Harry Dao Jr, MD

A 42-year-old woman with psoriasis presents for a checkup at the dermatology clinic. Her psoriasis has been fairly stable on methotrexate with no recent flares. She presents her concern of the coronavirus pandemic continuing into the flu season and mentions she would like to minimize her chances of having a respiratory illness. The influenza vaccine has just become available, and she inquires when she can get the vaccine and whether it will interfere with her treatment. What are your recommendations for the patient?

Psoriasis is an immune-mediated, inflammatory skin condition stemming from hyperproliferation of keratinocytes that classically involves erythematous skin plaques with overlying scale. Treatment options vary widely and include topical modalities, phototherapy, immunosuppressants, and biologic agents. Selection of treatment largely depends on the severity and extent of body surface area involvement; systemic therapy generally is indicated when the affected body surface area is greater than 5% to 10%. In patients on systemic therapy, increased susceptibility to infection is a priority concern for prescribing physicians. In the context of continuing immunosuppressive medications, vaccines that reduce susceptibility to infectious diseases can play an important role in reducing morbidity and mortality for these patients; however, an important consideration is that in patients with chronic conditions and frequent hospital visits, vaccines may be administered by various clinicians who may not be familiar with the management of immunosuppressive treatments. It is pivotal for prescribing dermatologists to provide appropriate vaccination instructions for the patient and any future clinicians to ensure vaccine efficacy in these patients.

The intramuscular influenza vaccine is a killed vaccine that is administered annually and has been shown to be safe for use in both immunocompetent and immunocompromised patients.^1,2 Despite its safety, questions remain regarding the efficacy of vaccines while a patient is unable to mount a normal immune response and whether the treatment must be altered to maximize immunogenicity. The common systemic treatment options for psoriasis and any recommendations that can be made regarding administration of the influenza vaccine in that context are outlined in the Table. Given the sparsity of clinical data measuring vaccine immunogenicity in patients with psoriasis, vaccine guidelines are drawn from patients with various conditions who are receiving the same dose of medication as indicated for psoriasis.

A 42-year-old woman with psoriasis presents for a checkup at the dermatology clinic. Her psoriasis has been fairly stable on methotrexate with no recent flares. She presents her concern of the coronavirus pandemic continuing into the flu season and mentions she would like to minimize her chances of having a respiratory illness. The influenza vaccine has just become available, and she inquires when she can get the vaccine and whether it will interfere with her treatment. What are your recommendations for the patient?

Psoriasis is an immune-mediated, inflammatory skin condition stemming from hyperproliferation of keratinocytes that classically involves erythematous skin plaques with overlying scale. Treatment options vary widely and include topical modalities, phototherapy, immunosuppressants, and biologic agents. Selection of treatment largely depends on the severity and extent of body surface area involvement; systemic therapy generally is indicated when the affected body surface area is greater than 5% to 10%. In patients on systemic therapy, increased susceptibility to infection is a priority concern for prescribing physicians. In the context of continuing immunosuppressive medications, vaccines that reduce susceptibility to infectious diseases can play an important role in reducing morbidity and mortality for these patients; however, an important consideration is that in patients with chronic conditions and frequent hospital visits, vaccines may be administered by various clinicians who may not be familiar with the management of immunosuppressive treatments. It is pivotal for prescribing dermatologists to provide appropriate vaccination instructions for the patient and any future clinicians to ensure vaccine efficacy in these patients.

The intramuscular influenza vaccine is a killed vaccine that is administered annually and has been shown to be safe for use in both immunocompetent and immunocompromised patients.^1,2 Despite its safety, questions remain regarding the efficacy of vaccines while a patient is unable to mount a normal immune response and whether the treatment must be altered to maximize immunogenicity. The common systemic treatment options for psoriasis and any recommendations that can be made regarding administration of the influenza vaccine in that context are outlined in the Table. Given the sparsity of clinical data measuring vaccine immunogenicity in patients with psoriasis, vaccine guidelines are drawn from patients with various conditions who are receiving the same dose of medication as indicated for psoriasis.

A 42-year-old woman with psoriasis presents for a checkup at the dermatology clinic. Her psoriasis has been fairly stable on methotrexate with no recent flares. She presents her concern of the coronavirus pandemic continuing into the flu season and mentions she would like to minimize her chances of having a respiratory illness. The influenza vaccine has just become available, and she inquires when she can get the vaccine and whether it will interfere with her treatment. What are your recommendations for the patient?

Psoriasis is an immune-mediated, inflammatory skin condition stemming from hyperproliferation of keratinocytes that classically involves erythematous skin plaques with overlying scale. Treatment options vary widely and include topical modalities, phototherapy, immunosuppressants, and biologic agents. Selection of treatment largely depends on the severity and extent of body surface area involvement; systemic therapy generally is indicated when the affected body surface area is greater than 5% to 10%. In patients on systemic therapy, increased susceptibility to infection is a priority concern for prescribing physicians. In the context of continuing immunosuppressive medications, vaccines that reduce susceptibility to infectious diseases can play an important role in reducing morbidity and mortality for these patients; however, an important consideration is that in patients with chronic conditions and frequent hospital visits, vaccines may be administered by various clinicians who may not be familiar with the management of immunosuppressive treatments. It is pivotal for prescribing dermatologists to provide appropriate vaccination instructions for the patient and any future clinicians to ensure vaccine efficacy in these patients.

The intramuscular influenza vaccine is a killed vaccine that is administered annually and has been shown to be safe for use in both immunocompetent and immunocompromised patients.^1,2 Despite its safety, questions remain regarding the efficacy of vaccines while a patient is unable to mount a normal immune response and whether the treatment must be altered to maximize immunogenicity. The common systemic treatment options for psoriasis and any recommendations that can be made regarding administration of the influenza vaccine in that context are outlined in the Table. Given the sparsity of clinical data measuring vaccine immunogenicity in patients with psoriasis, vaccine guidelines are drawn from patients with various conditions who are receiving the same dose of medication as indicated for psoriasis.

Well-known for its typical presentation, classic herpes zoster (HZ) presents as a dermatomal eruption of painful erythematous papules that evolve into grouped vesicles or bullae.^1,2 Thereafter, the lesions can become pustular or hemorrhagic.¹ Although the diagnosis most often is made clinically, confirmatory techniques for diagnosis include viral culture, direct fluorescent antibody testing, or polymerase chain reaction (PCR) assay.^1,3

The main risk factor for HZ is advanced age, most commonly affecting elderly patients.⁴ It is hypothesized that a physiological decline in varicella-zoster virus (VZV)–specific cell-mediated immunity among elderly individuals helps trigger reactivation of the virus within the dorsal root ganglion.^1,5 Similarly affected are immunocompromised individuals, including those with human immunodeficiency virus (HIV) infection, due to suppression of T cells immune to VZV,^1,5 as well as immunosuppressed transplant recipients who have diminished VZV-specific cellular responses and VZV IgG antibody avidity.⁶

Secondary complications of VZV infection (eg, postherpetic neuralgia, bacterial superinfection progressing to cellulitis) lead to increased morbidity.^7,8 Disseminated cutaneous HZ is another grave complication of VZV infection and almost exclusively occurs with immunosuppression.^1,8 It manifests as an eruption of at least 20 widespread vesiculobullous lesions outside the primary and adjacent dermatomes.⁶ Immunocompromised patients also are at increased risk for visceral involvement of VZV infection, which may affect vital organs such as the brain, liver, or lungs.^7,8 Given the atypical presentation of VZV infection among some immunocompromised individuals, these patients are at increased risk for diagnostic delay and morbidity in the absence of high clinical suspicion for disseminated HZ.

Case Reports

Patient 1
A 52-year-old man developed a painless nonpruritic rash on the left leg of 4 days’ duration. It initially appeared as an erythematous maculopapular rash on the medial aspect of the left knee without any prodromal symptoms. Over the next 4 days, erythematous vesicles developed that progressed to pustules, and the rash spread both proximally and distally along the left leg. Shortly following hospital admission, he developed a fever (temperature, 38.4°C). His medical history included alcoholic liver cirrhosis and AIDS, with a CD4 count of 174 cells/µL (reference range, 500–1500 cells/µL). He had been taking antiretroviral therapy (abacavir-lamivudine and dolutegravir) and prophylaxis against opportunistic infections (dapsone and itraconazole).

Physical examination was remarkable for an extensive rash consisting of multiple 1-cm clusters of approximately 40 pustules each scattered in a nondermatomal distribution along the left leg (Figure 1). Many of the vesicles were confluent with an erythematous base and were in different stages of evolution with some crusted and others emanating a thin liquid exudate. The lesions were nontender and without notable induration. The leg was warm and edematous.

Clinically, the differential diagnosis included disseminated HZ with bacterial superinfection, Vibrio vulnificus infection, and herpes simplex virus (HSV) infection. The patient was treated with intravenous vancomycin, levofloxacin, and acyclovir, and no new lesions developed throughout the course of treatment. On this regimen, his fever resolved after 1 day, the active lesions began to crust, and the edema and erythema diminished. Results of bacterial cultures and plasma PCR and IgM for HSV types 1 and 2 were negative. Viral culture results were negative, but a PCR assay for VZV was positive, reflective of acute reactivation of VZV.

Patient 2
A 63-year-old man developed a pruritic burning rash involving the face, trunk, arms, and legs of 6 days’ duration. His medical history included a heart transplant 6 months prior to presentation, type 2 diabetes mellitus, and chronic kidney disease. He was taking antirejection therapy with mycophenolate mofetil (MMF), prednisone, and tacrolimus.

Physical examination was remarkable for an extensive rash consisting of clusters of 1- to 2-mm vesicles scattered in a nondermatomal pattern. Isolated vesicles involved the forehead, nose, and left ear, and diffuse vesicles with a relatively symmetric distribution were scattered across the back, chest, and proximal and distal arms and legs (Figure 2). Many of the vesicles had an associated overlying crust with hemorrhage. Some of the vesicles coalesced with central necrotic plaques.

Given a clinical suspicion for disseminated HZ, therapy with oral valacyclovir was initiated. Two punch biopsies were consistent with herpesvirus cytopathic changes. Multiple sections demonstrated ulceration as well as acantholysis and necrosis of keratinocytes with multinucleation and margination of chromatin. There was an intense lichenoid and perivascular lymphocytic infiltrate in the dermis. Immunohistochemistry staining was positive for VZV and negative for HSV, indicating acute reactivation of VZV (Figure 3). Upon completion of an antiviral regimen, the patient returned to clinic with healed crusted lesions.

Comment

Frequently, the clinical features of HZ in immunocompromised patients mirror those in immunocompetent hosts.⁸ However, each of our 2 patients developed an unusual presentation of atypical generalized HZ.⁷ In this clinical variant, lesions develop along a single dermatome, then a diffuse vesicular eruption subsequently develops without dermatomal localization. These lesions can be chronic, persisting for months or years.⁷

The classic clinical presentation of HZ is distinct and often is readily diagnosed by visual inspection.⁷ However, atypical presentations and their associated complications can pose diagnostic and therapeutic challenges.⁷ Painless HZ lesions in a nondermatomal pattern were described in a patient who also had AIDS.⁹ Interestingly, multiple reports have found that patients with a severe but painless rash are less likely to have experienced a viral prodrome consisting of hyperesthesia, paresthesia, or pruritus.^2,10 This observation suggests that lack of a prodrome, as in the case of patient 1 in our report, may aid in the recognition of painless HZ. Because of these atypical presentations, laboratory testing is even more important than in immunocompetent hosts, as diagnosis may be more difficult to establish on clinical presentation alone.

Several studies^11-32 have evaluated modalities for treatment and prophylaxis for disseminated HZ in immunocompromised hosts, given its increased risk and potentially fatal complications in this population. The current guidelines in patients with HIV/AIDS, solid organ transplantation (SOT), and hematopoietic stem cell transplantation (HSCT) are summarized in the eTable.

HIV/AIDS Patients
Given their efficacy and low rate of toxicity, oral acyclovir, valacyclovir, and famciclovir are recommended treatment options for HIV patients with localized, mild, dermatomal HZ.¹¹ Two exceptions include HZ ophthalmicus and Ramsay Hunt syndrome for which some experts recommend intravenous acyclovir given the risk for vision loss and facial palsy, respectively. Intravenous acyclovir often is the drug of choice for treating complicated, disseminated, or severe HZ in HIV-infected patients, though prospective efficacy data remain limited.¹¹

With regard to prevention of infection, a large randomized trial in 2016 found that acyclovir prophylaxis resulted in a 68% reduction in HZ over 2 years among HIV patients.¹² Despite data that acyclovir may be effective for this purpose, long-term antiviral prophylaxis is not routinely recommended for HZ,^11,13 as it has been linked to rare cases of acyclovir-resistant HZ in HIV patients.^14,15 However, antiviral prophylaxis against HSV type 2 reactivation in HIV patients also confers protection against VZV reactivation.^11,12

Solid Organ Transplantation
Localized, mild to moderately severe dermatomal HZ can be treated with oral acyclovir, valacyclovir, or famciclovir. As in HIV patients, SOT patients with severe, disseminated, or complicated HZ should receive IV acyclovir.¹¹ In the first 3 to 6 months following the procedure, SOT patients receive cytomegalovirus prophylaxis with ganciclovir or valgan-ciclovir, which also provides protection against HZ.^13-18 For patients not receiving cytomegalovirus prophylaxis, HSV prophylaxis with oral acyclovir or valacyclovir is given for at least the first month after transplantation, which also confers protection against HZ.^16,19 Antiviral therapy is critical during the early posttransplantation period when patients are most severely immunosuppressed and thus have the highest risk for VZV-associated complications.²⁰ Although immunosuppression is lifelong in most SOT recipients, there is insufficient evidence for extending prophylaxis beyond 6 months.^16,21

As a possible risk factor for HZ,²² MMF use is another consideration among SOT patients, similar to patient 2 in our report. A 2003 observational study supported withdrawal of MMF therapy during active VZV infection due to clinical observation of an association with HZ.²³ However, a multicenter, randomized, controlled trial reported no cases of HZ in renal transplant recipients on MMF.²⁴ Additionally, MMF has been observed to enhance the antiviral activity of acyclovir, at least in vitro.²⁵ Given the lack of evidence of MMF as a risk factor for HZ, there is insufficient evidence for cessation of use during VZVreactivation in SOT patients.

Hematopoietic Stem Cell Transplantation
The preferred agents for treatment of localized mild dermatomal HZ are oral acyclovir or valacyclovir, as data on the safety and efficacy of famciclovir among HSCT recipients are limited.^13,26 Patients should receive antiviral prophylaxis with one of these agents during the first year following allogeneic or autologous HSCT. This 1-year course has proven highly effective in reducing HZ in the first year following transplantation when most severe cases occur,^21,26-29 and it has been associated with a persistently decreased risk for HZ even after discontinuation.²¹ Prophylaxis may be continued beyond 1 year in allogeneic HSCT recipients experiencing graft-versus-host disease who should receive acyclovir until 6 months after the end of immunosuppressive therapy.^21,26

Vaccination remains a potential strategy to reduce the incidence of HZ in this patient population. A heat-inactivated vaccine administered within the first 3 months after the procedure has been shown to be safe among autologous and allogeneic HSCT patients.^30,31 The vaccine notably reduced the incidence of HZ in patients who underwent autologous HSCT,³² but no known data are available on its clinical efficacy in allogeneic HSCT patients. Accordingly, there are no known official recommendations to date regarding vaccine use in these patient populations.²⁶

Conclusion

It is incumbent upon clinicians to recognize the spectrum of atypical presentations of HZ and maintain a low threshold for performing appropriate diagnostic or confirmatory studies among at-risk patients with impaired immune function. Disseminated HZ can have potentially life-threatening visceral complications such as encephalitis, hepatitis, or pneumonitis.^7,8 As such, an understanding of prevention and treatment modalities for VZV infection among immunocompromised patients is critical. Because the morbidity associated with complications of VZV infection is substantial and the risks associated with antiviral agents are minimal, antiviral prophylaxis is recommended for 6 months following SOT or 1 year following HSCT, and prompt treatment is warranted in cases of reasonable clinical suspicion for HZ.

Acknowledgment
The authors gratefully acknowledge the generosity of our patients in permitting photography of their skin findings for the furthering of medical education.

Well-known for its typical presentation, classic herpes zoster (HZ) presents as a dermatomal eruption of painful erythematous papules that evolve into grouped vesicles or bullae.^1,2 Thereafter, the lesions can become pustular or hemorrhagic.¹ Although the diagnosis most often is made clinically, confirmatory techniques for diagnosis include viral culture, direct fluorescent antibody testing, or polymerase chain reaction (PCR) assay.^1,3

The main risk factor for HZ is advanced age, most commonly affecting elderly patients.⁴ It is hypothesized that a physiological decline in varicella-zoster virus (VZV)–specific cell-mediated immunity among elderly individuals helps trigger reactivation of the virus within the dorsal root ganglion.^1,5 Similarly affected are immunocompromised individuals, including those with human immunodeficiency virus (HIV) infection, due to suppression of T cells immune to VZV,^1,5 as well as immunosuppressed transplant recipients who have diminished VZV-specific cellular responses and VZV IgG antibody avidity.⁶

Secondary complications of VZV infection (eg, postherpetic neuralgia, bacterial superinfection progressing to cellulitis) lead to increased morbidity.^7,8 Disseminated cutaneous HZ is another grave complication of VZV infection and almost exclusively occurs with immunosuppression.^1,8 It manifests as an eruption of at least 20 widespread vesiculobullous lesions outside the primary and adjacent dermatomes.⁶ Immunocompromised patients also are at increased risk for visceral involvement of VZV infection, which may affect vital organs such as the brain, liver, or lungs.^7,8 Given the atypical presentation of VZV infection among some immunocompromised individuals, these patients are at increased risk for diagnostic delay and morbidity in the absence of high clinical suspicion for disseminated HZ.

Case Reports

Patient 1
A 52-year-old man developed a painless nonpruritic rash on the left leg of 4 days’ duration. It initially appeared as an erythematous maculopapular rash on the medial aspect of the left knee without any prodromal symptoms. Over the next 4 days, erythematous vesicles developed that progressed to pustules, and the rash spread both proximally and distally along the left leg. Shortly following hospital admission, he developed a fever (temperature, 38.4°C). His medical history included alcoholic liver cirrhosis and AIDS, with a CD4 count of 174 cells/µL (reference range, 500–1500 cells/µL). He had been taking antiretroviral therapy (abacavir-lamivudine and dolutegravir) and prophylaxis against opportunistic infections (dapsone and itraconazole).

Physical examination was remarkable for an extensive rash consisting of multiple 1-cm clusters of approximately 40 pustules each scattered in a nondermatomal distribution along the left leg (Figure 1). Many of the vesicles were confluent with an erythematous base and were in different stages of evolution with some crusted and others emanating a thin liquid exudate. The lesions were nontender and without notable induration. The leg was warm and edematous.

Clinically, the differential diagnosis included disseminated HZ with bacterial superinfection, Vibrio vulnificus infection, and herpes simplex virus (HSV) infection. The patient was treated with intravenous vancomycin, levofloxacin, and acyclovir, and no new lesions developed throughout the course of treatment. On this regimen, his fever resolved after 1 day, the active lesions began to crust, and the edema and erythema diminished. Results of bacterial cultures and plasma PCR and IgM for HSV types 1 and 2 were negative. Viral culture results were negative, but a PCR assay for VZV was positive, reflective of acute reactivation of VZV.

Patient 2
A 63-year-old man developed a pruritic burning rash involving the face, trunk, arms, and legs of 6 days’ duration. His medical history included a heart transplant 6 months prior to presentation, type 2 diabetes mellitus, and chronic kidney disease. He was taking antirejection therapy with mycophenolate mofetil (MMF), prednisone, and tacrolimus.

Physical examination was remarkable for an extensive rash consisting of clusters of 1- to 2-mm vesicles scattered in a nondermatomal pattern. Isolated vesicles involved the forehead, nose, and left ear, and diffuse vesicles with a relatively symmetric distribution were scattered across the back, chest, and proximal and distal arms and legs (Figure 2). Many of the vesicles had an associated overlying crust with hemorrhage. Some of the vesicles coalesced with central necrotic plaques.

Given a clinical suspicion for disseminated HZ, therapy with oral valacyclovir was initiated. Two punch biopsies were consistent with herpesvirus cytopathic changes. Multiple sections demonstrated ulceration as well as acantholysis and necrosis of keratinocytes with multinucleation and margination of chromatin. There was an intense lichenoid and perivascular lymphocytic infiltrate in the dermis. Immunohistochemistry staining was positive for VZV and negative for HSV, indicating acute reactivation of VZV (Figure 3). Upon completion of an antiviral regimen, the patient returned to clinic with healed crusted lesions.

Comment

Frequently, the clinical features of HZ in immunocompromised patients mirror those in immunocompetent hosts.⁸ However, each of our 2 patients developed an unusual presentation of atypical generalized HZ.⁷ In this clinical variant, lesions develop along a single dermatome, then a diffuse vesicular eruption subsequently develops without dermatomal localization. These lesions can be chronic, persisting for months or years.⁷

The classic clinical presentation of HZ is distinct and often is readily diagnosed by visual inspection.⁷ However, atypical presentations and their associated complications can pose diagnostic and therapeutic challenges.⁷ Painless HZ lesions in a nondermatomal pattern were described in a patient who also had AIDS.⁹ Interestingly, multiple reports have found that patients with a severe but painless rash are less likely to have experienced a viral prodrome consisting of hyperesthesia, paresthesia, or pruritus.^2,10 This observation suggests that lack of a prodrome, as in the case of patient 1 in our report, may aid in the recognition of painless HZ. Because of these atypical presentations, laboratory testing is even more important than in immunocompetent hosts, as diagnosis may be more difficult to establish on clinical presentation alone.

Several studies^11-32 have evaluated modalities for treatment and prophylaxis for disseminated HZ in immunocompromised hosts, given its increased risk and potentially fatal complications in this population. The current guidelines in patients with HIV/AIDS, solid organ transplantation (SOT), and hematopoietic stem cell transplantation (HSCT) are summarized in the eTable.

HIV/AIDS Patients
Given their efficacy and low rate of toxicity, oral acyclovir, valacyclovir, and famciclovir are recommended treatment options for HIV patients with localized, mild, dermatomal HZ.¹¹ Two exceptions include HZ ophthalmicus and Ramsay Hunt syndrome for which some experts recommend intravenous acyclovir given the risk for vision loss and facial palsy, respectively. Intravenous acyclovir often is the drug of choice for treating complicated, disseminated, or severe HZ in HIV-infected patients, though prospective efficacy data remain limited.¹¹

With regard to prevention of infection, a large randomized trial in 2016 found that acyclovir prophylaxis resulted in a 68% reduction in HZ over 2 years among HIV patients.¹² Despite data that acyclovir may be effective for this purpose, long-term antiviral prophylaxis is not routinely recommended for HZ,^11,13 as it has been linked to rare cases of acyclovir-resistant HZ in HIV patients.^14,15 However, antiviral prophylaxis against HSV type 2 reactivation in HIV patients also confers protection against VZV reactivation.^11,12

Solid Organ Transplantation
Localized, mild to moderately severe dermatomal HZ can be treated with oral acyclovir, valacyclovir, or famciclovir. As in HIV patients, SOT patients with severe, disseminated, or complicated HZ should receive IV acyclovir.¹¹ In the first 3 to 6 months following the procedure, SOT patients receive cytomegalovirus prophylaxis with ganciclovir or valgan-ciclovir, which also provides protection against HZ.^13-18 For patients not receiving cytomegalovirus prophylaxis, HSV prophylaxis with oral acyclovir or valacyclovir is given for at least the first month after transplantation, which also confers protection against HZ.^16,19 Antiviral therapy is critical during the early posttransplantation period when patients are most severely immunosuppressed and thus have the highest risk for VZV-associated complications.²⁰ Although immunosuppression is lifelong in most SOT recipients, there is insufficient evidence for extending prophylaxis beyond 6 months.^16,21

As a possible risk factor for HZ,²² MMF use is another consideration among SOT patients, similar to patient 2 in our report. A 2003 observational study supported withdrawal of MMF therapy during active VZV infection due to clinical observation of an association with HZ.²³ However, a multicenter, randomized, controlled trial reported no cases of HZ in renal transplant recipients on MMF.²⁴ Additionally, MMF has been observed to enhance the antiviral activity of acyclovir, at least in vitro.²⁵ Given the lack of evidence of MMF as a risk factor for HZ, there is insufficient evidence for cessation of use during VZVreactivation in SOT patients.

Hematopoietic Stem Cell Transplantation
The preferred agents for treatment of localized mild dermatomal HZ are oral acyclovir or valacyclovir, as data on the safety and efficacy of famciclovir among HSCT recipients are limited.^13,26 Patients should receive antiviral prophylaxis with one of these agents during the first year following allogeneic or autologous HSCT. This 1-year course has proven highly effective in reducing HZ in the first year following transplantation when most severe cases occur,^21,26-29 and it has been associated with a persistently decreased risk for HZ even after discontinuation.²¹ Prophylaxis may be continued beyond 1 year in allogeneic HSCT recipients experiencing graft-versus-host disease who should receive acyclovir until 6 months after the end of immunosuppressive therapy.^21,26

Vaccination remains a potential strategy to reduce the incidence of HZ in this patient population. A heat-inactivated vaccine administered within the first 3 months after the procedure has been shown to be safe among autologous and allogeneic HSCT patients.^30,31 The vaccine notably reduced the incidence of HZ in patients who underwent autologous HSCT,³² but no known data are available on its clinical efficacy in allogeneic HSCT patients. Accordingly, there are no known official recommendations to date regarding vaccine use in these patient populations.²⁶

Conclusion

It is incumbent upon clinicians to recognize the spectrum of atypical presentations of HZ and maintain a low threshold for performing appropriate diagnostic or confirmatory studies among at-risk patients with impaired immune function. Disseminated HZ can have potentially life-threatening visceral complications such as encephalitis, hepatitis, or pneumonitis.^7,8 As such, an understanding of prevention and treatment modalities for VZV infection among immunocompromised patients is critical. Because the morbidity associated with complications of VZV infection is substantial and the risks associated with antiviral agents are minimal, antiviral prophylaxis is recommended for 6 months following SOT or 1 year following HSCT, and prompt treatment is warranted in cases of reasonable clinical suspicion for HZ.

Acknowledgment
The authors gratefully acknowledge the generosity of our patients in permitting photography of their skin findings for the furthering of medical education.

Well-known for its typical presentation, classic herpes zoster (HZ) presents as a dermatomal eruption of painful erythematous papules that evolve into grouped vesicles or bullae.^1,2 Thereafter, the lesions can become pustular or hemorrhagic.¹ Although the diagnosis most often is made clinically, confirmatory techniques for diagnosis include viral culture, direct fluorescent antibody testing, or polymerase chain reaction (PCR) assay.^1,3

The main risk factor for HZ is advanced age, most commonly affecting elderly patients.⁴ It is hypothesized that a physiological decline in varicella-zoster virus (VZV)–specific cell-mediated immunity among elderly individuals helps trigger reactivation of the virus within the dorsal root ganglion.^1,5 Similarly affected are immunocompromised individuals, including those with human immunodeficiency virus (HIV) infection, due to suppression of T cells immune to VZV,^1,5 as well as immunosuppressed transplant recipients who have diminished VZV-specific cellular responses and VZV IgG antibody avidity.⁶

Secondary complications of VZV infection (eg, postherpetic neuralgia, bacterial superinfection progressing to cellulitis) lead to increased morbidity.^7,8 Disseminated cutaneous HZ is another grave complication of VZV infection and almost exclusively occurs with immunosuppression.^1,8 It manifests as an eruption of at least 20 widespread vesiculobullous lesions outside the primary and adjacent dermatomes.⁶ Immunocompromised patients also are at increased risk for visceral involvement of VZV infection, which may affect vital organs such as the brain, liver, or lungs.^7,8 Given the atypical presentation of VZV infection among some immunocompromised individuals, these patients are at increased risk for diagnostic delay and morbidity in the absence of high clinical suspicion for disseminated HZ.

Case Reports

Patient 1
A 52-year-old man developed a painless nonpruritic rash on the left leg of 4 days’ duration. It initially appeared as an erythematous maculopapular rash on the medial aspect of the left knee without any prodromal symptoms. Over the next 4 days, erythematous vesicles developed that progressed to pustules, and the rash spread both proximally and distally along the left leg. Shortly following hospital admission, he developed a fever (temperature, 38.4°C). His medical history included alcoholic liver cirrhosis and AIDS, with a CD4 count of 174 cells/µL (reference range, 500–1500 cells/µL). He had been taking antiretroviral therapy (abacavir-lamivudine and dolutegravir) and prophylaxis against opportunistic infections (dapsone and itraconazole).

Physical examination was remarkable for an extensive rash consisting of multiple 1-cm clusters of approximately 40 pustules each scattered in a nondermatomal distribution along the left leg (Figure 1). Many of the vesicles were confluent with an erythematous base and were in different stages of evolution with some crusted and others emanating a thin liquid exudate. The lesions were nontender and without notable induration. The leg was warm and edematous.

Clinically, the differential diagnosis included disseminated HZ with bacterial superinfection, Vibrio vulnificus infection, and herpes simplex virus (HSV) infection. The patient was treated with intravenous vancomycin, levofloxacin, and acyclovir, and no new lesions developed throughout the course of treatment. On this regimen, his fever resolved after 1 day, the active lesions began to crust, and the edema and erythema diminished. Results of bacterial cultures and plasma PCR and IgM for HSV types 1 and 2 were negative. Viral culture results were negative, but a PCR assay for VZV was positive, reflective of acute reactivation of VZV.

Patient 2
A 63-year-old man developed a pruritic burning rash involving the face, trunk, arms, and legs of 6 days’ duration. His medical history included a heart transplant 6 months prior to presentation, type 2 diabetes mellitus, and chronic kidney disease. He was taking antirejection therapy with mycophenolate mofetil (MMF), prednisone, and tacrolimus.

Physical examination was remarkable for an extensive rash consisting of clusters of 1- to 2-mm vesicles scattered in a nondermatomal pattern. Isolated vesicles involved the forehead, nose, and left ear, and diffuse vesicles with a relatively symmetric distribution were scattered across the back, chest, and proximal and distal arms and legs (Figure 2). Many of the vesicles had an associated overlying crust with hemorrhage. Some of the vesicles coalesced with central necrotic plaques.

Given a clinical suspicion for disseminated HZ, therapy with oral valacyclovir was initiated. Two punch biopsies were consistent with herpesvirus cytopathic changes. Multiple sections demonstrated ulceration as well as acantholysis and necrosis of keratinocytes with multinucleation and margination of chromatin. There was an intense lichenoid and perivascular lymphocytic infiltrate in the dermis. Immunohistochemistry staining was positive for VZV and negative for HSV, indicating acute reactivation of VZV (Figure 3). Upon completion of an antiviral regimen, the patient returned to clinic with healed crusted lesions.

Comment

Frequently, the clinical features of HZ in immunocompromised patients mirror those in immunocompetent hosts.⁸ However, each of our 2 patients developed an unusual presentation of atypical generalized HZ.⁷ In this clinical variant, lesions develop along a single dermatome, then a diffuse vesicular eruption subsequently develops without dermatomal localization. These lesions can be chronic, persisting for months or years.⁷

The classic clinical presentation of HZ is distinct and often is readily diagnosed by visual inspection.⁷ However, atypical presentations and their associated complications can pose diagnostic and therapeutic challenges.⁷ Painless HZ lesions in a nondermatomal pattern were described in a patient who also had AIDS.⁹ Interestingly, multiple reports have found that patients with a severe but painless rash are less likely to have experienced a viral prodrome consisting of hyperesthesia, paresthesia, or pruritus.^2,10 This observation suggests that lack of a prodrome, as in the case of patient 1 in our report, may aid in the recognition of painless HZ. Because of these atypical presentations, laboratory testing is even more important than in immunocompetent hosts, as diagnosis may be more difficult to establish on clinical presentation alone.

Several studies^11-32 have evaluated modalities for treatment and prophylaxis for disseminated HZ in immunocompromised hosts, given its increased risk and potentially fatal complications in this population. The current guidelines in patients with HIV/AIDS, solid organ transplantation (SOT), and hematopoietic stem cell transplantation (HSCT) are summarized in the eTable.

HIV/AIDS Patients
Given their efficacy and low rate of toxicity, oral acyclovir, valacyclovir, and famciclovir are recommended treatment options for HIV patients with localized, mild, dermatomal HZ.¹¹ Two exceptions include HZ ophthalmicus and Ramsay Hunt syndrome for which some experts recommend intravenous acyclovir given the risk for vision loss and facial palsy, respectively. Intravenous acyclovir often is the drug of choice for treating complicated, disseminated, or severe HZ in HIV-infected patients, though prospective efficacy data remain limited.¹¹

With regard to prevention of infection, a large randomized trial in 2016 found that acyclovir prophylaxis resulted in a 68% reduction in HZ over 2 years among HIV patients.¹² Despite data that acyclovir may be effective for this purpose, long-term antiviral prophylaxis is not routinely recommended for HZ,^11,13 as it has been linked to rare cases of acyclovir-resistant HZ in HIV patients.^14,15 However, antiviral prophylaxis against HSV type 2 reactivation in HIV patients also confers protection against VZV reactivation.^11,12

Solid Organ Transplantation
Localized, mild to moderately severe dermatomal HZ can be treated with oral acyclovir, valacyclovir, or famciclovir. As in HIV patients, SOT patients with severe, disseminated, or complicated HZ should receive IV acyclovir.¹¹ In the first 3 to 6 months following the procedure, SOT patients receive cytomegalovirus prophylaxis with ganciclovir or valgan-ciclovir, which also provides protection against HZ.^13-18 For patients not receiving cytomegalovirus prophylaxis, HSV prophylaxis with oral acyclovir or valacyclovir is given for at least the first month after transplantation, which also confers protection against HZ.^16,19 Antiviral therapy is critical during the early posttransplantation period when patients are most severely immunosuppressed and thus have the highest risk for VZV-associated complications.²⁰ Although immunosuppression is lifelong in most SOT recipients, there is insufficient evidence for extending prophylaxis beyond 6 months.^16,21

As a possible risk factor for HZ,²² MMF use is another consideration among SOT patients, similar to patient 2 in our report. A 2003 observational study supported withdrawal of MMF therapy during active VZV infection due to clinical observation of an association with HZ.²³ However, a multicenter, randomized, controlled trial reported no cases of HZ in renal transplant recipients on MMF.²⁴ Additionally, MMF has been observed to enhance the antiviral activity of acyclovir, at least in vitro.²⁵ Given the lack of evidence of MMF as a risk factor for HZ, there is insufficient evidence for cessation of use during VZVreactivation in SOT patients.

Hematopoietic Stem Cell Transplantation
The preferred agents for treatment of localized mild dermatomal HZ are oral acyclovir or valacyclovir, as data on the safety and efficacy of famciclovir among HSCT recipients are limited.^13,26 Patients should receive antiviral prophylaxis with one of these agents during the first year following allogeneic or autologous HSCT. This 1-year course has proven highly effective in reducing HZ in the first year following transplantation when most severe cases occur,^21,26-29 and it has been associated with a persistently decreased risk for HZ even after discontinuation.²¹ Prophylaxis may be continued beyond 1 year in allogeneic HSCT recipients experiencing graft-versus-host disease who should receive acyclovir until 6 months after the end of immunosuppressive therapy.^21,26

Vaccination remains a potential strategy to reduce the incidence of HZ in this patient population. A heat-inactivated vaccine administered within the first 3 months after the procedure has been shown to be safe among autologous and allogeneic HSCT patients.^30,31 The vaccine notably reduced the incidence of HZ in patients who underwent autologous HSCT,³² but no known data are available on its clinical efficacy in allogeneic HSCT patients. Accordingly, there are no known official recommendations to date regarding vaccine use in these patient populations.²⁶

Conclusion

It is incumbent upon clinicians to recognize the spectrum of atypical presentations of HZ and maintain a low threshold for performing appropriate diagnostic or confirmatory studies among at-risk patients with impaired immune function. Disseminated HZ can have potentially life-threatening visceral complications such as encephalitis, hepatitis, or pneumonitis.^7,8 As such, an understanding of prevention and treatment modalities for VZV infection among immunocompromised patients is critical. Because the morbidity associated with complications of VZV infection is substantial and the risks associated with antiviral agents are minimal, antiviral prophylaxis is recommended for 6 months following SOT or 1 year following HSCT, and prompt treatment is warranted in cases of reasonable clinical suspicion for HZ.

Acknowledgment
The authors gratefully acknowledge the generosity of our patients in permitting photography of their skin findings for the furthering of medical education.

To the Editor:

We present a case of Mycobacterium chelonae-abscessus cutaneous infection in a sporotrichoid pattern, a rare presentation most often found in immunocompromised patients. A 34-year-old man with lupus nephritis who was taking oral prednisone, mycophenolate mofetil, and hydroxychloroquine presented with multiple erythematous fluctuant nodules and plaques on the left volar forearm in a sporotrichoid pattern of 3 months’ duration (Figure, A). He denied recent travel, exposure to fish or fish tanks, and penetrating wounds. Punch biopsy showed granulomatous inflammation and scarring with negative tissue cultures. Repeat biopsies and cultures were obtained when the lesions increased in number over 2 months.

Final biopsy showed upper dermal granulomatous inflammation with karyorrhectic debris, suggesting infection, and acid-fast bacilli. Culture grew M chelonae-abscessus on Löwenstein-Jensen agar at 37°C and blood culture media from which the complex was identified using high-performance liquid chromatography. Empiric therapy with renal dosing based on the Infectious Diseases Society of America statement of susceptibilities¹ was initiated with clarithromycin, doxycycline, and ciprofloxacin for 4 months. Furthermore, the prednisone dose was tapered to 7.5 mg daily. Two months later, the lesions regressed and ciprofloxacin was discontinued (Figure, B).

The sporotrichoid spread of nodules suggests infection with mycobacteria, Sporothrix schenckii, Leishmania, Francisella tularensis, or Nocardia. Most cultures for nontuberculous mycobacteria will grow on Löwenstein-Jensen agar between 28°C and 37°C. Runyon rapidly growing (group IV) mycobacteria are defined by their ubiquitous presence in the environment and ability to develop colonies in 7 days.² Cutaneous infections are increasing in prevalence, as reported in a retrospective study spanning nearly 30 years.³ The presentation is variable but often includes the distal extremities and usually is a nodule, ulcer, or abscess at a single site; a sporotrichoid pattern is more rare. Preceding skin trauma is the major risk factor for immunocompetent hosts, and the infection can spontaneously resolve in 8 to 12 months.¹ In contrast, immunosuppressed patients may have no known source of infection and often have a progressive course with an increasing number of lesions and increased time until clearance.⁴

It is difficult to differentiate M chelonae and M abscessus based on growth characteristics, and they share the same 16S ribosomal RNA sequence commonly used to differentiate other mycobacterial species.²Mycobacterium abscessus can be more difficult to treat, thus distinction via polymerase chain reaction of the heat-shock protein 65 gene, hsp65, can be valuable in cases recalcitrant to initial therapy.¹

The likelihood of M chelonae and M abscessus isolates to be initially sensitive to clarithromycin is 100%,¹ and this antibiotic remains the cornerstone of therapy. A clinical trial of treatments for M chelonae-abscessus found that clarithromycin monotherapy can be successful or complicated by resistance⁵; therefore, multidrug therapy is recommended. The antibiotic regimen for our patient was chosen to limit renal toxicity.

In summary, we report a case of M chelonae-abscessus cutaneous infection in a sporotrichoid pattern in a patient with lupus nephritis on immunosuppressive drugs. As the incidence of rapidly growing mycobacterial cutaneous infections rises, dermatologists must be aware of this pattern of infection.

To the Editor:

We present a case of Mycobacterium chelonae-abscessus cutaneous infection in a sporotrichoid pattern, a rare presentation most often found in immunocompromised patients. A 34-year-old man with lupus nephritis who was taking oral prednisone, mycophenolate mofetil, and hydroxychloroquine presented with multiple erythematous fluctuant nodules and plaques on the left volar forearm in a sporotrichoid pattern of 3 months’ duration (Figure, A). He denied recent travel, exposure to fish or fish tanks, and penetrating wounds. Punch biopsy showed granulomatous inflammation and scarring with negative tissue cultures. Repeat biopsies and cultures were obtained when the lesions increased in number over 2 months.

Final biopsy showed upper dermal granulomatous inflammation with karyorrhectic debris, suggesting infection, and acid-fast bacilli. Culture grew M chelonae-abscessus on Löwenstein-Jensen agar at 37°C and blood culture media from which the complex was identified using high-performance liquid chromatography. Empiric therapy with renal dosing based on the Infectious Diseases Society of America statement of susceptibilities¹ was initiated with clarithromycin, doxycycline, and ciprofloxacin for 4 months. Furthermore, the prednisone dose was tapered to 7.5 mg daily. Two months later, the lesions regressed and ciprofloxacin was discontinued (Figure, B).

The sporotrichoid spread of nodules suggests infection with mycobacteria, Sporothrix schenckii, Leishmania, Francisella tularensis, or Nocardia. Most cultures for nontuberculous mycobacteria will grow on Löwenstein-Jensen agar between 28°C and 37°C. Runyon rapidly growing (group IV) mycobacteria are defined by their ubiquitous presence in the environment and ability to develop colonies in 7 days.² Cutaneous infections are increasing in prevalence, as reported in a retrospective study spanning nearly 30 years.³ The presentation is variable but often includes the distal extremities and usually is a nodule, ulcer, or abscess at a single site; a sporotrichoid pattern is more rare. Preceding skin trauma is the major risk factor for immunocompetent hosts, and the infection can spontaneously resolve in 8 to 12 months.¹ In contrast, immunosuppressed patients may have no known source of infection and often have a progressive course with an increasing number of lesions and increased time until clearance.⁴

It is difficult to differentiate M chelonae and M abscessus based on growth characteristics, and they share the same 16S ribosomal RNA sequence commonly used to differentiate other mycobacterial species.²Mycobacterium abscessus can be more difficult to treat, thus distinction via polymerase chain reaction of the heat-shock protein 65 gene, hsp65, can be valuable in cases recalcitrant to initial therapy.¹

The likelihood of M chelonae and M abscessus isolates to be initially sensitive to clarithromycin is 100%,¹ and this antibiotic remains the cornerstone of therapy. A clinical trial of treatments for M chelonae-abscessus found that clarithromycin monotherapy can be successful or complicated by resistance⁵; therefore, multidrug therapy is recommended. The antibiotic regimen for our patient was chosen to limit renal toxicity.

In summary, we report a case of M chelonae-abscessus cutaneous infection in a sporotrichoid pattern in a patient with lupus nephritis on immunosuppressive drugs. As the incidence of rapidly growing mycobacterial cutaneous infections rises, dermatologists must be aware of this pattern of infection.

To the Editor:

We present a case of Mycobacterium chelonae-abscessus cutaneous infection in a sporotrichoid pattern, a rare presentation most often found in immunocompromised patients. A 34-year-old man with lupus nephritis who was taking oral prednisone, mycophenolate mofetil, and hydroxychloroquine presented with multiple erythematous fluctuant nodules and plaques on the left volar forearm in a sporotrichoid pattern of 3 months’ duration (Figure, A). He denied recent travel, exposure to fish or fish tanks, and penetrating wounds. Punch biopsy showed granulomatous inflammation and scarring with negative tissue cultures. Repeat biopsies and cultures were obtained when the lesions increased in number over 2 months.

Final biopsy showed upper dermal granulomatous inflammation with karyorrhectic debris, suggesting infection, and acid-fast bacilli. Culture grew M chelonae-abscessus on Löwenstein-Jensen agar at 37°C and blood culture media from which the complex was identified using high-performance liquid chromatography. Empiric therapy with renal dosing based on the Infectious Diseases Society of America statement of susceptibilities¹ was initiated with clarithromycin, doxycycline, and ciprofloxacin for 4 months. Furthermore, the prednisone dose was tapered to 7.5 mg daily. Two months later, the lesions regressed and ciprofloxacin was discontinued (Figure, B).

The sporotrichoid spread of nodules suggests infection with mycobacteria, Sporothrix schenckii, Leishmania, Francisella tularensis, or Nocardia. Most cultures for nontuberculous mycobacteria will grow on Löwenstein-Jensen agar between 28°C and 37°C. Runyon rapidly growing (group IV) mycobacteria are defined by their ubiquitous presence in the environment and ability to develop colonies in 7 days.² Cutaneous infections are increasing in prevalence, as reported in a retrospective study spanning nearly 30 years.³ The presentation is variable but often includes the distal extremities and usually is a nodule, ulcer, or abscess at a single site; a sporotrichoid pattern is more rare. Preceding skin trauma is the major risk factor for immunocompetent hosts, and the infection can spontaneously resolve in 8 to 12 months.¹ In contrast, immunosuppressed patients may have no known source of infection and often have a progressive course with an increasing number of lesions and increased time until clearance.⁴

It is difficult to differentiate M chelonae and M abscessus based on growth characteristics, and they share the same 16S ribosomal RNA sequence commonly used to differentiate other mycobacterial species.²Mycobacterium abscessus can be more difficult to treat, thus distinction via polymerase chain reaction of the heat-shock protein 65 gene, hsp65, can be valuable in cases recalcitrant to initial therapy.¹

The likelihood of M chelonae and M abscessus isolates to be initially sensitive to clarithromycin is 100%,¹ and this antibiotic remains the cornerstone of therapy. A clinical trial of treatments for M chelonae-abscessus found that clarithromycin monotherapy can be successful or complicated by resistance⁵; therefore, multidrug therapy is recommended. The antibiotic regimen for our patient was chosen to limit renal toxicity.

In summary, we report a case of M chelonae-abscessus cutaneous infection in a sporotrichoid pattern in a patient with lupus nephritis on immunosuppressive drugs. As the incidence of rapidly growing mycobacterial cutaneous infections rises, dermatologists must be aware of this pattern of infection.