Herpes Simplex Virus-associated Erythema Multiforme in Prepubertal Children
Purpose.—Erythema multiforme (EM) is a condition characterized by the sudden appearance of round red papules, some of which develop into target lesions. In most cases, EM is caused by herpes simplex virus (HSV). The clinical features and response to treatment of EM in prepubertal children were analyzed.
Patients.—Participants were 12 children—7 boys and 5 girls—with HSV-associated EM. All were referred by pediatricians. Ten children had a preceding history of herpes labialis or herpes facialis. In 8 cases, HSV was isolated from viral culture from the preceding herpes lesions. In all 12 patients, polymerase chain reaction amplification of DNA from EM skin biopsy specimens showed detectable HSV. Three fourths of the children had recurrent disease, characterized by more than 2 episodes of EM per year. Some patients had recurrences in the spring or after sun exposure, suggesting that ultraviolet light is an important precipitating factor.
Treatment and Outcomes.—Initial treatment with topical acyclovir produced no response in 4 patients. In 6 children, 10 days of oral acyclovir (25 mg/kg/day) given at the start of an episode had no effect on its course. Even with early treatment, EM occurred in every patient. Three patients received 6 months of prophylactic therapy with acyclovir, 20 mg/kg/day. All remained disease free during this period, whereas they had averaged 3.5 episodes during the preceding 6 months. In the 3 years after stopping prophylactic acyclovir, 1 patient had 1 brief recurrence of EM. Another patient had monthly recurrences related to oral corticosteroid treatment. These recurrences ended when the steroid was stopped and prophylactic oral acyclovir was started.
Conclusions.—This experience underscores the importance of HSV in childhood EM. This is a recurrent disorder that may not respond to oral steroids or to oral or topical acyclovir. Once an episode has started, no treatment is effective. Acyclovir prophylaxis may be effective for children with frequent recurrences. After prophylactic treatment, episodes may become less frequent or may stop altogether.
• Schofield et al. have proposed an algorithm for treating adult patients with recurrent EM. First, they suggest a 5-day course of acyclovir for patients who have a clinically obvious precipitating HSV infection. For those in whom HSV infection is not clearly associated with EM, they propose a 6-month course of prophylactic acyclovir therapy. For unresponsive cases they then advocate a trial of either hydroxychloroquine or dapsone, or should these be ineffective, azathioprine.
A Genetically Inactivated Herpes Simplex Virus Type 2 (HSV-2) Vaccine Provides Effective Protection Against Primary and Recurrent HSV-2 Disease
Objective.—Because of the increasing incidence of genital herpes, there is a need for an effective vaccine against primary and recurrent herpes simplex virus (HSV) disease. Toward this end, the investigators have developed a disabled infectious single-cycle (DISC) HSV-2 virus. Because it lacks essential glycoprotein H gene sequences, the virus can complete only 1 replication cycle in normal cells. As such, it should safely stimulate broad humoral and cell-mediated antiviral immune responses. Guinea pig tests of this new HSV-2 vaccine are reported.
Findings.—Tests were performed in a guinea pig model of recurrent HSV-2 infection. Vaccinated animals were completely protected against primary HSV-2 disease. Primary disease was prevented even when the animals were challenged with HSV-2 6 months after vaccination. The vaccine offered good protection against primary disease even when given in low doses. Protection against recurrent disease was nearly complete. Furthermore, vaccination of animals that were already infected with wildtype HSV-2 reduced the symptoms of recurrent disease.
Conclusions.—The DISC HSV-2 vaccine used in this study has given encouraging results in the prevention of primary and recurrent HSV-2 disease. The virus, which was designed specifically for human use, may also be useful for therapeutic purposes to control recurrences in subjects already infected. The DISC HSV-2 is a promising vaccine against HSV disease in humans.
• The approach used by these investigators is highly promising. Hopefully, human studies will confirm the results presented here in animals.
A Rapid Assay to Screen for Drug-resistant Herpes Simplex Virus
Background.—The identification of herpes simplex virus isolates that are resistant to acyclovir and other antiviral drugs has become more important in recent years. Individuals who are immunocompromised rely on specific antiviral therapy, although resistance to antiviral drugs can develop, especially when they are taken for long periods. In this case, the antiviral therapy must be changed in order for the patient to continue to improve.
Findings.—A modified plaque reduction assay was developed. In this assay, the number of plaques seen in the absence of acyclovir was compared to the number of plaques seen in the presence of a single cutoff concentration of acyclovir (2 µg/mL). The cell line used in this assay expresses β-galactosidase only after infection with herpes simplex virus. Small plaques can easily be identified after histochemical staining. For this reason, the assay can be performed on dilutions of untitered specimens in the small wells of a 24-well plate, and the results can be read 2 days after inoculation of the virus.
Discussion.—This newly-developed assay to screen for drug-resistant herpes simplex virus isolates performed well compared to a standard plaque reduction assay. The new assay may be valuable for rapid identification of herpes simplex virus isolates that are resistant to acyclovir and other antiviral agents. With this assay, it may be possible to conduct a study to determine the significance of relative levels of resistant subpopulations and to allow laboratories to notify physicians of the emergence of resistant populations.
• The problem of acyclovir-resistance is by and large restricted to the immunosuppressed population, especially patients with underlying HIV infection, who may be on prophylactic therapy for a protracted period. The methodology described by Tebas et al. offers a distinct advantage over the standard plaque reduction assay for determining drug resistance. With the standard assay, results are usually not available for 7-10 days. By this time, treatment decisions often have already been made.
Congenitally Acquired Herpes Zoster Infection in a Newborn
Introduction.—In early pregnancy, transplacental infection with varicel- la-zoster virus (VZV) can produce congenital abnormalities. A newborn with congenital herpes zoster in 1 dermatome whose mother had VZV at 30 weeks’ gestation is presented.
Case Report.—Male infant, delivered transvaginally at 39 weeks and 3 days of gestation, was observed at birth to have crateriform vesicles without erythema on the left extensor forearm, involving the C7 dermatome. His mother was diagnosed at 30 weeks’ gestation with varicella infection. Her eruptions subsided after 3 weeks of treatment. At birth, the infant’s IgM antibody titer against VZV by the indirect immunofluorescence method was l,280x (normal range, 0-10). He was treated with acyclovir 100 mg/day orally for 5 days and topical vidarabine ointment. On treatment day 20, the vesicles healed without pigmentation.
Conclusion.—Congenital varicella zoster may be acquired by transplacental VZV infection. The estimated interval between transplacental infection and onset of herpes zoster was 11 weeks.
• There have been few reports of congenital herpes zoster infection in newborns. Generally, if infection occurs early in pregnancy, the congenital varicella syndrome may follow with abnormalities of the fetus including cutaneous scars, often, in a dermatomal distribution, as well as limb and eye abnormalities. If varicella-zoster infection occurs late in pregnancy, neonatal varicella may ensue with its occasional disastrous outcome. Previous case reports of congenital herpes zoster have shown an interval between maternal infection and infant infection of about 4 months. In this case, maternal infection occurred 11 weeks before delivery. Congenital herpes zoster, therefore, can be a complication of late maternal varicella infection.
Cost-benefit of Oral Acyclovir in the Treatment of Herpes Zoster
Introduction.—Oral acyclovir is an expensive and effective antiviral agent used in the treatment of herpes zoster. Compared to patients who are elderly or immunocompromised, in patients who are young and healthy, herpes zoster has a rather benign course. The cost benefit of treatment with oral acyclovir was evaluated in young healthy patients with herpes zoster.
Methods.—The medical records of 42 healthy young adult patients with herpes zoster treated with 800 mg of oral acyclovir 5 times daily were compared with those of 40 healthy young adult patients with herpes zoster who did not receive treatment of herpes zoster. Patients were followed for duration of zoster-associated pain and complications.
Results.—There were no significant between-group differences in the duration of zoster-associated pain or complications.
Conclusion.—The cost of a 7-day course of oral acyclovir is $250-$300. This expense is not justified in healthy young adults who experience no decrease in duration of zoster-associated pain or complications, particularly in developing countries with limited resources.
• This study, which shows little benefit from acyclovir treatment of herpes zoster in young adults, contrasts with previous studies that show decreased duration of pain and a decreased incidence of postherpetic neuralgia in older individuals. Given the high cost of treatment, acyclovir or its successors, valacyclovir or famciclovir, can only be recommended in this latter group of individuals.
Human Herpesvirus 8 Variants in Sarcoid Tissues
Background.—Patients with sarcoidosis have noncaseating epithelioid cell granulomas in various tissue types. Although the cause of sarcoidosis is uncertain, mycobacteria may be involved. Sarcoid tissues were studied for the presence of mycobacterial genomic sequences and human herpesvirus 8 (HHV-8).
Methods.—Biopsy samples of various tissues from 17 patients with sarcoidosis were studied: 27 lymph node, 8 transbronchial, 2 skin, and 2 oral mucosa specimens. One hundred thirty-seven samples from 96 patients without sarcoidosis were studied as controls. Polymerase chain reaction techniques were used to determine the presence of HHV-8 and mycobacteria.
Results.—In tissues from all sites, HHV-8 DNA was found significantly more often in sarcoid than in nonsarcoid tissues. Eighty-two percent of specimens that were positive for ORF 26 were also positive for ORF 25. The overall prevalence of HHV-8 ORF 26 was higher in sarcoid tissues than in nonsarcoid tissues. Mycobacterial-like DNA was more likely to be present in sarcoid vs. nonsarcoid specimens of lymph node tissue but not in other types of tissues.
In a masked phase of the study, 8 of 8 patients were positive for HHV-8 ORF 26 DNA compared with just 3 of 56 controls. There were 10 unique HHV-8 ORF 26 sequences, which could be placed into 4 groups according to their peptide motifs. Different HHV-8 sequences were found in 7 of 9 patients, using biopsy samples taken from different sites. Mycobacterialike sequences were found in 3 of 8 patients with sarcoidosis vs. 4 of 56 controls. None of the mycobacterial sequences identified were homologous to those of known species.
Conclusions.—Sarcoid tissues show variant HHV-8 DNA sequences, whereas nonsarcoid control tissues do not. Sarcoid lymph node tissue is more likely to show mycobacterial-like sequences than nonsarcoid lymph node tissue, but this difference does not extend to other types of tissues. The finding of mycobacterial-like sequences does not reflect infection by a particular mycobacterial species.
• The findings of a very high detection rate of HHV-8 DNA in sarcoid tissues but not in nonsarcoid tissues suggests a close association between HHV-8 and sarcoidosis. However, a causal relationship between the virus and the disease has not, as yet, been established. The absence of DNA from Mycobacterium tuberculosis in these patients suggests a lack of association of sarcoidosis with this organism.
Penile Cytomegalovirus Ulceration in AIDS
Introduction.—In patients with acquired immunodeficiency syndrome, cytomegalovirus infections frequently occur and the most frequently involved sites are the gastrointestinal tract and the eye. It is rare to see cutaneous cytomegalovirus infections. A patient with a large penile ulcer due to cytomegalovirus is presented.
Case Report.—Man, 32, with hepatitis C and esophageal candidiasis was given a diagnosis of AIDS. Before hospital admission, he had been treated for a painless penile ulcer. The patient also had painful dysphagia. He had a 3-cm, circumferential, superficial penile ulceration. Epidermal changes with hyperplasia, hyperkeratosis, neoangiogenesis, and cytomegalic endothelial cells were seen on histopathologic examination. The patient also had 2 ulcerations of the esophagus, which looked like cytomegalovirus esophagitis.
Results.—Complete healing of the penile ulcer and esophageal ulcerations occurred after specific treatment with IV ganciclovir at 5 mg/kg twice daily for 1 month. The maintenance dose was 5 mg/kg/day. Two months later, the patient died of a cerebral vascular accident.
Conclusion.—Torpid skin ulcerations, preferentially perianal, are the most frequent cutaneous manifestations of cytomegalovirus infection in AIDS patients. There have also been reports of oral manifestations, with ulcerated and necrotic lesions of the tongue, buccal mucosa, and pharynx.
• Clearly, most periorificial ulcers in immunosuppressed patients are secondary to herpes simplex infection. Nevertheless—especially in the HIV- positive population—cytomegalovirus infection must be considered, as documentation of such infection would necessitate an entirely different therapeutic approach.
Hyperthermia Therapy for Warts Utilizing a Self-administered Exothermic Patch: Review of Two Cases
Introduction.—Previous studies reported the effectiveness of hyperthermia therapy for treating warts. Methods used included a hot water technique, ultrasound hyperthermia, and radiofrequency current producing heat. A new hyperthermia therapy that uses heat generated by a disposable exothermic patch is evaluated in this study.
Methods.—The self-administered, self-adhesive patch contains a mixture of chemicals that react exothermically in the presence of oxygen. After its sealed pouch is opened, the patch is affixed to the wart and surrounding skin. Temperature at the treated site is elevated to 42°C to 43°C and maintained for approximately 2 hours. The wart virus is inactivated, infected cells are moved to progressively higher levels of the epidermis, and the wart is shed completely.
Results.—Two patients whose warts had failed to respond to other treatments were treated successfully with the exothermic patch. The patches were applied for periods of 4-6 hours or overnight. In 1 case, treatment continued nightly for 3.5 weeks; the wart completely resolved after 4 weeks and has not recurred during 14 months of follow-up. The second patient did not follow instructions during the first 6 weeks of treatment, and no progress was made. After 3 additional weeks the size of the wart was considerably reduced. With 3 more weeks of heat therapy and application of 17% salicylic acid, the wart disappeared and had not recurred 8 months later.
Discussion.—Warts are often difficult to treat, and some patients fail to respond to a series of different therapies. Most of the cutaneous nongenital human papillomavirus (HPV) types responsible for warts favor cool sites of the body. The exothermic patch significantly elevates the temperature at the wart site, preventing further spread of the heat-sensitive virus and promoting its resolution. This form of treatment for warts is convenient to use and should prove cost-effective.
• A new, simple, effective therapy for warts would always be welcome. Obviously, additional clinical trials are needed to confirm the effectiveness of this modality.
Skin Autografts in Epidermodysplasia Verruciformis: Human Papillomavirus-associated Cutaneous Changes Need Over 20 Years for Malignant Conversion
Introduction.—A rare lifelong disease, epidermodysplasia verruciformis is associated with human papillomaviruses. At the age of 5-7 years, benign macular, verruca plana-like or pityriasis versicolor-like lesions start to develop, and there is a persistence of skin changes throughout life. In normal persons, there is a 20-30 year time lag between the primary infection by high-risk genital human papillomaviruses and the develop¬ment of human papillomavirus-associated neoplastic changes.
Methods.—To study whether such a time lag exists in patients with epidermodysplasia verruciformis, affected individuals having surgery for carcinomas with consecutive autografts from uninvolved and non-sun- exposed skin were observed for up to 20 years.
Results.—There were 5 patients with epidermodysplasia verruciformis in whom multiple, malignant, locally destructive changes involving the forehead constantly developed. Within 1-2 years after surgery, numerous premalignant lesions of actinic keratosis-type appeared in uninvolved skin at the graft margins of both sides. Within the grafted skin, benign macular lesions started to develop several years after transplantation, whereas the appearance of premalignant and malignant changes were seen around the grafts. There was a 2.5- to 10-year time lag in the development of epidermodysplasia verruciformis human papillomavirus-associated benign lesions in the skin that previously displayed no visible changes. Progression to malignancy did not occur within 20 years of follow-up.
Conclusion.—Comparable with the genital carcinogenesis associated with high-risk human papilloma viruses, the skin human papillomavirus-associated carcinogenesis appears to be a very slow process. In all affected individuals, epidermodysplasia verruciformis-related human papillomavirus is probably in a latent state, possibly in hair follicles. Local immuno-suppression and immunotolerance to epidermodysplasia verruciformis human papillomavirus-harboring cells is a characteristic feature, and could be related to ultraviolet-B-induced local production of transforming growth factor β1 and tumor necrosis factor α in these patients.
• Epidermodysplasia verruciformis is a rare genetic disease characterized by the development of benign and malignant human papillomavirus-induced skin lesions. In this study, in 5 patients with epidermodysplasia verruciformis, multiple squamous cell carcinomas developed which required excision and grafting with skin from sun-protected uninvolved skin. The authors had an opportunity to observe the evolution of virally induced benign and malignant skin lesions in these patients. Benign lesions required 2.5-10 years to develop, whereas malignant lesions required 20 years or more.
Common Association of HPV 2 With Anogenital Warts in Prepubertal Children
Introduction.—Anogenital (AG) warts in children have a number of possible causes, including perinatal transmission from a human papilloma virus (HPV)-infected maternal birth canal, heteroinoculation from a parent’s hand warts, or sexual abuse. Because certain HPV types appear to be highly site specific in adults, HPV typing of AG warts in children may help to identify the mode of transmission. A cohort of prepubertal children with AG warts was examined to determine whether HPV typing could provide this information.
Methods.—The study included 31 children younger than 12 years who were referred to a dermatology outpatient clinic from January 1989 through July 1992. Adult household members were also examined and screened for AG infections. After initial examinations, the taking of detailed histories, and treatment, children and their families were assessed by an expert in child abuse. Mode of transmission of AG infection was categorized as sexual, perinatal, autoinoculation, heteroinoculation, or uncertain. The AG warts were HPV typed by nonisotopic in situ hybridization using digoxigenin-labeled probes for HPV types 1-5,6,11,16,18, 31, and 33.
Results.—Patients were 12 boys and 19 girls with a mean age of 4.5 years at their first visit. Fourteen had concurrent cutaneous warts. On the basis of historical, clinical, and laboratory data, mode of transmission of AG warts was categorized as perinatal in 12 children, autoinoculation in 8, heteroinoculation in 2, and uncertain in 7; sexual abuse was diagnosed in 2 children. The most commonly identified HPV types were HPV 2 (13 patients), HPV 6 (7), and HPV 11 (5). More than 1 type was present simultaneously in 6 children.
Conclusion.—In this cohort of prepubertal children, the high prevalence of cutaneous HPV 2 and the low prevalence of sexual abuse suggest that AG warts in this age group are most likely the result of autoinoculation or heteroinoculation from cutaneous warts. However, the exact mode of transmission of these warts is uncertain.
• This article reviews many important issues that need to be considered when treating a child with AG warts and suspecting child abuse. It has been hoped that HPV typing of AG warts in children would help determine the actual mode of transmission: cutaneous (from the child’s [autoinoculation] or parents’ [heteroinoculation] hands), perinatal (transmission from an infected birth canal) , or through sexual abuse. In this study, HPV 2 was detected most often in children with AG warts, with HPV types 6, 11, and 16 detected less commonly. Human papilloma virus 2 is considered a cutaneous HPV type; and HPV 6, 11, and 16 are considered mucosal HPV types. The incidence of sexual abuse reported here (2 of 31 children with AG warts) was quite low. The authors concluded that in this particular sample, HPV typing of AG warts provided very little additional helpful information in determining the exact mode of transmission to the child.
Treatment of Condylomata Acuminata With Oral Isotretinoin
Background.—Many different techniques have been used for the treatment of condyloma acuminatum, but none has been completely effective. Topical treatments, because they do not completely eradicate the human papillomavirus, are associated with high relapse rates. The synthetic retinoid isotretinoin is a potent immunomodulator with dramatic effects on epithelial cell differentiation and proliferation. A trial of oral isotretinoin for the treatment of condyloma acuminatum is reported.
Methods.—The study included 56 men with clinical visible condyloma acuminatum on the external genitalia and/or perianal area. In each patient, at least 1 form of standard therapy had been tried unsuccessfully. All patients received 3 months of treatment with oral isotretinoin, 1 mg/kg/ day. The treatment was evaluated for safety and efficacy.
Results.—There were 53 evaluable patients at the end of treatment. Oral isotretinoin was associated with a complete response rate of 40% and a partial response rate of 13%. Thus, 47% of patients had no response. Lesion age and area were inversely related to the response to oral isotretinoin. Among complete responders, the rate of recurrence during 1 year’s follow-up was 9.5%.
Conclusions.—Oral isotretinoin is studied for the treatment of condyloma acuminatum. It has significant effectiveness with a low recurrence rate and acceptable toxicity. It offers a noninvasive treatment alternative for immature and small condyloma acuminatum.
• Most wart remedies tested in an uncontrolled fashion appear to be effective yet are disappointing when controlled studies are undertaken. A double-blind, control study of oral isotretinoin for the treatment of condyloma acuminatum would certainly be welcome. My own experience with the use of this drug for the treatment of multiple common warts has been disappointing.
Viral Parakeratosis: A Diagnostic Clue for Bowenoid Papulosis
Introduction.—The histologic distinction between bowenoid papulosis (BP) and Bowen’s disease (BD) is sometimes difficult and may even lead to unjustified therapeutic measures, such as vulvectomy or partial amputation of the penis. Focal parakeratosis in the horny layer of the epidermis similar to the parakeratosis commonly observed in human papilloma virus (HPV)-induced skin lesions was detected on routine histopathologic examination of BP lesions. This phenomenon may help with differentiation of BP and DB lesions.
Methods.—Twenty, 22, and 22 specimens from BP, BD, and HPV- induced lesions, respectively, were fixed in formalin, stained with hema- toxylin-eosin, examined histologically, and compared. Specimens were reviewed retrospectively from patients with a diagnosis of either BP, BD, or HPV-induced lesions.
Results.—Focal accumulations of uniformly round nuclei present in the horny layer were observed in 90% of BP and 90.9% of HPV-induced lesions. A few round-shaped nuclei were seen in specimens from BD lesions, but they were not uniformly round and lacked the accumulative distribution.
Conclusion.—Focal parakeratosis with retention of uniformly round nuclei and perinuclear vacuoles may be considered characteristic features of BP that can help differentiate BP from BD. This type of parakeratosis has not been described previously. The term “viral parakeratosis” is proposed for this finding.
• Some observers think that only clinicopathologic correlation is acceptable for distinguishing BP from BD of the genitalia. It has long been recognized that HPV induces perinuclear vacuolation in squamous cells. Perinuclear vacuolation observed in cervical epithelium has been referred to as koilocytosis. Viral cytopathic changes have been identified in a high proportion of patients with cervical intraepithelial neoplasia. One recent study found that the presence of koilocytosis in a cervical biopsy specimen was associated with a low risk of high-grade cervical intraepithelial neoplasia. The current study by Vakilzadeh seems to indicate that the presence of viral parakeratosis (a manifestation of koilocytosis in the stratum corneum) often indicates a benign biological course in genital lesions with epithelial atypia resembling BD, so-called BP.
Resolution of Recalcitrant Molluscum Contagiosum Virus Lesions in Human Immunodeficiency Virus-infected Patients Treated With Cidofovir
Introduction.—Molluscum contagiosum virus (MCV), a DNA virus of the poxvirus family, causes cutaneous lesions that are often unresponsive to treatment. Recent advances in research, however, have raised hopes for specific antiviral therapy for MCV. The 3 patients reported here had advanced MCV lesions refractory to many therapies. Treatment with cidofovir, a nucleotide analogue of deoxycytidine monophosphate, brought long-lasting response.
Case Reports.—Three men, ages 26, 31, and 37, were all HIV- infected and had lesions on the face and neck that were diagnosed as MCV. Initial treatments—which included liquid nitrogen, topical tretinoin, and fluorouracil cream—achieved only partial or transient responses. The first patient experienced dramatic clearing of MCV lesions after receiving IV cidofovir for his treatment resistant bilateral cytomegalovirus (CMV) retinitis. The second patient received cidofovir compounded as a 3% cream in a combination vehicle. After 1 month of treatment, MCV lesions had completely resolved. In the third case, IV cidofovir was started for both CMV retinitis and 90% facial MCV involvement. This patient also had no clinical evidence of MCV after 1 month of treatment.
Discussion.—Cidofovir appeared to have clinical activity against MCV, clearing the advanced MCV lesions in these immunocompromised patients. All were also receiving antiretroviral medications that may have contributed to the efficacy of cidofovir.
• Cidofovir is currently approved for IV use in the treatment of CMV retinitis; early studies suggest that a topical gel may have some activity against acyclovir-resistant herpes simplex and human papillomavirus infections. An uncontrolled study found that oral cimetidine may be effective in the treatment of MCV in immunocompetent children. Obviously, controlled trials of both of these agents are needed to confirm their efficacy.