than chromosomal DNA during active infection.⁷ However, these plasmid-contained genes persist in body tissues and fluids even after the infection is cleared, and their detection may not necessarily correlate with ongoing disease.⁸ Detection of chromosomal 16s rRNA genes is a better predictor of true organism viability.

The sensitivity of PCR for borrelial DNA depends on the type of sample. If a skin biopsy sample is taken of the leading edge of an erythema migrans lesion, the sensitivity is 69% and the specificity is 100%. In patients with Lyme arthritis, PCR of the synovial fluid has a sensitivity of up to 80%. However, the sensitivity of PCR of the cerebrospinal fluid of patients with neurologic manifestations of Lyme disease is only 19%.⁷ PCR of other clinical samples, including blood and urine, is not recommended, as spirochetes are primarily confined to tissues, and very few are present in these body fluids.^3,12

The disadvantage of PCR is that a positive result does not always mean active infection, as the DNA of the dead microbe persists for several months even after successful treatment.⁸

INDIRECT METHODS

Enzyme-linked immunosorbent assay

ELISAs detect anti-Borrelia antibodies. Early-generation ELISAs, still used in many laboratories, use whole-cell extracts of B burgdorferi. Examples are the Vidas Lyme screen (Biomérieux, biomerieux-usa.com) and the Wampole B burgdorferi IgG/M EIA II assay (Alere, www.alere.com). Newer ELISAs use recombinant proteins.¹³

Three major targets for ELISA antibodies are flagellin (Fla), outer surface protein C (OspC), and VisE, especially the invariable region 6 (IR6). Among these, VisE-IR6 is the most conserved region in B burgdorferi.

Early-generation assays have a sensitivity of 89% and specificity of 72%.¹¹ However, the patient’s serum may have antibodies that cross-react with unrelated bacterial antigens, leading to false-positive results (Table 3). Whole-cell sonicate assays are not recommended as an independent test and must be confirmed with Western blot testing when assay results are indeterminate or positive.¹¹

Newer-generation ELISAs detect antibodies targeting recombinant proteins of VisE, especially a synthetic peptide C6, within IR6.¹³ VisE-IR6 is the most conserved region of the B burgdorferi complex, and its detection is a highly specific finding, supporting the diagnosis of Lyme disease. Antibodies against VisE-IR6 antigen are the earliest to develop.⁵ An example of a newer-generation serologic test is the VisE C6 Lyme EIA kit, approved as a first-tier test by the US Food and Drug Administration in 2001. This test has a specificity of 99%,^14,15 and its specificity is further increased when used in conjunction with Western blot (99.5%).¹⁵ The advantage of the C6 antibody test is that it is more sensitive than 2-tier testing during early infection (sensitivity 29%–74% vs 17%–40% in early localized infection, and 56%–90% vs 27%–78% in early disseminated infection).⁶

During early infection, older and newer ELISAs are less sensitive because of the limited number of antigens expressed at this stage.¹³ All patients suspected of having early Lyme disease who are seronegative at initial testing should have follow-up testing to look for seroconversion.¹³

Western blot

Western blot (immunoblot) testing identifies IgM and IgG antibodies against specific B burgdorferi antigens. It is considered positive if it detects at least 2 of a possible 3 specific IgM bands in the first 4 weeks of disease or at least 5 of 10 specific IgG bands after 4 weeks of disease (Table 4 and Figure 2).¹⁶

The nature of the bands indicates the duration of infection: Western blot bands against 23-kD OspC and 41-kD FlaB are seen in early localized infection, whereas bands against all 3 B burgdorferi proteins will be seen after several weeks of disease.¹⁷ The IgM result should be interpreted carefully, as only 2 bands are required for the test to be positive, and IgM binds to antigen less specifically than IgG.¹²

 

 

Interpreting the IgM Western blot test: The ‘1-month rule’

If clinical symptoms and signs of Lyme disease have been present for more than 1 month, IgM reactivity alone should not be used to support the diagnosis, in view of the likelihood of a false-positive test result in this situation.¹⁸ This is called the “1-month rule” in the diagnosis of Lyme disease.¹³

In early localized infection, Western blot is only half as sensitive as ELISA testing. Since the overall sensitivity of a 2-step algorithm is equal to that of its least sensitive component, 2-tiered testing is not useful in early disease.¹³

Although currently considered the most specific test for confirmation of Lyme disease, Western blot has limitations. It is technically and interpretively complex and is thus not universally available.¹³ The blots are scored by visual examination, compromising the reproducibility of the test, although densitometric blot analysis techniques and automated scanning and scoring attempt to address some of these limitations.¹³ Like the ELISA, Western blot can have false-positive results in healthy individuals without tick exposure, as nonspecific IgM immunoblots develop faint bands. This is because of cross-reaction between B burgdorferi antigens and antigens from other microorganisms. Around 50% of healthy adults show low-level serum IgG reactivity against the FlaB antigen, leading to false-positive results as well. In cases in which the Western blot result is indeterminate, other etiologies must be considered.

False-positive IgM Western blots are a significant problem. In a 5-year retrospective study done at 63 US Air Force healthcare facilities, 113 (53.3%) of 212 IgM Western blots were falsely positive.¹⁹ A false-positive test was defined as one that failed to meet seropositivity (a first-tier test omitted or negative, > 30 days of symptoms with negative IgG blot), lack of exposure including residing in areas without documented tick habitats, patients having atypical or no symptoms, and negative serology within 30 days of a positive test.

In a similar study done in a highly endemic area, 50 (27.5%) of 182 patients had a false-positive test.²⁰ Physicians need to be careful when interpreting IgM Western blots. It is always important to consider locale, epidemiology, and symptoms when interpreting the test.

Limitations of serologic tests for Lyme disease

Currently available serologic tests have inherent limitations:

• Antibodies against B burgdorferi take at least 1 week to develop
• The background rate of seropositivity in endemic areas can be up to 4%, affecting the utility of a positive test result
• Serologic tests cannot be used as tests of cure because antibodies can persist for months to years even after appropriate antimicrobial therapy and cure of disease; thus, a positive serologic result could represent active infection or remote exposure²¹
• Antibodies can cross-react with related bacteria, including other borrelial or treponemal spirochetes
• False-positive serologic test results can also occur in association with other medical conditions such as polyclonal gammopathies and systemic lupus erythematosus.¹²

RECOMMENDATIONS FOR TESTING

Standard 2-tier testing

The CDC released recommendations for diagnosing Lyme disease after a second national conference of serologic diagnosis of Lyme disease in October 1994.¹⁸ The 2-tiered testing method, involving a sensitive ELISA followed by the Western blot to confirm positive and indeterminate ELISA results, was suggested as the gold standard for diagnosis (Figure 3). Of note, negative ELISA results do not require further testing.¹¹

The sensitivity of 2-tiered testing depends on the stage of the disease. Unfortunately, this method has a wide range of sensitivity (17% to 78%) in stage 1 disease. In the same stage, the sensitivity increases from 14.1% in patients with a single erythema migrans lesion and early localized infection to 65.4% in those with multiple lesions. The algorithm has excellent sensitivity in late stage 3 infection (96% to 100%).⁵

A 2-step ELISA algorithm

A 2-step ELISA algorithm (without the Western blot) that includes the whole-cell sonicate assay followed by the VisE C6 peptide assay actually showed higher sensitivity and comparable specificity compared with 2-tiered testing in early localized disease (sensitivity 61%–74% vs 29%–48%, respectively; specificity 99.5% for both methods).²² This higher sensitivity was even more pronounced in early disseminated infection (sensitivity 100% vs 40%, respectively). By late infection, the sensitivities of both testing strategies reached 100%. Compared with the Western blot, the 2-step ELISA algorithm was simpler to execute in a reproducible fashion.⁵

The Infectious Diseases Society of America is revising its current guidelines, with an update expected late this year, which may shift the recommendation from 2-tiered testing to the 2-step ELISA algorithm.

Multiplex testing

To overcome the intrinsic problems of protein-based assays, a multiplexed, array-based assay for the diagnosis of tick-borne infections called Tick-Borne Disease Serochip (TBD-Serochip) was established using recombinant antigens that identify key immunodominant epitopes.⁸ More studies are needed to establish the validity and usefulness of these tests in clinical practice.

Who should not be tested?

The American College of Physicians⁶ recommends against testing in patients:

• Presenting with nonspecific symptoms (eg, headache, myalgia, fatigue, arthralgia) without objective signs of Lyme disease
• With low pretest probability of infection based on epidemiologic exposures and clinical features
• Living in Lyme-endemic areas with no history of tick exposure⁶
• Presenting less than 1 week after tick exposure⁵
• Seeking a test of cure for treated Lyme disease.

DIAGNOSIS IN SPECIAL SITUATIONS

Early Lyme disease

The classic erythema migrans lesion on physical examination of a patient with suspected Lyme disease is diagnostic and does not require laboratory confirmation.¹⁰

In ambiguous cases, 2-tiered testing of a serum sample during the acute presentation and again 4 to 6 weeks later can be useful. In patients who remain seronegative on paired serum samples despite symptoms lasting longer than 6 weeks and no antibiotic treatment in the interim, the diagnosis of Lyme disease is unlikely, and another diagnosis should be sought.³

Antimicrobial therapy may block the serologic response; hence, negative serologic testing in patients started on empiric antibiotics should not rule out Lyme disease.⁶

PCR or bacterial culture testing is not recommended in the evaluation of suspected early Lyme disease.

Central nervous system Lyme disease

Central nervous system Lyme disease is diagnosed by 2-tiered testing using peripheral blood samples because all patients with this infectious manifestation should have mounted an adequate IgG response in the blood.¹¹

B cells migrate to and proliferate inside the central nervous system, leading to intrathecal production of anti-Borrelia antibodies. An index of cerebrospinal fluid to serum antibody greater than 1 is thus also indicative of neuroborreliosis.¹² Thus, performing lumbar puncture to detect intrathecal production of antibodies may support the diagnosis of central nervous system Lyme disease; however, it is not necessary.¹¹

Antibodies persist in the central nervous system for many years after appropriate antimicrobial treatment.

Lyme arthritis

Articular involvement in Lyme disease is characterized by a robust humoral response such that a negative IgG serologic test virtually rules out Lyme arthritis.²³ PCR testing of synovial fluid for borrelial DNA has a sensitivity of 80% but may become falsely negative after 1 to 2 months of antibiotic treatment.^24,25 In an algorithm suggested by Puius et al,²³ PCR testing of synovial fluid should be done in patients who have minimal to no response after 2 months of appropriate oral antimicrobial therapy to determine whether intravenous antibiotics are merited.

Table 5 summarizes the tests of choice in different clinical stages of infection.

Acknowledgment: The authors would like to acknowledge Anita Modi, MD, and Ceena N. Jacob, MD, for reviewing the manuscript and providing valuable suggestions, and Belinda Yen-Lieberman, PhD, for contributing pictures of the Western blot test results.

Two cases of bacteremia have been described in two patients who received fecal microbiota transplants from the same donor.

Writing in the New England Journal of Medicine, researchers reported the two case studies of extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli bacteremia, one of which ended in the death of the patient. These cases were previously announced by the Food and Drug Administration in a June 2019 safety alert.

Zachariah DeFilipp, MD, from Massachusetts General Hospital at Harvard Medical School, Boston, and coauthors wrote that fecal microbiota transplantation is rarely associated with complications. Placebo-controlled trials and a systematic review have found similar rates of complications in immunocompromised and immunocompetent recipients. Only four cases of gram-negative bacteremia previously have been reported, and in three of these, there was a plausible alternative explanation for the bacteremia.

In this paper, both patients received fecal microbiota transplantation via frozen oral capsules containing donor stool. These capsules were prepared prior to the implementation of screening for ESBL-producing organisms at the institution, and were not retrospectively tested since this expanded donor screening.

The first patient was a 69-year-old man with liver cirrhosis attributed to hepatitis C infection who was enrolled in a trial of fecal microbiota transplantation via oral capsules to treat hepatic encephalopathy. The first sign of the adverse event was a fever and cough, which developed 17 days after the final dose of 15 capsules. He was treated for pneumonia but failed to improve after 2 days, at which time gram-negative rods were discovered in blood cultures taken at the initial presentation.

After admission and further treatment, blood cultures were found to have ESBL-producing E. coli, and after further treatment, the patient was clinically stable. A stool sample taken after treatment was negative for ESBL-producing E. coli.

The second case study was a 73-year-old man with therapy-related myelodysplastic syndrome who was undergoing allogeneic hematopoietic stem cell transplantation and was receiving fecal microbiota transplantation via oral capsule as part of a phase 2 trial.

Eight days after the last dose of oral capsules, and 5 days after the stem-cell infusion, the man developed a fever, chills, febrile neutropenia and showed altered mental status. He was treated with cefepime but developed hypoxia and labored breathing later that evening, which prompted clinicians to intubate and begin mechanical ventilation.

His blood culture results showed gram-negative rods, and meropenem was added to his antibiotic regimen. However, the patient’s condition worsened, and he died of severe sepsis 2 days later with blood cultures confirmed as positive for ESBL-producing E. coli.

A follow-up investigation revealed that both patients received stool from the same donor. Each lot of three capsules from that donor was found to contain ESBL-producing E. coli with a resistance pattern similar to that seen in the two recipients.

Twenty-two patients had received capsules from this donor. Researchers contacted all the recipients and offered them stool screening for ESBL-producing E. coli. Twelve underwent testing, which found that five had samples that grew on ESBL-producing E. coli–selective medium.

The remaining seven patients who had follow-up testing were receiving treatment for recurrent or refractory Clostridioides difficile infection, and four of these grew samples on the selective medium.

“When FMT is successful, the recipient’s metagenomic burden of antimicrobial resistance genes mimics that of the donor,” the authors wrote. “Although we cannot conclusively attribute positive screening results for ESBL-producing organisms in other asymptomatic recipients to FMT, the rates of positive tests are, in our opinion, unexpectedly high and probably represent transmission through FMT.”

The authors said the donor had no risk factors for carriage of multidrug-resistant organism and had previously donated fecal material before the introduction of routine screening for ESBL-producing organisms.

However, they noted that both patients had risk factors for bacteremia, namely advanced cirrhosis and allogeneic hematopoietic stem cell transplantation and they also received oral antibiotics around the time of the fecal microbiota transplantation.

“Despite the infectious complications reported here, the benefits of FMT should be balanced with the associated risks when considering treatment options for patients with recurrent or refractory C. difficile infection,” the authors wrote. “Ongoing assessment of the risks and benefit of FMT research is needed, as are continuing efforts to improve donor screening to limit transmission of microorganisms that could lead to adverse infectious events.”

The American Gastroenterological Association FMT National Registry is a critical effort to track short- and long-term patient outcomes and potential risks associated with FMT. The registry's goal is to track 4,000 patients for 10 years. If you perform FMT, please contribute to this important initiative. Learn more at www.gastro.org/FMTRegistry.

The study was supported by a grant from the American College of Gastroenterology. Three authors declared personal fees and grants from the medical sector outside the submitted work, and two were attached to a diagnostics company involved in the study.

SOURCE: DeFilipp Z et al. N Engl J Med. 2019 Oct 30. doi: 10.1056/NEJMoa1910437.

* This story was updated on Oct. 31, 2019.

Two cases of bacteremia have been described in two patients who received fecal microbiota transplants from the same donor.

Writing in the New England Journal of Medicine, researchers reported the two case studies of extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli bacteremia, one of which ended in the death of the patient. These cases were previously announced by the Food and Drug Administration in a June 2019 safety alert.

Zachariah DeFilipp, MD, from Massachusetts General Hospital at Harvard Medical School, Boston, and coauthors wrote that fecal microbiota transplantation is rarely associated with complications. Placebo-controlled trials and a systematic review have found similar rates of complications in immunocompromised and immunocompetent recipients. Only four cases of gram-negative bacteremia previously have been reported, and in three of these, there was a plausible alternative explanation for the bacteremia.

In this paper, both patients received fecal microbiota transplantation via frozen oral capsules containing donor stool. These capsules were prepared prior to the implementation of screening for ESBL-producing organisms at the institution, and were not retrospectively tested since this expanded donor screening.

The first patient was a 69-year-old man with liver cirrhosis attributed to hepatitis C infection who was enrolled in a trial of fecal microbiota transplantation via oral capsules to treat hepatic encephalopathy. The first sign of the adverse event was a fever and cough, which developed 17 days after the final dose of 15 capsules. He was treated for pneumonia but failed to improve after 2 days, at which time gram-negative rods were discovered in blood cultures taken at the initial presentation.

After admission and further treatment, blood cultures were found to have ESBL-producing E. coli, and after further treatment, the patient was clinically stable. A stool sample taken after treatment was negative for ESBL-producing E. coli.

The second case study was a 73-year-old man with therapy-related myelodysplastic syndrome who was undergoing allogeneic hematopoietic stem cell transplantation and was receiving fecal microbiota transplantation via oral capsule as part of a phase 2 trial.

Eight days after the last dose of oral capsules, and 5 days after the stem-cell infusion, the man developed a fever, chills, febrile neutropenia and showed altered mental status. He was treated with cefepime but developed hypoxia and labored breathing later that evening, which prompted clinicians to intubate and begin mechanical ventilation.

His blood culture results showed gram-negative rods, and meropenem was added to his antibiotic regimen. However, the patient’s condition worsened, and he died of severe sepsis 2 days later with blood cultures confirmed as positive for ESBL-producing E. coli.

A follow-up investigation revealed that both patients received stool from the same donor. Each lot of three capsules from that donor was found to contain ESBL-producing E. coli with a resistance pattern similar to that seen in the two recipients.

Twenty-two patients had received capsules from this donor. Researchers contacted all the recipients and offered them stool screening for ESBL-producing E. coli. Twelve underwent testing, which found that five had samples that grew on ESBL-producing E. coli–selective medium.

The remaining seven patients who had follow-up testing were receiving treatment for recurrent or refractory Clostridioides difficile infection, and four of these grew samples on the selective medium.

“When FMT is successful, the recipient’s metagenomic burden of antimicrobial resistance genes mimics that of the donor,” the authors wrote. “Although we cannot conclusively attribute positive screening results for ESBL-producing organisms in other asymptomatic recipients to FMT, the rates of positive tests are, in our opinion, unexpectedly high and probably represent transmission through FMT.”

The authors said the donor had no risk factors for carriage of multidrug-resistant organism and had previously donated fecal material before the introduction of routine screening for ESBL-producing organisms.

However, they noted that both patients had risk factors for bacteremia, namely advanced cirrhosis and allogeneic hematopoietic stem cell transplantation and they also received oral antibiotics around the time of the fecal microbiota transplantation.

“Despite the infectious complications reported here, the benefits of FMT should be balanced with the associated risks when considering treatment options for patients with recurrent or refractory C. difficile infection,” the authors wrote. “Ongoing assessment of the risks and benefit of FMT research is needed, as are continuing efforts to improve donor screening to limit transmission of microorganisms that could lead to adverse infectious events.”

The American Gastroenterological Association FMT National Registry is a critical effort to track short- and long-term patient outcomes and potential risks associated with FMT. The registry's goal is to track 4,000 patients for 10 years. If you perform FMT, please contribute to this important initiative. Learn more at www.gastro.org/FMTRegistry.

The study was supported by a grant from the American College of Gastroenterology. Three authors declared personal fees and grants from the medical sector outside the submitted work, and two were attached to a diagnostics company involved in the study.

SOURCE: DeFilipp Z et al. N Engl J Med. 2019 Oct 30. doi: 10.1056/NEJMoa1910437.

* This story was updated on Oct. 31, 2019.

Two cases of bacteremia have been described in two patients who received fecal microbiota transplants from the same donor.

Writing in the New England Journal of Medicine, researchers reported the two case studies of extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli bacteremia, one of which ended in the death of the patient. These cases were previously announced by the Food and Drug Administration in a June 2019 safety alert.

Zachariah DeFilipp, MD, from Massachusetts General Hospital at Harvard Medical School, Boston, and coauthors wrote that fecal microbiota transplantation is rarely associated with complications. Placebo-controlled trials and a systematic review have found similar rates of complications in immunocompromised and immunocompetent recipients. Only four cases of gram-negative bacteremia previously have been reported, and in three of these, there was a plausible alternative explanation for the bacteremia.

In this paper, both patients received fecal microbiota transplantation via frozen oral capsules containing donor stool. These capsules were prepared prior to the implementation of screening for ESBL-producing organisms at the institution, and were not retrospectively tested since this expanded donor screening.

The first patient was a 69-year-old man with liver cirrhosis attributed to hepatitis C infection who was enrolled in a trial of fecal microbiota transplantation via oral capsules to treat hepatic encephalopathy. The first sign of the adverse event was a fever and cough, which developed 17 days after the final dose of 15 capsules. He was treated for pneumonia but failed to improve after 2 days, at which time gram-negative rods were discovered in blood cultures taken at the initial presentation.

After admission and further treatment, blood cultures were found to have ESBL-producing E. coli, and after further treatment, the patient was clinically stable. A stool sample taken after treatment was negative for ESBL-producing E. coli.

The second case study was a 73-year-old man with therapy-related myelodysplastic syndrome who was undergoing allogeneic hematopoietic stem cell transplantation and was receiving fecal microbiota transplantation via oral capsule as part of a phase 2 trial.

Eight days after the last dose of oral capsules, and 5 days after the stem-cell infusion, the man developed a fever, chills, febrile neutropenia and showed altered mental status. He was treated with cefepime but developed hypoxia and labored breathing later that evening, which prompted clinicians to intubate and begin mechanical ventilation.

His blood culture results showed gram-negative rods, and meropenem was added to his antibiotic regimen. However, the patient’s condition worsened, and he died of severe sepsis 2 days later with blood cultures confirmed as positive for ESBL-producing E. coli.

A follow-up investigation revealed that both patients received stool from the same donor. Each lot of three capsules from that donor was found to contain ESBL-producing E. coli with a resistance pattern similar to that seen in the two recipients.

Twenty-two patients had received capsules from this donor. Researchers contacted all the recipients and offered them stool screening for ESBL-producing E. coli. Twelve underwent testing, which found that five had samples that grew on ESBL-producing E. coli–selective medium.

The remaining seven patients who had follow-up testing were receiving treatment for recurrent or refractory Clostridioides difficile infection, and four of these grew samples on the selective medium.

“When FMT is successful, the recipient’s metagenomic burden of antimicrobial resistance genes mimics that of the donor,” the authors wrote. “Although we cannot conclusively attribute positive screening results for ESBL-producing organisms in other asymptomatic recipients to FMT, the rates of positive tests are, in our opinion, unexpectedly high and probably represent transmission through FMT.”

The authors said the donor had no risk factors for carriage of multidrug-resistant organism and had previously donated fecal material before the introduction of routine screening for ESBL-producing organisms.

However, they noted that both patients had risk factors for bacteremia, namely advanced cirrhosis and allogeneic hematopoietic stem cell transplantation and they also received oral antibiotics around the time of the fecal microbiota transplantation.

“Despite the infectious complications reported here, the benefits of FMT should be balanced with the associated risks when considering treatment options for patients with recurrent or refractory C. difficile infection,” the authors wrote. “Ongoing assessment of the risks and benefit of FMT research is needed, as are continuing efforts to improve donor screening to limit transmission of microorganisms that could lead to adverse infectious events.”

The American Gastroenterological Association FMT National Registry is a critical effort to track short- and long-term patient outcomes and potential risks associated with FMT. The registry's goal is to track 4,000 patients for 10 years. If you perform FMT, please contribute to this important initiative. Learn more at www.gastro.org/FMTRegistry.

The study was supported by a grant from the American College of Gastroenterology. Three authors declared personal fees and grants from the medical sector outside the submitted work, and two were attached to a diagnostics company involved in the study.

SOURCE: DeFilipp Z et al. N Engl J Med. 2019 Oct 30. doi: 10.1056/NEJMoa1910437.

* This story was updated on Oct. 31, 2019.

The Diagnosis: Herpes Simplex Virus 

A skin biopsy was sent for tissue culture and was negative for mycobacterial, bacterial, and fungal growth. Histopathologic examination showed ballooning degeneration of keratinocytes with herpetic cytopathic effect consistent with herpetic ulceration (Figure). A swab of the lesion on the buttock was sent for human herpesvirus (HHV) and varicella-zoster virus nucleic acid testing, which was positive for HHV-2. She was started on oral valacyclovir 1000 mg twice daily for 10 days and then was continued on chronic suppression with 500 mg once daily. The patient's ulcerations healed slowly over the following few weeks.  

Human herpesvirus 2 is the most common cause of genital ulcer disease and may present as chronic and recurrent ulcers in immunocompromised patients.¹ It usually is spread by sexual contact. Primary infection typically occurs in the cells of the dermis and epidermis. Two weeks after the primary infection, extragenital lesions can occur in the lumbosacral area on the buttocks, fingers, groin, or thighs, as seen in our patient,² which is a direct result of viral shedding and spread. Reactivation of HHV from the ganglia can occur with or without symptoms. Common locations for viral shedding in women are the cervix, vulva, and perianal areas.³ Patients should be counseled to avoid sexual contact during recurrences. 

Cancer patients have a particularly increased risk for developing HHV-2 due to their limited cell-mediated immunity and exposure to immunosuppressive drugs.⁴ Moreover, approximately 5% of immunocompromised patients develop resistance to antiviral therapy.⁵ Although this phenomenon was not observed in our patient, identification of novel strategies to treat these new groups of patients will be essential.  

The differential diagnosis includes perianal candidiasis, which is classified by erythematous plaques with satellite vesicles and pustules. Contact dermatitis is common in the buttock area and usually secondary to ingredients in cleansing wipes and topical treatments. It is defined by a well-demarcated, symmetric rash, which is more eczematous in nature. Cutaneous T-cell lymphoma was high in our differential given the patient's history of the disease. There are many variants, and tumor-stage disease may result in ulceration of the skin. Cutaneous T-cell lymphoma is differentiated by histology with immunophenotyping in conjunction with the clinical picture. Epstein-Barr virus (EBV) may cause genital ulcerations, which can be diagnosed with a positive EBV serology and detection of EBV by a polymerase chain reaction swab of the ulceration. 

The Diagnosis: Herpes Simplex Virus 

A skin biopsy was sent for tissue culture and was negative for mycobacterial, bacterial, and fungal growth. Histopathologic examination showed ballooning degeneration of keratinocytes with herpetic cytopathic effect consistent with herpetic ulceration (Figure). A swab of the lesion on the buttock was sent for human herpesvirus (HHV) and varicella-zoster virus nucleic acid testing, which was positive for HHV-2. She was started on oral valacyclovir 1000 mg twice daily for 10 days and then was continued on chronic suppression with 500 mg once daily. The patient's ulcerations healed slowly over the following few weeks.  

Human herpesvirus 2 is the most common cause of genital ulcer disease and may present as chronic and recurrent ulcers in immunocompromised patients.¹ It usually is spread by sexual contact. Primary infection typically occurs in the cells of the dermis and epidermis. Two weeks after the primary infection, extragenital lesions can occur in the lumbosacral area on the buttocks, fingers, groin, or thighs, as seen in our patient,² which is a direct result of viral shedding and spread. Reactivation of HHV from the ganglia can occur with or without symptoms. Common locations for viral shedding in women are the cervix, vulva, and perianal areas.³ Patients should be counseled to avoid sexual contact during recurrences. 

Cancer patients have a particularly increased risk for developing HHV-2 due to their limited cell-mediated immunity and exposure to immunosuppressive drugs.⁴ Moreover, approximately 5% of immunocompromised patients develop resistance to antiviral therapy.⁵ Although this phenomenon was not observed in our patient, identification of novel strategies to treat these new groups of patients will be essential.  

The differential diagnosis includes perianal candidiasis, which is classified by erythematous plaques with satellite vesicles and pustules. Contact dermatitis is common in the buttock area and usually secondary to ingredients in cleansing wipes and topical treatments. It is defined by a well-demarcated, symmetric rash, which is more eczematous in nature. Cutaneous T-cell lymphoma was high in our differential given the patient's history of the disease. There are many variants, and tumor-stage disease may result in ulceration of the skin. Cutaneous T-cell lymphoma is differentiated by histology with immunophenotyping in conjunction with the clinical picture. Epstein-Barr virus (EBV) may cause genital ulcerations, which can be diagnosed with a positive EBV serology and detection of EBV by a polymerase chain reaction swab of the ulceration. 

The Diagnosis: Herpes Simplex Virus 

A skin biopsy was sent for tissue culture and was negative for mycobacterial, bacterial, and fungal growth. Histopathologic examination showed ballooning degeneration of keratinocytes with herpetic cytopathic effect consistent with herpetic ulceration (Figure). A swab of the lesion on the buttock was sent for human herpesvirus (HHV) and varicella-zoster virus nucleic acid testing, which was positive for HHV-2. She was started on oral valacyclovir 1000 mg twice daily for 10 days and then was continued on chronic suppression with 500 mg once daily. The patient's ulcerations healed slowly over the following few weeks.  

Human herpesvirus 2 is the most common cause of genital ulcer disease and may present as chronic and recurrent ulcers in immunocompromised patients.¹ It usually is spread by sexual contact. Primary infection typically occurs in the cells of the dermis and epidermis. Two weeks after the primary infection, extragenital lesions can occur in the lumbosacral area on the buttocks, fingers, groin, or thighs, as seen in our patient,² which is a direct result of viral shedding and spread. Reactivation of HHV from the ganglia can occur with or without symptoms. Common locations for viral shedding in women are the cervix, vulva, and perianal areas.³ Patients should be counseled to avoid sexual contact during recurrences. 

Cancer patients have a particularly increased risk for developing HHV-2 due to their limited cell-mediated immunity and exposure to immunosuppressive drugs.⁴ Moreover, approximately 5% of immunocompromised patients develop resistance to antiviral therapy.⁵ Although this phenomenon was not observed in our patient, identification of novel strategies to treat these new groups of patients will be essential.  

The differential diagnosis includes perianal candidiasis, which is classified by erythematous plaques with satellite vesicles and pustules. Contact dermatitis is common in the buttock area and usually secondary to ingredients in cleansing wipes and topical treatments. It is defined by a well-demarcated, symmetric rash, which is more eczematous in nature. Cutaneous T-cell lymphoma was high in our differential given the patient's history of the disease. There are many variants, and tumor-stage disease may result in ulceration of the skin. Cutaneous T-cell lymphoma is differentiated by histology with immunophenotyping in conjunction with the clinical picture. Epstein-Barr virus (EBV) may cause genital ulcerations, which can be diagnosed with a positive EBV serology and detection of EBV by a polymerase chain reaction swab of the ulceration.