Herpes Simplex May Be Culprit in Cutaneous Graft-Vs.-Host Disease

SEOUL, SOUTH KOREA – Acute cutaneous graft-versus-host disease in stem cell transplant recipients may be a manifestation of herpes simplex virus–associated erythema multiforme.

This novel hypothesis is supported by a chain of scientific evidence backed by a plausible mechanism of action, said Laure Aurelian, Ph.D., at the World Congress of Dermatology. And, if the hypothesis is correct, the implications for clinical practice will be significant.

"Viral etiology, we believe, should be seriously considered in the management of patients with graft-versus-host disease [GVHD] in the skin, because the way they are treated now – with acyclovir after stem cell transplantation has occurred – is definitely not helpful. If we are correct, then initiating the antiviral therapy earlier, and probably by IV, is the right way to go," said Dr. Aurelian of the University of Maryland, Baltimore.

After stem cell transplantation, the standard practice of initiating oral acyclovir at 800 mg twice daily starting on day 3 post procedure to preemptively quell the immunosuppression-triggered reactivation of latent herpes simplex virus (HSV) infection is too late, she said. "This standard of care is obviously not helping," given how often acute GVHD occurs.

In earlier work, Dr. Aurelian and her colleagues demonstrated that circulating CD34+ stem cells play a key role in HSV-associated erythema multiforme in patients without cancer. They showed that these stem cells, when infected by the virus, fragment the viral DNA and transport the HSV DNA polymerase gene, known as Pol, to distant sites in the skin.

The hallmarks of HSV-associated erythema multiforme, Dr. Aurelian said, are the presence and expression of Pol in lesional skin and in circulating CD34+ stem cells, which are increased in number in peripheral blood during acute episodes.

More recently, the investigators showed that acute GVHD of the skin following stem cell transplantation for hematologic malignancies closely resembles HSV-associated erythema multiforme clinically, histologically, and at the molecular level. In fact, acute skin GVHD is actually an erythema multiforme–reactive dermatosis involving HSV, Dr. Aurelian noted.

Clinically, acute cutaneous GVHD and HSV-associated erythema multiforme are characterized by bilaterally symmetrical, erythematous, maculopapular eruptions with a predilection for acral areas.

The minimal histopathologic criteria for acute skin GVHD also resemble those for erythema multiforme, including the finding of apoptotic cells in the epidermal basal layer, the outer root sheath of the hair follicle, and the lower malpighian layer.

In a recent study, the investigators found that lesional skin biopsies expressed Pol in 15 of 19 patients with acute skin GVHD beginning 3-15 days after stem cell transplantation, in 18 of 25 patients with HSV-associated erythema multiforme following a confirmed recurrence of HSV, and in none of 20 patients with drug-induced bullous erythema multiforme unrelated to HSV infection. None of the skin lesions from patients with GVHD or HSV-associated erythema multiforme expressed the VP5 antigen, indicating the absence of HSV viral replication.

The severity of GVHD as reflected in the amount of involved body surface area strongly correlates with the number of lesional cells expressing the Pol antigen, she added.

Dr. Aurelian proposed the following scenario regarding the pathogenesis of acute cutaneous GVHD: Patients undergoing stem cell transplant for hematologic malignancies are immunosuppressed beforehand, often resulting in reactivation of a latent HSV infection. After the stem cell transplant, a large influx of the CD34+ stem cells, which are infected by HSV, fragment HSV DNA and transport these fragments – most notably, Pol – to distant cutaneous sites. Pol expression in the skin triggers lesion development by recruiting interferon-gamma–producing virus-specific CD4+ helper T cells. An inflammatory cascade follows, and after the onset of skin lesions, a population of auto-reactive T cells accumulates.

"Basically, what begins as a viral disease turns into an autoimmune disease," the researcher explained.

Dr. Aurelian emphasized that while the skin lesions of acute GVHD contain the molecular markers of HSV-associated erythema multiforme, that’s not necessarily the case for GVHD affecting other organs.

She and her coworkers have found, for example, that intestinal biopsies obtained from patients with GVHD of the colon are consistently negative for HSV DNA fragments.

"So there is real [GVHD] in certain organs, and in our opinion there is a skin lesion that is actually an erythema multiforme reactive dermatosis associated with HSV infection," she said.

Dr. Aurelian declared having no financial conflicts of interest.

SEOUL, SOUTH KOREA – Acute cutaneous graft-versus-host disease in stem cell transplant recipients may be a manifestation of herpes simplex virus–associated erythema multiforme.

This novel hypothesis is supported by a chain of scientific evidence backed by a plausible mechanism of action, said Laure Aurelian, Ph.D., at the World Congress of Dermatology. And, if the hypothesis is correct, the implications for clinical practice will be significant.

"Viral etiology, we believe, should be seriously considered in the management of patients with graft-versus-host disease [GVHD] in the skin, because the way they are treated now – with acyclovir after stem cell transplantation has occurred – is definitely not helpful. If we are correct, then initiating the antiviral therapy earlier, and probably by IV, is the right way to go," said Dr. Aurelian of the University of Maryland, Baltimore.

After stem cell transplantation, the standard practice of initiating oral acyclovir at 800 mg twice daily starting on day 3 post procedure to preemptively quell the immunosuppression-triggered reactivation of latent herpes simplex virus (HSV) infection is too late, she said. "This standard of care is obviously not helping," given how often acute GVHD occurs.

In earlier work, Dr. Aurelian and her colleagues demonstrated that circulating CD34+ stem cells play a key role in HSV-associated erythema multiforme in patients without cancer. They showed that these stem cells, when infected by the virus, fragment the viral DNA and transport the HSV DNA polymerase gene, known as Pol, to distant sites in the skin.

The hallmarks of HSV-associated erythema multiforme, Dr. Aurelian said, are the presence and expression of Pol in lesional skin and in circulating CD34+ stem cells, which are increased in number in peripheral blood during acute episodes.

More recently, the investigators showed that acute GVHD of the skin following stem cell transplantation for hematologic malignancies closely resembles HSV-associated erythema multiforme clinically, histologically, and at the molecular level. In fact, acute skin GVHD is actually an erythema multiforme–reactive dermatosis involving HSV, Dr. Aurelian noted.

Clinically, acute cutaneous GVHD and HSV-associated erythema multiforme are characterized by bilaterally symmetrical, erythematous, maculopapular eruptions with a predilection for acral areas.

The minimal histopathologic criteria for acute skin GVHD also resemble those for erythema multiforme, including the finding of apoptotic cells in the epidermal basal layer, the outer root sheath of the hair follicle, and the lower malpighian layer.

In a recent study, the investigators found that lesional skin biopsies expressed Pol in 15 of 19 patients with acute skin GVHD beginning 3-15 days after stem cell transplantation, in 18 of 25 patients with HSV-associated erythema multiforme following a confirmed recurrence of HSV, and in none of 20 patients with drug-induced bullous erythema multiforme unrelated to HSV infection. None of the skin lesions from patients with GVHD or HSV-associated erythema multiforme expressed the VP5 antigen, indicating the absence of HSV viral replication.

The severity of GVHD as reflected in the amount of involved body surface area strongly correlates with the number of lesional cells expressing the Pol antigen, she added.

Dr. Aurelian proposed the following scenario regarding the pathogenesis of acute cutaneous GVHD: Patients undergoing stem cell transplant for hematologic malignancies are immunosuppressed beforehand, often resulting in reactivation of a latent HSV infection. After the stem cell transplant, a large influx of the CD34+ stem cells, which are infected by HSV, fragment HSV DNA and transport these fragments – most notably, Pol – to distant cutaneous sites. Pol expression in the skin triggers lesion development by recruiting interferon-gamma–producing virus-specific CD4+ helper T cells. An inflammatory cascade follows, and after the onset of skin lesions, a population of auto-reactive T cells accumulates.

"Basically, what begins as a viral disease turns into an autoimmune disease," the researcher explained.

Dr. Aurelian emphasized that while the skin lesions of acute GVHD contain the molecular markers of HSV-associated erythema multiforme, that’s not necessarily the case for GVHD affecting other organs.

She and her coworkers have found, for example, that intestinal biopsies obtained from patients with GVHD of the colon are consistently negative for HSV DNA fragments.

"So there is real [GVHD] in certain organs, and in our opinion there is a skin lesion that is actually an erythema multiforme reactive dermatosis associated with HSV infection," she said.

Dr. Aurelian declared having no financial conflicts of interest.

SEOUL, SOUTH KOREA – Acute cutaneous graft-versus-host disease in stem cell transplant recipients may be a manifestation of herpes simplex virus–associated erythema multiforme.

This novel hypothesis is supported by a chain of scientific evidence backed by a plausible mechanism of action, said Laure Aurelian, Ph.D., at the World Congress of Dermatology. And, if the hypothesis is correct, the implications for clinical practice will be significant.

"Viral etiology, we believe, should be seriously considered in the management of patients with graft-versus-host disease [GVHD] in the skin, because the way they are treated now – with acyclovir after stem cell transplantation has occurred – is definitely not helpful. If we are correct, then initiating the antiviral therapy earlier, and probably by IV, is the right way to go," said Dr. Aurelian of the University of Maryland, Baltimore.

After stem cell transplantation, the standard practice of initiating oral acyclovir at 800 mg twice daily starting on day 3 post procedure to preemptively quell the immunosuppression-triggered reactivation of latent herpes simplex virus (HSV) infection is too late, she said. "This standard of care is obviously not helping," given how often acute GVHD occurs.

In earlier work, Dr. Aurelian and her colleagues demonstrated that circulating CD34+ stem cells play a key role in HSV-associated erythema multiforme in patients without cancer. They showed that these stem cells, when infected by the virus, fragment the viral DNA and transport the HSV DNA polymerase gene, known as Pol, to distant sites in the skin.

The hallmarks of HSV-associated erythema multiforme, Dr. Aurelian said, are the presence and expression of Pol in lesional skin and in circulating CD34+ stem cells, which are increased in number in peripheral blood during acute episodes.

More recently, the investigators showed that acute GVHD of the skin following stem cell transplantation for hematologic malignancies closely resembles HSV-associated erythema multiforme clinically, histologically, and at the molecular level. In fact, acute skin GVHD is actually an erythema multiforme–reactive dermatosis involving HSV, Dr. Aurelian noted.

Clinically, acute cutaneous GVHD and HSV-associated erythema multiforme are characterized by bilaterally symmetrical, erythematous, maculopapular eruptions with a predilection for acral areas.

The minimal histopathologic criteria for acute skin GVHD also resemble those for erythema multiforme, including the finding of apoptotic cells in the epidermal basal layer, the outer root sheath of the hair follicle, and the lower malpighian layer.

In a recent study, the investigators found that lesional skin biopsies expressed Pol in 15 of 19 patients with acute skin GVHD beginning 3-15 days after stem cell transplantation, in 18 of 25 patients with HSV-associated erythema multiforme following a confirmed recurrence of HSV, and in none of 20 patients with drug-induced bullous erythema multiforme unrelated to HSV infection. None of the skin lesions from patients with GVHD or HSV-associated erythema multiforme expressed the VP5 antigen, indicating the absence of HSV viral replication.

The severity of GVHD as reflected in the amount of involved body surface area strongly correlates with the number of lesional cells expressing the Pol antigen, she added.

Dr. Aurelian proposed the following scenario regarding the pathogenesis of acute cutaneous GVHD: Patients undergoing stem cell transplant for hematologic malignancies are immunosuppressed beforehand, often resulting in reactivation of a latent HSV infection. After the stem cell transplant, a large influx of the CD34+ stem cells, which are infected by HSV, fragment HSV DNA and transport these fragments – most notably, Pol – to distant cutaneous sites. Pol expression in the skin triggers lesion development by recruiting interferon-gamma–producing virus-specific CD4+ helper T cells. An inflammatory cascade follows, and after the onset of skin lesions, a population of auto-reactive T cells accumulates.

"Basically, what begins as a viral disease turns into an autoimmune disease," the researcher explained.

Dr. Aurelian emphasized that while the skin lesions of acute GVHD contain the molecular markers of HSV-associated erythema multiforme, that’s not necessarily the case for GVHD affecting other organs.

She and her coworkers have found, for example, that intestinal biopsies obtained from patients with GVHD of the colon are consistently negative for HSV DNA fragments.

"So there is real [GVHD] in certain organs, and in our opinion there is a skin lesion that is actually an erythema multiforme reactive dermatosis associated with HSV infection," she said.

Dr. Aurelian declared having no financial conflicts of interest.