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Viral diseases
Viral Diseases Paul A. Krusinski, MD
New knowledge about cutaneous viral infections has increased tremendously in the last ten years. The discovery of new viruses as the cause of old diseases provides us with better advice for our patients so infected. The development of newer antiviral agents gives our patients and us much hope for possible control and eventual eradication of these diseases. This brief discussion assumes that the reader is familiar with the classical clinical features of these common cutaneous viral infections. It will explore new advances about these diseasesl their current therapy, and possible future therapeutic interventions.
Herpes Simplex Virus: Type 1 (HSV 1) A topical therapy for recurrent cold sores has finally become available. Used every 2 hours the nucleoside analogue penciclovir (available in 1% cream) has been shown to cause healing 29% faster, reduce pain 32% faster, and stop viral shedding 47% faster. 1 Other topicals, eg, n-docosanol cream and foscarnet sodium lauryl sulfate gel, are being investigated for use against cold sores. Recurrent erythema multiforme has now been clearly linked to recurrent herpes simplex. Tatrinall, in a rigorously controlled study, as effectively demonstrated that suppressive treatment with 6 months of acyclovir prevents recurrent erythema multiforme in 64% of patients. 2 Furthermore, two of the eleven treated patients did not experience recurrence after the antiviral was stopped.
Herpes Simplex Virus: Type 2 (HSV 2) New revelations about assymptomatic shedding of HSV 2 demonstrate that it occurs more frequently than previously thought. Some patients with newly acquired genital infections were found to shed HSV 2 from clinically normal skin and mucous membrane sites up to 15% of the time when measured by viral culture and 40% of the time when measured by polymerase chain reaction (PCR). Others have demonstrated viral shedding from clinically atypical genital lesions that are not suspicious for herpes simplex. This discouraging evidence is offset by the ability of orally 90
administered acyclovir or valacyclovir to suppress asymptomatic shedding by more than 95%. 3 The correct epidemologic use of antiviral therapy to prevent spread of this disease, however, has not yet been elucidated. Exposure to acyclovir during pregnancy does not seem to be associated with an increase in birth defects.4 Others have shown that use of acyclovir after 36 weeks of pregnancy in women with a history of recurrent genital herpes simplex decreases the need for Caesarian section and is not associated with adverse fetal effects.5 The use of antivirals during pregnancy should be undertaken only with the greatest caution with consideration of the benefits of therapy vs the risk. Patients should actively participate in this decision. Thymidine kinase negative (or deficient) strains of HSV II unresponsive to acyclovir, famciclovir, and valacyclovir have been isolated primarily from patients with AIDS. Treatment with foscarnet is helpful but must be given intravenously, is associated with recurrence, and has serious systemic side effects. These mutant strains seem to have less neurologic latency, and treatments with curettage, topical trifluoridine, or topical cidofovir have been reported to be effective and safe. 6
Varicella Zoster Virus (VZV) In spite of the existence of adequate antiviral therapy (acyclovir syrup) and a moderately effective vaccine (Varivax, Merck), varicella is responsible for approximately 10,000 deaths per year in this country. Varicella is also the most common predisposing risk factor for severe invasive group A Streptococal infection in patients below the age of 10 years. 7 A greater public health effort for more widespread use of these therapies is clearly needed. A modified varicella-like syndrome after incidental exposure to wild strain varicella has been seen in up to 18% of vaccinees in a 10-year post-vaccination follow study. 8 These patients have a milder disease with fewer lesions, less fever, shorter course, rare complications, and fewer secondary cases. Exposure to the wild strain in this way serves as an anemnestic Curr Probl Dermatol, March/April 2000
immunologic stimulus for these patients. In nonimmunized children exposed to a family member with varicella, acyclovir administered for one week from day 7 to 9 after exposure decreased the number of secondary cases. 9 Those who developed secondary cases had a much milder illness in spite of an 84% seroconversion. There is evidence to Suggest that administration of VZV vaccine to older individuals substantially enhances their cell-mediated immunity (CMI) against the virus. 1° If waning CMI to VZV predisposes to developing zoster, elderly persons may benefit from vaccination (as a booster) to prevent zoster and postherpetic neuralgia (PHN). Large, long term studies are underway to assess this. By combining large numbers of patients early antiviral therapy has definitely been shown to decrease PHN. A meta-analysis of five homogenous trials of immunocompetent zoster patients given oral acyclovir 800 mg, 5 times daily for 7 to 10 days within 72 hours of the onset of the rash reduced the incidence of pain 6 months later (PHN) by 46%. 11 Likewise, the early addition of amitriptyline (25 mg daily) given with concomitant antiviral therapy reduced pain prevalence at 6 months by one half. 12 Chronic VZV infections with acyclovir resistance have been seen primarily in patients with AIDS. These have been successfully treated with topical trifluorothymidine and intralesional interferon alfa. 13
Human Papilloma Virus Our treatment of warts of all varieties and locations is, at best, mediocre. Myriads of agents and modalities have given a clearance rate ranging from 30% to 90%. If we are to successfully treat this recalcitrant group of epidermal pathogens (especially those that may be oncogenic), biological response modifiers (BRM) may provide an avenue for our future attack. The first of these to become available is imiquimod 5% cream used 3 times weekly for external genital warts. While total clearance occurs in 50% of patients, almost all patients have reduction of size and number of w a r t s . 14 Imiquimod works by inducing multiple cytokines locally (particularly interferon and tumor necrosis factor). Other biological response modifiers like papirime compounds that are analogues of 2"-5" oligoadenylate mimic the intercellular effect of interferon and are now undergoing trials against a variety of wart types. Similar trials using tea polyphenols (polyphenon E ointment) are underway. Since the later is a food prodCurr Probl Dermatol, March~April 2000
uct it may be available without a prescription and may be safe for use in children and in pregnancy. The ultimate biologic response modifier, a successful prophylactic vaccine, is our best hope for eradication of the 30 types of HPV that infect anogenital skin and mucous membranes. 15 Vaccines against the viral genes E5, E6, and E7 or their products may provide the greatest help since they encode cellular proteins that are involved in cell cycle control that assigns oncogenic activity to HPV 16, 18, 45, and related viruses which can lead to anogenital malignancy. 16
Human Herpes Virus (HHV): Type 6 and Type 7 Shortly after HHV 6 and HHV7 were isolated from human adult lymphocytes, both viruses were demonstrated to cause roseola (exanthem subitum).17,18 Since then HHV6 has been found to be a major cause of severe febrile illness and febrile seizures in childhood not associated with rash. HHV6 also has been found to be a potentially life threatening pathogen after transplantation: causing bone marrow suppression, pneumonitis, and encephalitis. 19 Fortunately there are many antiviral drugs that show promise for use against severe infections caused by HHV-6. Ganciclovir, foscarmet, ampligen, butapressin and 9-(4-hydroxy2(hydroxymethyl butyl) guanine all show in vitro activity against HHV-6. HHV-7 has recently been suggested as a cause of pityriasis rosea. 2°
Human Herpes Virus: Type 8 (HHV-8) Kaposi's sarcoma associated herpes virus (HHV-8) has been linked to all forms of Kaposi's sarcoma, body cavity lymphoma in AIDS, and Castleman's disease. 21 It is hoped that this HHV will show susceptibility to antiviral agents or vaccine in order to prophylactically treat groups at risk for this malignancy.
Parvovirus g-19 Erythema infectiosum (5th disease) is the most common manifestation of infection by Human Parvovirus B-19. It is usually a banal illness of children between 4 and 10 years of age. In adults, arttn'algias and severe arthritis can be problematic. Infection during pregnancy can lead to spontaneous abortion, and patients with hematologic disorders may develop aplastic crisis, a life threatening sequela. 91
Emerging New Viruses New viruses that have cutaneous findings continue to emerge and pose a threat to human life. For example, a usually banal disorder of hand, foot, and mouth disease in Taiwan recently hospitalized 320 children with associated meningitis, encephalitis, pneumonitis, or acute flaccid paralysis .22 Fifty five of these children died. Enterovirus 71 was the suspected agent. Human monkeypox outbreaks in the Democratic Republic of the Congo demonstrate a disease similar to smallpox with a case fatality rate that has varied from 1% to 15%. 23 It is thought that most cases are from animal contact since the secondary (human to human) attack rate was only 9%. At this time reports that monkeypox might replace smallpox are unsubstantiated. Fatal Herpes Simian B virus (Cercopithecime Herpesvirus I) infections have occurred in primate handlers, usually in laboratory settings. 24 Early diagnosis and early treatment with acyclovir and/or ganciclovir can be life saving. Prevention through careful use of protective gear and work standards is most important.
REFERENCES 1. Raborn GW, et al. (abstract). 36th ICAAC, New Orleans, Sept. 1996. 2. Tatnall, et al. Br J Dermatol 1995;132:267-270. 3. Wald A, Warren T, Hu H, Miller G, Mart L, Ryncory A, Selke S, Zehr J, Vargas M, Corey L. "Suppression of subclinical shedding of herpes simplex virus type II in the genital tract with valacyclovir" abstract. 38th ICAAC, Sept. 2428, 1998, San Diego, CA. 4. Wald A, Zehr J. Barnum G, Davis LG, Corey L. "Suppression of subclinical shedding of Herpes Simplex Virus type II with acyclovir." Ann Intern Med 1996; 124:8-15. 5. Morbidity and Mortality Weekly Report, Oct. 1993.Scott L, et al. (abstract) Proc Soc Gynecol Invest 1993;180, 6. Scott L, et al. [abstract] Proc Soc Gynecol Invest 1993;180. Zabawski EJ, Cockerell CJ, "Topical and intralesional cidofovir: A review of pharmacology and therapeutic effects." J Am Acad Dermatol 1998;39:741-5. 7. Zabawski EJ, Cockerell CJ. "Topical and intralesional cidofovir: A review of pharmacology and therapeutic effects." J Am Acad Dermatol 1998;39:741-5. 8. Davies HP, McGeer A, Schwartz B, Green K, Conn D, Simon AE, Low DE. "Invasive Group A streptococcal infections in Ontario, Canada." N Engl J Med 1996;335:547-54.
92
9. Clements DA, "Modified varicella-like syndrome." Infect Dis Clin North Am 1996, Sept 10 (3) 617-29. 10. Asano Y, Yoshikawa T, Suga S, Kobayashi I, et al, "Postexposure prophylasix of varicella in family contacts by oral acyclovir," Pediatrics 1993;92:219-222. 11. Levin MJ, Hayward AR. "The varicella vaccine. Prevention of herpes zoster." Inf Dis Clinics of NAmer. 10(3): 657-75, 1996 Sep. 12. Jackson JL, Gibbons R, Meyer G, Inouye L. "The effect of treating herpes zoster with oral acyclovir in preventing postherpetic neuralgia." Arch Int Med 1997;157:909-12, 13. Bowsher D. "The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, doubleblind, placebo-controlled trial," J Pain Symptoms Manage 1997;13:327-31. 14. Rossi S, Whitfield M, Berger T. "The treatment of acyclovirresistant herpes zoster with trifluorothyimidine and interferon alfa". Arch Dermatol Jan 1995;131:24-26. 15. Beutner KR. Spruance SL, Hougham AJ, Fox TL, Owens ML, Douglas JM Jr. "Treatment of genital warts with an immune-response modifier (imiquimod). JAAD 38 (2 Pt 1): 230-9, 1998 Feb. 16. Frazier IH. "The role of vaccines in the control of STDs: HPV vaccines," Gernitourn-Med 1996;Dec.;72:398-403. 17. Pfister H. "The role of human papillomavirus in anogenital cancer." Obstet-Gynecol-Clin North Am. 1996 Sept;23:57995. 18. Hall CB, Long CE, Schnabel KC, Caserta MT, McGintyre KM, et al. "Human herpesvirus-6 in children," N Engl J Med 1994;331:432-8. Tanaka K, Koudo T, Jorigoe S, Okada S, Mulai T, Yamamishi K. "Human herpes virus 7: another causal agent for roseola (exanthem sibitum)" J Pediatr 1994; 125:1-5. 19. Tanaka K, Koudo T, Jorigoe S, Okada S, Mulai T, Yamamishi K. "Human herpes virus 7: another causal agent for roseola (exanthem sibitum)" J Pediatr 1994; 125:1-5 20. Singh' N, Carrigan D. "Human herpesvirus-6 in transplantation: an emerging pathogen," Ann Intern Med 1996;124: 1065-71. 21. Drago F. Ranieri E. Malaguti F. Losi E. Rebora A. "Human herpesvirus 7 in pityriasis rosea [letter]. Lancet 349 (9062): 1367-8, 1997 May 10. 22. "Deaths among children during an outbreak of hand, foot, and mouth disease-Taiwan Republic of China," Apr.-July 1998, Mort, Mort Weekly Report, Aug. 1998;43:629-32. 23. Brennan JG and Henderson DA, "Poxvirus dilemmas-monkeypox, smallpox, and biologic terrorism" N Engl J Med Aug. 1998;339-556-9. 24. Perlino C, Hilliard J, Koehler J. "Fatal Cercopithecine herpesvirus I (B virus) infection following a mucocutaneous exposure and interim recommendations for worker protection," Morb Mort Weekly Rep, December 1998;47:1073-6.
Curr Probl Dermatol, March/April 2000
New knowledge about cutaneous viral infections has increased tremendously in the last ten years. The discovery of new viruses as the cause of old diseases provides us with better advice for our patients so infected. The development of newer antiviral agents gives our patients and us much hope for possible control and eventual eradication of these diseases. This brief discussion assumes that the reader is familiar with the classical clinical features of these common cutaneous viral infections. It will explore new advances about these diseasesl their current therapy, and possible future therapeutic interventions.
Herpes Simplex Virus: Type 1 (HSV 1) A topical therapy for recurrent cold sores has finally become available. Used every 2 hours the nucleoside analogue penciclovir (available in 1% cream) has been shown to cause healing 29% faster, reduce pain 32% faster, and stop viral shedding 47% faster. 1 Other topicals, eg, n-docosanol cream and foscarnet sodium lauryl sulfate gel, are being investigated for use against cold sores. Recurrent erythema multiforme has now been clearly linked to recurrent herpes simplex. Tatrinall, in a rigorously controlled study, as effectively demonstrated that suppressive treatment with 6 months of acyclovir prevents recurrent erythema multiforme in 64% of patients. 2 Furthermore, two of the eleven treated patients did not experience recurrence after the antiviral was stopped.
Herpes Simplex Virus: Type 2 (HSV 2) New revelations about assymptomatic shedding of HSV 2 demonstrate that it occurs more frequently than previously thought. Some patients with newly acquired genital infections were found to shed HSV 2 from clinically normal skin and mucous membrane sites up to 15% of the time when measured by viral culture and 40% of the time when measured by polymerase chain reaction (PCR). Others have demonstrated viral shedding from clinically atypical genital lesions that are not suspicious for herpes simplex. This discouraging evidence is offset by the ability of orally 90
administered acyclovir or valacyclovir to suppress asymptomatic shedding by more than 95%. 3 The correct epidemologic use of antiviral therapy to prevent spread of this disease, however, has not yet been elucidated. Exposure to acyclovir during pregnancy does not seem to be associated with an increase in birth defects.4 Others have shown that use of acyclovir after 36 weeks of pregnancy in women with a history of recurrent genital herpes simplex decreases the need for Caesarian section and is not associated with adverse fetal effects.5 The use of antivirals during pregnancy should be undertaken only with the greatest caution with consideration of the benefits of therapy vs the risk. Patients should actively participate in this decision. Thymidine kinase negative (or deficient) strains of HSV II unresponsive to acyclovir, famciclovir, and valacyclovir have been isolated primarily from patients with AIDS. Treatment with foscarnet is helpful but must be given intravenously, is associated with recurrence, and has serious systemic side effects. These mutant strains seem to have less neurologic latency, and treatments with curettage, topical trifluoridine, or topical cidofovir have been reported to be effective and safe. 6
Varicella Zoster Virus (VZV) In spite of the existence of adequate antiviral therapy (acyclovir syrup) and a moderately effective vaccine (Varivax, Merck), varicella is responsible for approximately 10,000 deaths per year in this country. Varicella is also the most common predisposing risk factor for severe invasive group A Streptococal infection in patients below the age of 10 years. 7 A greater public health effort for more widespread use of these therapies is clearly needed. A modified varicella-like syndrome after incidental exposure to wild strain varicella has been seen in up to 18% of vaccinees in a 10-year post-vaccination follow study. 8 These patients have a milder disease with fewer lesions, less fever, shorter course, rare complications, and fewer secondary cases. Exposure to the wild strain in this way serves as an anemnestic Curr Probl Dermatol, March/April 2000
immunologic stimulus for these patients. In nonimmunized children exposed to a family member with varicella, acyclovir administered for one week from day 7 to 9 after exposure decreased the number of secondary cases. 9 Those who developed secondary cases had a much milder illness in spite of an 84% seroconversion. There is evidence to Suggest that administration of VZV vaccine to older individuals substantially enhances their cell-mediated immunity (CMI) against the virus. 1° If waning CMI to VZV predisposes to developing zoster, elderly persons may benefit from vaccination (as a booster) to prevent zoster and postherpetic neuralgia (PHN). Large, long term studies are underway to assess this. By combining large numbers of patients early antiviral therapy has definitely been shown to decrease PHN. A meta-analysis of five homogenous trials of immunocompetent zoster patients given oral acyclovir 800 mg, 5 times daily for 7 to 10 days within 72 hours of the onset of the rash reduced the incidence of pain 6 months later (PHN) by 46%. 11 Likewise, the early addition of amitriptyline (25 mg daily) given with concomitant antiviral therapy reduced pain prevalence at 6 months by one half. 12 Chronic VZV infections with acyclovir resistance have been seen primarily in patients with AIDS. These have been successfully treated with topical trifluorothymidine and intralesional interferon alfa. 13
Human Papilloma Virus Our treatment of warts of all varieties and locations is, at best, mediocre. Myriads of agents and modalities have given a clearance rate ranging from 30% to 90%. If we are to successfully treat this recalcitrant group of epidermal pathogens (especially those that may be oncogenic), biological response modifiers (BRM) may provide an avenue for our future attack. The first of these to become available is imiquimod 5% cream used 3 times weekly for external genital warts. While total clearance occurs in 50% of patients, almost all patients have reduction of size and number of w a r t s . 14 Imiquimod works by inducing multiple cytokines locally (particularly interferon and tumor necrosis factor). Other biological response modifiers like papirime compounds that are analogues of 2"-5" oligoadenylate mimic the intercellular effect of interferon and are now undergoing trials against a variety of wart types. Similar trials using tea polyphenols (polyphenon E ointment) are underway. Since the later is a food prodCurr Probl Dermatol, March~April 2000
uct it may be available without a prescription and may be safe for use in children and in pregnancy. The ultimate biologic response modifier, a successful prophylactic vaccine, is our best hope for eradication of the 30 types of HPV that infect anogenital skin and mucous membranes. 15 Vaccines against the viral genes E5, E6, and E7 or their products may provide the greatest help since they encode cellular proteins that are involved in cell cycle control that assigns oncogenic activity to HPV 16, 18, 45, and related viruses which can lead to anogenital malignancy. 16
Human Herpes Virus (HHV): Type 6 and Type 7 Shortly after HHV 6 and HHV7 were isolated from human adult lymphocytes, both viruses were demonstrated to cause roseola (exanthem subitum).17,18 Since then HHV6 has been found to be a major cause of severe febrile illness and febrile seizures in childhood not associated with rash. HHV6 also has been found to be a potentially life threatening pathogen after transplantation: causing bone marrow suppression, pneumonitis, and encephalitis. 19 Fortunately there are many antiviral drugs that show promise for use against severe infections caused by HHV-6. Ganciclovir, foscarmet, ampligen, butapressin and 9-(4-hydroxy2(hydroxymethyl butyl) guanine all show in vitro activity against HHV-6. HHV-7 has recently been suggested as a cause of pityriasis rosea. 2°
Human Herpes Virus: Type 8 (HHV-8) Kaposi's sarcoma associated herpes virus (HHV-8) has been linked to all forms of Kaposi's sarcoma, body cavity lymphoma in AIDS, and Castleman's disease. 21 It is hoped that this HHV will show susceptibility to antiviral agents or vaccine in order to prophylactically treat groups at risk for this malignancy.
Parvovirus g-19 Erythema infectiosum (5th disease) is the most common manifestation of infection by Human Parvovirus B-19. It is usually a banal illness of children between 4 and 10 years of age. In adults, arttn'algias and severe arthritis can be problematic. Infection during pregnancy can lead to spontaneous abortion, and patients with hematologic disorders may develop aplastic crisis, a life threatening sequela. 91
Emerging New Viruses New viruses that have cutaneous findings continue to emerge and pose a threat to human life. For example, a usually banal disorder of hand, foot, and mouth disease in Taiwan recently hospitalized 320 children with associated meningitis, encephalitis, pneumonitis, or acute flaccid paralysis .22 Fifty five of these children died. Enterovirus 71 was the suspected agent. Human monkeypox outbreaks in the Democratic Republic of the Congo demonstrate a disease similar to smallpox with a case fatality rate that has varied from 1% to 15%. 23 It is thought that most cases are from animal contact since the secondary (human to human) attack rate was only 9%. At this time reports that monkeypox might replace smallpox are unsubstantiated. Fatal Herpes Simian B virus (Cercopithecime Herpesvirus I) infections have occurred in primate handlers, usually in laboratory settings. 24 Early diagnosis and early treatment with acyclovir and/or ganciclovir can be life saving. Prevention through careful use of protective gear and work standards is most important.
REFERENCES 1. Raborn GW, et al. (abstract). 36th ICAAC, New Orleans, Sept. 1996. 2. Tatnall, et al. Br J Dermatol 1995;132:267-270. 3. Wald A, Warren T, Hu H, Miller G, Mart L, Ryncory A, Selke S, Zehr J, Vargas M, Corey L. "Suppression of subclinical shedding of herpes simplex virus type II in the genital tract with valacyclovir" abstract. 38th ICAAC, Sept. 2428, 1998, San Diego, CA. 4. Wald A, Zehr J. Barnum G, Davis LG, Corey L. "Suppression of subclinical shedding of Herpes Simplex Virus type II with acyclovir." Ann Intern Med 1996; 124:8-15. 5. Morbidity and Mortality Weekly Report, Oct. 1993.Scott L, et al. (abstract) Proc Soc Gynecol Invest 1993;180, 6. Scott L, et al. [abstract] Proc Soc Gynecol Invest 1993;180. Zabawski EJ, Cockerell CJ, "Topical and intralesional cidofovir: A review of pharmacology and therapeutic effects." J Am Acad Dermatol 1998;39:741-5. 7. Zabawski EJ, Cockerell CJ. "Topical and intralesional cidofovir: A review of pharmacology and therapeutic effects." J Am Acad Dermatol 1998;39:741-5. 8. Davies HP, McGeer A, Schwartz B, Green K, Conn D, Simon AE, Low DE. "Invasive Group A streptococcal infections in Ontario, Canada." N Engl J Med 1996;335:547-54.
92
9. Clements DA, "Modified varicella-like syndrome." Infect Dis Clin North Am 1996, Sept 10 (3) 617-29. 10. Asano Y, Yoshikawa T, Suga S, Kobayashi I, et al, "Postexposure prophylasix of varicella in family contacts by oral acyclovir," Pediatrics 1993;92:219-222. 11. Levin MJ, Hayward AR. "The varicella vaccine. Prevention of herpes zoster." Inf Dis Clinics of NAmer. 10(3): 657-75, 1996 Sep. 12. Jackson JL, Gibbons R, Meyer G, Inouye L. "The effect of treating herpes zoster with oral acyclovir in preventing postherpetic neuralgia." Arch Int Med 1997;157:909-12, 13. Bowsher D. "The effects of pre-emptive treatment of postherpetic neuralgia with amitriptyline: a randomized, doubleblind, placebo-controlled trial," J Pain Symptoms Manage 1997;13:327-31. 14. Rossi S, Whitfield M, Berger T. "The treatment of acyclovirresistant herpes zoster with trifluorothyimidine and interferon alfa". Arch Dermatol Jan 1995;131:24-26. 15. Beutner KR. Spruance SL, Hougham AJ, Fox TL, Owens ML, Douglas JM Jr. "Treatment of genital warts with an immune-response modifier (imiquimod). JAAD 38 (2 Pt 1): 230-9, 1998 Feb. 16. Frazier IH. "The role of vaccines in the control of STDs: HPV vaccines," Gernitourn-Med 1996;Dec.;72:398-403. 17. Pfister H. "The role of human papillomavirus in anogenital cancer." Obstet-Gynecol-Clin North Am. 1996 Sept;23:57995. 18. Hall CB, Long CE, Schnabel KC, Caserta MT, McGintyre KM, et al. "Human herpesvirus-6 in children," N Engl J Med 1994;331:432-8. Tanaka K, Koudo T, Jorigoe S, Okada S, Mulai T, Yamamishi K. "Human herpes virus 7: another causal agent for roseola (exanthem sibitum)" J Pediatr 1994; 125:1-5. 19. Tanaka K, Koudo T, Jorigoe S, Okada S, Mulai T, Yamamishi K. "Human herpes virus 7: another causal agent for roseola (exanthem sibitum)" J Pediatr 1994; 125:1-5 20. Singh' N, Carrigan D. "Human herpesvirus-6 in transplantation: an emerging pathogen," Ann Intern Med 1996;124: 1065-71. 21. Drago F. Ranieri E. Malaguti F. Losi E. Rebora A. "Human herpesvirus 7 in pityriasis rosea [letter]. Lancet 349 (9062): 1367-8, 1997 May 10. 22. "Deaths among children during an outbreak of hand, foot, and mouth disease-Taiwan Republic of China," Apr.-July 1998, Mort, Mort Weekly Report, Aug. 1998;43:629-32. 23. Brennan JG and Henderson DA, "Poxvirus dilemmas-monkeypox, smallpox, and biologic terrorism" N Engl J Med Aug. 1998;339-556-9. 24. Perlino C, Hilliard J, Koehler J. "Fatal Cercopithecine herpesvirus I (B virus) infection following a mucocutaneous exposure and interim recommendations for worker protection," Morb Mort Weekly Rep, December 1998;47:1073-6.
Curr Probl Dermatol, March/April 2000