- Email: [email protected]
Severe erythema multiforme responding to interferon alfa
Severe erythema multiforme responding to interferon alfa Pedram Geraminejad, MD,a Hobart W. Walling, MD, PhD,a Michael D. Voigt, MD,b and Mary Seabury Stone, MDa,c Iowa City, Iowa Erythema multiforme (EM) is a targetoid eruption with interface pathology often triggered by a hypersensitivity response to a variety of infections, most commonly herpes simplex virus. Hepatitis C virus is rarely associated with EM. We present a 37-year-old man with an 8-year history of severe EM unresponsive to valacyclovir, acitretin, and cyclosporin, and marginally responsive to high-dose prednisone. The eruption had cleared 6 years previously during treatment with interferon for his concurrent hepatitis C virus. Although his viral titer was undetectable, we initiated therapy with interferon and ribavirin. The patient responded dramatically within 2 months and remained clear of EM after 1 year of continued interferon therapy. This is the third case reported in the world literature documenting a response of EM to interferon, and the first case in which hepatitis C virus was undetectable in serum prior to interferon therapy. ( J Am Acad Dermatol 2006;54:S18-21.)
E
rythema multiforme (EM) is a targetoid eruption clinicopathologically related to Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).1 Clinically, SJS and TEN are more severe and tend to be associated with medications, while EM is milder in this spectrum of disease and tends to be etiologically related to viral infections, most commonly herpes simplex virus.1 Interferons are endogenous cytokines whose antiviral properties have been utilized in the treatment of hepatitis C virus (HCV) infection. We report a 37-year-old male with quiescent HCV infection whose severe EM was unresponsive to traditional therapy and who cleared with interferon alfa (IFN-a). This is the first reported case of EM responding to interferon in a patient without active HCV viremia.
CASE REPORT A 37-year-old man was seen in consultation for an 8-year history of a painful, unremitting, generalized
Supported by Stiefel Laboratories. From the Departments of Dermatology,a Gastroenterology,b and Pathology,c University of Iowa Hospitals and Clinics, Iowa City. Funding sources: None. Conflicts of interest: None identified. Reprints not available from the authors. Correspondence to: Hobart W. Walling, MD, PhD, University of Iowa, Department of Dermatology, 200 Hawkins Dr, Boyd Tower, Iowa City, IA 52242. E-mail: [email protected]. 0190-9622/$32.00 ª 2006 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.04.042
S18
annular eruption involving the face, trunk, and extremities. The patient was not taking any medications during the onset of the rash and denied any history of oral or genital herpes simplex virus infection. On physical examination, multiple, 2- to 8-cm, ringed targetoid plaques with central erosion were seen on the proximal extremities (Fig 1), with few lesions on the distal extremities and palms. The involved body surface area approached 20%. The oral mucosa was clear. A cutaneous biopsy showed vacuolar change with interface dermatitis and necrotic keratinocytes at various levels of the epidermis (Fig 2), consistent with EM. About 2 years after the cutaneous eruption initially began, the patient had been diagnosed with HCV and was treated with IFN-a) and ribavirin for 1 year. During this period, the patient’s eruption fully cleared. After completion of his treatment for HCV, the rash recurred despite complete clinical response to IFN- a/ribavirin therapy and nondetectable HCV viral levels by polymerase chain reaction (PCR). Over the ensuing years, multiple other treatment modalities were attempted to control the EM, including adequate trials of valacyclovir, acitretin, and cyclosporin, with no improvement. Prednisone at 60 mg/day or greater was required for any perceptible improvement. The patient’s history indicated a beneficial response to IFN-a and/or ribavirin. Literature review suggests other cases of EM associated with HCV exist, despite nondetectable serum levels by PCR, although IFN-a therapy was not attempted.2-3 Given his other treatment failures and the high doses of
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Fig 1. Erythema multiforme before IFN-ribavirin therapy. A, Atypical bi-ringed targets with central bullae formation and erosion are seen on the leg. B, Other areas show annular borders with dusky purpuric centers and desquamative scale. Acral accentuation was seen.
prednisone necessary to alleviate the eruption, we offered the patient treatment with pegylated IFN-a (PEG IFN-2A) with the addition of ribavirin to maximize the chance for efficacy. On January 23, 2004, the patient was started on PEG IFN-2A at 180 g subcutaneous weekly and ribavirin 600 mg po bid. His eruption initially flared during the first week of treatment with an increase in the number and size of skin lesions, tenderness, and desquamation. By the third week, the patient had significant improvement, and, 8 weeks into therapy, he was completely clear. His only side effect was mild fatigue. He was weaned from the ribavirin after 24 weeks with no flares in his skin. He did, however, develop mild neutropenia from the PEG IFN-2A requiring filgrastim (Neupogen) twice weekly. The PEG IFN-2A was tapered to 90 g per week, and he remained clear for 12 additional weeks, or more than 1 year after the initiation of this systemic therapy (Fig 3). Because of a change in insurance coverage, the patient was compelled to discontinue the PEG IFN-2A. His EM lesions began to return within 4 weeks and continued to escalate off therapy.
DISCUSSION EM is part of the spectrum of disease that includes SJS and, the most severe condition, TEN.1,4 Classic EM consists of tri-ringed targetoid lesions predomi-
Fig 2. Hematoxylin-eosin stained sections show a subepidermal split with confluent epidermal necrosis and scattered Civette bodies. Mild superficial perivascular and interface lymphocytic inflammatory infiltrate are seen, consistent with erythema multiforme. (A and B, Hematoxylin-eosin stain; original magnifications: A, 3100; B, 3200.)
Fig 3. Residual postinflammatory hyperpigmentation and clearance of EM after 10 months of treatment with IFN.
nantly in an acral distribution. All show vacuolar interface dermatitis histologically, with keratinocyte necrosis, which may be individual or confluent as the severity progresses. In SJS, lesions predominate the trunk, involve more than 1 mucosal site, and may show Nikolsky’s sign. TEN shows diffuse involvement, with necrosis and sloughing over 10% of body surface area.1 A number of etiologic conditions have been associated with this group of diseases. SJS and TEN are most often triggered by medications, while infectious agents, particularly HSV and Mycoplasma pneumoniae, are the most common trigger for EM.1
S20 Geraminejad et al
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Indeed, PCR studies have shown HSV DNA in the skin lesions of both recurrent and single episode EM, but not in cases of atypical EM.5,6 This finding is of great therapeutic significance, and a trial of antiherpetic therapy is often appropriate as first-line therapy. When antiherpetic therapy fails, immunosuppressant medications are often the next step in managing recurrent EM. However, our patient did not respond to cyclosporin, a potent inhibitor of cell-mediated immunity, combined with high dose prednisone. Acitretin, which affects keratinocyte differentiation and modulates keratinocyte apoptosis, was also ineffective. Other infectious agents may be associated with EM. At least 4 cases of EM associated with HCV have been documented in the literature.2,3,7,8 Berard et al2 described a case of EM associated with active HCV viremia, which cleared with 2 courses of IFN then recurred off therapy. Antinori et al3 described a case of spontaneously clearing EM that preceded seroconversion of transfusion-acquired HCV. Calista Landi8 reported a case of EM, lichen planus, and erythema nodosum in a patient with high-titer HCV viremia; IFN was administered for 2 years to treat the active HCV, with secondary resolution of the dermatoses. Dumas et al7 recently described a 40-year-old man with HCV viremia and chronic EM who cleared the HCV after 2 courses of IFN-a for 6 and 8 months. The EM cleared while using the IFN-a, but, similar to our patient, the lesions recurred when IFN-a was discontinued, despite the HCV RNA remaining undetectable by PCR. A number of other cutaneous diseases have been linked to HCV infection, most classically lichen planus, in which HCV DNA has been detected.9 Whether HCV DNA is present in the skin lesions of patients with HCV-induced EM remains unestablished although its presence would provide a basis for the response to IFN-a. Other possible mechanisms in our case would be antiviral activity against a different undetectable or nonassayed virus or microbial agent or a nonspecific immunoregulatory effect. Interferons, including IFN-a, -b and -g, are a group of endogenous cytokines that have nonspecific antiviral activity. Interferons induce at least 3 enzymes with antiviral activity: a protein kinase that leads to phosphorylation of elongation factor 2, resulting in inhibition of peptide chain initiation; oligoisoadenylate synthase, which ultimately leads to activation of an RNAse and degradation of viral messenger RNA; and a phosphodiesterase that degrades the terminal nucleotides of transfer RNA, inhibiting peptide elongation. Ribavirin is a guanosine analogue that is phosphorylated intracellularly by host cell enzymes. Ribavirin appears to interfere
with the synthesis of guanosine triphosphate, inhibiting capping of viral messenger RNA as well as inhibiting viral RNAedependent RNA polymerase. There are several possible explanations for the clinical response to PEG IFN-2A in our patient. The first possibility is that despite the inability to detect HCV RNA by PCR, the patient has occult hepatitis C with residual HCV RNA in leukocytes or keratinocytes. A number of studies have shown that HCV RNA may be detected in the liver, cellular components, or cryoglobulin fraction of peripheral blood, despite being undetectable in the plasma of these patients. Occult HCV infection is recognized as an important cause of persistently elevated liver enzymes in seronegative cases of hepatitis, and of cryptogenic cirrhosis.10-17 Hepatitis C has the ability to modulate the immune response, which may lead to EM in susceptible individuals. Viral serine protease 3 I inhibits host IFN regulatory factor-3.18 Hepatitis C also powerfully downregulates other key cellular enzymes, such as hemeoxygenase, involved in cellular defense against oxidative stress. These effects may contribute to the production of skin lesions in EM, through disruption of cellular defense mechanisms.18 Another possibility is that, while the EM was triggered by HCV, the reaction has progressed through molecular mimicry or epitope, spreading to the point at which it is independent of the HCV RNA, and that the PEG IFN-2A was mainly effective by modulating this immune response. It is unlikely that ribavirin played a significant role because our patient showed no signs of disease after being weaned from the ribavirin. His flare of EM off IFN clearly establishes the efficacy of this agent for his disease. Evaluation of EM lesions by PCR, as has been done in lichen planus, may further elucidate the association between HCV and EM. If the effect of interferon is independent of its effect on HCV, IFN may be useful in treating EM unassociated with HCV. We thank Vincent Angeloni, MD, for providing clinical photographs and reviewing the manuscript.
REFERENCES 1. Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schroder W, Roujeau JC. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol 2002;138: 1019-24. 2. Berard F, Pincemaille B, Charhon A, Perrot H. Persistent erythema multiforme associated with chronic hepatitis C virus infection. Efficacy of interferon alpha. Ann Dermatol Venereol 1997;124:329-31. 3. Antinori S, Esposito R, Aliprandi CA, Tadini G. Erythema multiforme and hepatitis C. Lancet 1991;337:428.
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J AM ACAD DERMATOL VOLUME 54, NUMBER 2
4. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000;115:149-53. 5. Ng PP, Sun YJ, Tan HH, Tan SH. Detection of herpes simplex virus genomic DNA in various subsets of Erythema multiforme by polymerase chain reaction. Dermatology 2003;207:349-53. 6. Sun Y, Chan RK, Tan SH, Ng PP. Detection and genotyping of human herpes simplex viruses in cutaneous lesions of erythema multiforme by nested PCR. J Med Virol 2003;71:423-8. 7. Dumas V, Thieulent N, Souillet AL, Jullien D, Faure M, Claudy A. Recurrent erythema multiforme and chronic hepatitis C: efficacy of interferon alpha. Br J Dermatol 2000;142:1248-9. 8. Calista D, Landi G. Lichen planus, erythema nodosum, and erythema multiforme in a patient with chronic hepatitis C. Cutis 2001;67:454-6. 9. Kurokawa M, Hidaka T, Sasaki H, Nishikata I, Morishita K, Setoyama M. Analysis of hepatitis C virus (HCV) RNA in the lesions of lichen planus in patients with chronic hepatitis C: detection of anti-genomic- as well as genomic-strand HCV RNAs in lichen planus lesions. J Dermatol Sci 2003;32:65-70. 10. Castillo I, Pardo M, Bartolome J, Ortiz-Movilla N, RodriguezInigo E, de Lucas S, et al. Occult hepatitis C virus infection in patients in whom the etiology of persistently abnormal results of liver-function tests is unknown. J Infect Dis 2004; 189:7-14. 11. George SL, Gebhardt J, Klinzman D, Foster MB, Patrick KD, Schmidt WN, et al. Hepatitis C virus viremia in HIV-infected
12.
13.
14.
15. 16.
17.
18.
individuals with negative HCV antibody tests. J Acquir Immune Defic Syndr 2002;31:154-62. Schmidt WN, Wu P, Cederna J, Mitros FA, LaBrecque DR, Stapleton JT. Surreptitious hepatitis C virus (HCV) infection detected in the majority of patients with cryptogenic chronic hepatitis and negative HCV antibody tests. J Infect Dis 1997; 176:27-33. Stapleton JT, Klinzman D, Schmidt WN, Pfaller MA, Wu P, LaBrecque DR, et al. Prospective comparison of whole-bloodand plasma-based hepatitis C virus RNA detection systems: improved detection using whole blood as the source of viral RNA. J Clin Microbiol 1999;37:484-9. Arrojo IP, Pareja MO, Orta MD, Luque FN, Lamas MC, Gordo FS, et al. Detection of a healthy carrier of HCV with no evidence of antibodies for over four years. Transfusion 2003;43:953-7. Lerat H, Hollinger FB. Hepatitis C virus (HCV) occult infection or occult HCV RNA detection? J Infect Dis 2004;189:3-6. Bassett SE, Brasky KM, Lanford RE. Analysis of hepatitis C virusinoculated chimpanzees reveals unexpected clinical profiles. J Virol 1998;72:2589-99. Takaki A, Wiese M, Maertens G, Depla E, Seifert U, Liebetrau A, et al. Cellular immune responses persist and humoral responses decrease two decades after recovery from a singlesource outbreak of hepatitis C. Nat Med 2000;6:578-82. Foy E, Li K, Wang C, Sumpter R Jr, Ikeda M, Lemon SM, et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 2003;300:1145-8.
E
rythema multiforme (EM) is a targetoid eruption clinicopathologically related to Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).1 Clinically, SJS and TEN are more severe and tend to be associated with medications, while EM is milder in this spectrum of disease and tends to be etiologically related to viral infections, most commonly herpes simplex virus.1 Interferons are endogenous cytokines whose antiviral properties have been utilized in the treatment of hepatitis C virus (HCV) infection. We report a 37-year-old male with quiescent HCV infection whose severe EM was unresponsive to traditional therapy and who cleared with interferon alfa (IFN-a). This is the first reported case of EM responding to interferon in a patient without active HCV viremia.
CASE REPORT A 37-year-old man was seen in consultation for an 8-year history of a painful, unremitting, generalized
Supported by Stiefel Laboratories. From the Departments of Dermatology,a Gastroenterology,b and Pathology,c University of Iowa Hospitals and Clinics, Iowa City. Funding sources: None. Conflicts of interest: None identified. Reprints not available from the authors. Correspondence to: Hobart W. Walling, MD, PhD, University of Iowa, Department of Dermatology, 200 Hawkins Dr, Boyd Tower, Iowa City, IA 52242. E-mail: [email protected]. 0190-9622/$32.00 ª 2006 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.04.042
S18
annular eruption involving the face, trunk, and extremities. The patient was not taking any medications during the onset of the rash and denied any history of oral or genital herpes simplex virus infection. On physical examination, multiple, 2- to 8-cm, ringed targetoid plaques with central erosion were seen on the proximal extremities (Fig 1), with few lesions on the distal extremities and palms. The involved body surface area approached 20%. The oral mucosa was clear. A cutaneous biopsy showed vacuolar change with interface dermatitis and necrotic keratinocytes at various levels of the epidermis (Fig 2), consistent with EM. About 2 years after the cutaneous eruption initially began, the patient had been diagnosed with HCV and was treated with IFN-a) and ribavirin for 1 year. During this period, the patient’s eruption fully cleared. After completion of his treatment for HCV, the rash recurred despite complete clinical response to IFN- a/ribavirin therapy and nondetectable HCV viral levels by polymerase chain reaction (PCR). Over the ensuing years, multiple other treatment modalities were attempted to control the EM, including adequate trials of valacyclovir, acitretin, and cyclosporin, with no improvement. Prednisone at 60 mg/day or greater was required for any perceptible improvement. The patient’s history indicated a beneficial response to IFN-a and/or ribavirin. Literature review suggests other cases of EM associated with HCV exist, despite nondetectable serum levels by PCR, although IFN-a therapy was not attempted.2-3 Given his other treatment failures and the high doses of
J AM ACAD DERMATOL
Geraminejad et al S19
VOLUME 54, NUMBER 2
Fig 1. Erythema multiforme before IFN-ribavirin therapy. A, Atypical bi-ringed targets with central bullae formation and erosion are seen on the leg. B, Other areas show annular borders with dusky purpuric centers and desquamative scale. Acral accentuation was seen.
prednisone necessary to alleviate the eruption, we offered the patient treatment with pegylated IFN-a (PEG IFN-2A) with the addition of ribavirin to maximize the chance for efficacy. On January 23, 2004, the patient was started on PEG IFN-2A at 180 g subcutaneous weekly and ribavirin 600 mg po bid. His eruption initially flared during the first week of treatment with an increase in the number and size of skin lesions, tenderness, and desquamation. By the third week, the patient had significant improvement, and, 8 weeks into therapy, he was completely clear. His only side effect was mild fatigue. He was weaned from the ribavirin after 24 weeks with no flares in his skin. He did, however, develop mild neutropenia from the PEG IFN-2A requiring filgrastim (Neupogen) twice weekly. The PEG IFN-2A was tapered to 90 g per week, and he remained clear for 12 additional weeks, or more than 1 year after the initiation of this systemic therapy (Fig 3). Because of a change in insurance coverage, the patient was compelled to discontinue the PEG IFN-2A. His EM lesions began to return within 4 weeks and continued to escalate off therapy.
DISCUSSION EM is part of the spectrum of disease that includes SJS and, the most severe condition, TEN.1,4 Classic EM consists of tri-ringed targetoid lesions predomi-
Fig 2. Hematoxylin-eosin stained sections show a subepidermal split with confluent epidermal necrosis and scattered Civette bodies. Mild superficial perivascular and interface lymphocytic inflammatory infiltrate are seen, consistent with erythema multiforme. (A and B, Hematoxylin-eosin stain; original magnifications: A, 3100; B, 3200.)
Fig 3. Residual postinflammatory hyperpigmentation and clearance of EM after 10 months of treatment with IFN.
nantly in an acral distribution. All show vacuolar interface dermatitis histologically, with keratinocyte necrosis, which may be individual or confluent as the severity progresses. In SJS, lesions predominate the trunk, involve more than 1 mucosal site, and may show Nikolsky’s sign. TEN shows diffuse involvement, with necrosis and sloughing over 10% of body surface area.1 A number of etiologic conditions have been associated with this group of diseases. SJS and TEN are most often triggered by medications, while infectious agents, particularly HSV and Mycoplasma pneumoniae, are the most common trigger for EM.1
S20 Geraminejad et al
J AM ACAD DERMATOL FEBRUARY 2006
Indeed, PCR studies have shown HSV DNA in the skin lesions of both recurrent and single episode EM, but not in cases of atypical EM.5,6 This finding is of great therapeutic significance, and a trial of antiherpetic therapy is often appropriate as first-line therapy. When antiherpetic therapy fails, immunosuppressant medications are often the next step in managing recurrent EM. However, our patient did not respond to cyclosporin, a potent inhibitor of cell-mediated immunity, combined with high dose prednisone. Acitretin, which affects keratinocyte differentiation and modulates keratinocyte apoptosis, was also ineffective. Other infectious agents may be associated with EM. At least 4 cases of EM associated with HCV have been documented in the literature.2,3,7,8 Berard et al2 described a case of EM associated with active HCV viremia, which cleared with 2 courses of IFN then recurred off therapy. Antinori et al3 described a case of spontaneously clearing EM that preceded seroconversion of transfusion-acquired HCV. Calista Landi8 reported a case of EM, lichen planus, and erythema nodosum in a patient with high-titer HCV viremia; IFN was administered for 2 years to treat the active HCV, with secondary resolution of the dermatoses. Dumas et al7 recently described a 40-year-old man with HCV viremia and chronic EM who cleared the HCV after 2 courses of IFN-a for 6 and 8 months. The EM cleared while using the IFN-a, but, similar to our patient, the lesions recurred when IFN-a was discontinued, despite the HCV RNA remaining undetectable by PCR. A number of other cutaneous diseases have been linked to HCV infection, most classically lichen planus, in which HCV DNA has been detected.9 Whether HCV DNA is present in the skin lesions of patients with HCV-induced EM remains unestablished although its presence would provide a basis for the response to IFN-a. Other possible mechanisms in our case would be antiviral activity against a different undetectable or nonassayed virus or microbial agent or a nonspecific immunoregulatory effect. Interferons, including IFN-a, -b and -g, are a group of endogenous cytokines that have nonspecific antiviral activity. Interferons induce at least 3 enzymes with antiviral activity: a protein kinase that leads to phosphorylation of elongation factor 2, resulting in inhibition of peptide chain initiation; oligoisoadenylate synthase, which ultimately leads to activation of an RNAse and degradation of viral messenger RNA; and a phosphodiesterase that degrades the terminal nucleotides of transfer RNA, inhibiting peptide elongation. Ribavirin is a guanosine analogue that is phosphorylated intracellularly by host cell enzymes. Ribavirin appears to interfere
with the synthesis of guanosine triphosphate, inhibiting capping of viral messenger RNA as well as inhibiting viral RNAedependent RNA polymerase. There are several possible explanations for the clinical response to PEG IFN-2A in our patient. The first possibility is that despite the inability to detect HCV RNA by PCR, the patient has occult hepatitis C with residual HCV RNA in leukocytes or keratinocytes. A number of studies have shown that HCV RNA may be detected in the liver, cellular components, or cryoglobulin fraction of peripheral blood, despite being undetectable in the plasma of these patients. Occult HCV infection is recognized as an important cause of persistently elevated liver enzymes in seronegative cases of hepatitis, and of cryptogenic cirrhosis.10-17 Hepatitis C has the ability to modulate the immune response, which may lead to EM in susceptible individuals. Viral serine protease 3 I inhibits host IFN regulatory factor-3.18 Hepatitis C also powerfully downregulates other key cellular enzymes, such as hemeoxygenase, involved in cellular defense against oxidative stress. These effects may contribute to the production of skin lesions in EM, through disruption of cellular defense mechanisms.18 Another possibility is that, while the EM was triggered by HCV, the reaction has progressed through molecular mimicry or epitope, spreading to the point at which it is independent of the HCV RNA, and that the PEG IFN-2A was mainly effective by modulating this immune response. It is unlikely that ribavirin played a significant role because our patient showed no signs of disease after being weaned from the ribavirin. His flare of EM off IFN clearly establishes the efficacy of this agent for his disease. Evaluation of EM lesions by PCR, as has been done in lichen planus, may further elucidate the association between HCV and EM. If the effect of interferon is independent of its effect on HCV, IFN may be useful in treating EM unassociated with HCV. We thank Vincent Angeloni, MD, for providing clinical photographs and reviewing the manuscript.
REFERENCES 1. Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schroder W, Roujeau JC. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol 2002;138: 1019-24. 2. Berard F, Pincemaille B, Charhon A, Perrot H. Persistent erythema multiforme associated with chronic hepatitis C virus infection. Efficacy of interferon alpha. Ann Dermatol Venereol 1997;124:329-31. 3. Antinori S, Esposito R, Aliprandi CA, Tadini G. Erythema multiforme and hepatitis C. Lancet 1991;337:428.
Geraminejad et al S21
J AM ACAD DERMATOL VOLUME 54, NUMBER 2
4. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000;115:149-53. 5. Ng PP, Sun YJ, Tan HH, Tan SH. Detection of herpes simplex virus genomic DNA in various subsets of Erythema multiforme by polymerase chain reaction. Dermatology 2003;207:349-53. 6. Sun Y, Chan RK, Tan SH, Ng PP. Detection and genotyping of human herpes simplex viruses in cutaneous lesions of erythema multiforme by nested PCR. J Med Virol 2003;71:423-8. 7. Dumas V, Thieulent N, Souillet AL, Jullien D, Faure M, Claudy A. Recurrent erythema multiforme and chronic hepatitis C: efficacy of interferon alpha. Br J Dermatol 2000;142:1248-9. 8. Calista D, Landi G. Lichen planus, erythema nodosum, and erythema multiforme in a patient with chronic hepatitis C. Cutis 2001;67:454-6. 9. Kurokawa M, Hidaka T, Sasaki H, Nishikata I, Morishita K, Setoyama M. Analysis of hepatitis C virus (HCV) RNA in the lesions of lichen planus in patients with chronic hepatitis C: detection of anti-genomic- as well as genomic-strand HCV RNAs in lichen planus lesions. J Dermatol Sci 2003;32:65-70. 10. Castillo I, Pardo M, Bartolome J, Ortiz-Movilla N, RodriguezInigo E, de Lucas S, et al. Occult hepatitis C virus infection in patients in whom the etiology of persistently abnormal results of liver-function tests is unknown. J Infect Dis 2004; 189:7-14. 11. George SL, Gebhardt J, Klinzman D, Foster MB, Patrick KD, Schmidt WN, et al. Hepatitis C virus viremia in HIV-infected
12.
13.
14.
15. 16.
17.
18.
individuals with negative HCV antibody tests. J Acquir Immune Defic Syndr 2002;31:154-62. Schmidt WN, Wu P, Cederna J, Mitros FA, LaBrecque DR, Stapleton JT. Surreptitious hepatitis C virus (HCV) infection detected in the majority of patients with cryptogenic chronic hepatitis and negative HCV antibody tests. J Infect Dis 1997; 176:27-33. Stapleton JT, Klinzman D, Schmidt WN, Pfaller MA, Wu P, LaBrecque DR, et al. Prospective comparison of whole-bloodand plasma-based hepatitis C virus RNA detection systems: improved detection using whole blood as the source of viral RNA. J Clin Microbiol 1999;37:484-9. Arrojo IP, Pareja MO, Orta MD, Luque FN, Lamas MC, Gordo FS, et al. Detection of a healthy carrier of HCV with no evidence of antibodies for over four years. Transfusion 2003;43:953-7. Lerat H, Hollinger FB. Hepatitis C virus (HCV) occult infection or occult HCV RNA detection? J Infect Dis 2004;189:3-6. Bassett SE, Brasky KM, Lanford RE. Analysis of hepatitis C virusinoculated chimpanzees reveals unexpected clinical profiles. J Virol 1998;72:2589-99. Takaki A, Wiese M, Maertens G, Depla E, Seifert U, Liebetrau A, et al. Cellular immune responses persist and humoral responses decrease two decades after recovery from a singlesource outbreak of hepatitis C. Nat Med 2000;6:578-82. Foy E, Li K, Wang C, Sumpter R Jr, Ikeda M, Lemon SM, et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 2003;300:1145-8.