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Study |

Pityriasis Rosea Is Not Associated With Human Herpesvirus 7 FREE

Werner Kempf, MD; Volker Adams, PhD; Martin Kleinhans, MD; Gunter Burg, MD; Renato G. Panizzon, MD; Gabriella Campadelli-Fiume, PhD; Frank O. Nestle, MD
[+] Author Affiliations

From the Department of Dermatology, University Hospital, Zurich, Switzerland (Drs Kempf, Kleinhans, Burg, Panizzon, and Nestle); the Heart Center, University of Leipzig, Leipzig, Germany (Dr Adams); and the Section of Microbiology and Virology, Department of Experimental Pathology, University of Bologna, Bologna, Italy (Dr Campadelli-Fiume). Dr Panizzon is now with the Department of Dermatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.


Arch Dermatol. 1999;135(9):1070-1072. doi:10.1001/archderm.135.9.1070.
Text Size: A A A
Published online

Objective  To examine the proposed association between pityriasis rosea and human herpesvirus 7 (HHV-7).

Design  A retrospective cross-sectional survey.

Setting  University medical center in Switzerland.

Patients  Thirteen patients with pityriasis rosea and 14 persons with normal skin (control subjects).

Main Outcome Measures  Detection of HHV-7–specific DNA sequences and antigen (85-kd phosphoprotein [pp85]) by nested polymerase chain reaction and immunohistochemical analysis, respectively.

Results  Human herpesvirus 7 DNA sequences and expression of the HHV-7–specific immunodominant pp85 antigen were found in 1 (8%) of 13 lesional skin biopsy specimens of pityriasis rosea. The prevalence of HHV-7 DNA sequences and antigens is even slightly lower in lesional skin of patients with pityriasis rosea than in clinically and morphologically normal skin of 14 control persons, in 2 of whom (14%) HHV-7 DNA sequences and antigens could be detected.

Conclusion  The low detection rate of HHV-7 DNA sequences and antigens argues strongly against a causative role for HHV-7 in the pathogenesis of pityriasis rosea.

Figures in this Article

PITYRIASIS ROSEA (PR) is an acute exanthematous inflammatory skin eruption occurring usually once per lifetime in the second or third decade. Many epidemiological and clinical features suggest a viral pathogenesis for PR. They include the preferential occurrence of PR in the spring and fall and sometimes in communities; occasionally fever as a prodromal symptom; the occurrence of a preceding herald patch followed by the appearance of multiple skin lesions with a characteristic distribution; the spontaneous regression of skin changes within 6 to 12 weeks without therapeutic intervention; and recurrences during immunosuppression, as is often observed in patients with viral diseases.1,2

Several viruses such as picornaviruses, parvoviruses, and herpesviruses were proposed as causative agents of PR, but despite the detection of viruslike particles in the herald patch of PR,3 none has been conclusively associated with PR.47 In 1997, Drago and colleagues8,9 reported on the detection of DNA sequences from human herpesvirus 7 (HHV-7) in skin biopsy specimens, peripheral blood mononuclear cells (PBMCs), and plasma specimens of 12 patients with PR by using a nested polymerase chain reaction (PCR) protocol. In addition, viruslike particles were detected in cell cultures inoculated with the cell-free supernatant from cultured PBMCs of patients with PR and identified as herpesviruses by electron microscopy.9 Based on their findings, the authors proposed that PR is a clinical presentation of HHV-7 reactivation.

Human herpesvirus 7 is a ubiquitous virus. Primary infection occurs early in childhood at a high incidence10 and, in some patients, is associated with episodes of exanthem subitum or febrile illness.11 After primary infection, the virus then persists in the organism, replicates in salivary glands, and is shed in the saliva.12 The virus is reactivated in recipients of kidney and bone marrow transplants and, together with human cytomegalovirus and human herpesvirus 6, may complicate the engraftment of transplanted organs.13,14 Other associations of HHV-7 infection or reactivation with diseases in adults have not been established until now. The purpose of this study was to confirm and extend the proposed association between HHV-7 infection or reactivation and PR. We examined lesional skin specimens from 13 patients with PR and included in our study a control group from whom clinically and histologically normal skin specimens were obtained. The presence of HHV-7 was detected simultaneously with 2 different and unrelated approaches—a nested PCR protocol and immunohistochemical analysis. For the latter, we took advantage of a monoclonal antibody to HHV-7 extensively characterized in previous studies15,16 from our laboratories. This antibody, Mab5E1, is directed to an immunodominant phosphoprotein encoded by the U14 gene of HHV-716 and is suitable for detecting HHV-7 in archival, formalin-fixed paraffin-embedded tissues.17 Because it is directed to a structural component of the virion, reactivity is indicative of active viral infection.

We examined 13 skin biopsy specimens of PR lesions (including 4 herald patches) from 13 patients with clinically and histologically proven PR and specimens of histologically normal skin from 14 subjects undergoing plastic surgery. In all cases, the diagnosis of PR was based on a consideration of clinical and histological features. Of 13 patients with PR, 12 showed the typical clinical manifestation, with the development of multiple patchy erythematous and scaling skin lesions within days or as much as 2 weeks after the occurrence of a primary plaque. The spontaneous resolution of the lesions within 2 months was observed in all patients. Only 1 patient presented with an atypical manifestation of multiple papular lesions, but the lesions showed histologically typical features of PR and regressed spontaneously after 6 weeks. The histological features of all specimens were compatible with the diagnosis of PR. The median age of patients with PR was 25.8 years (age range, 17-49 years), whereas the median age of the control subjects was 24.3 years (age range, 16-44 years).

On histological examination, all PR lesions showed spongiosis, focal parakeratosis, and some dyskeratotic cells of the epidermis and a mixed perivascular inflammatory infiltrate in the upper dermis. The median time between the onset of the disease and a skin biopsy was 9.3 days (range, 2-17 days). The tissue specimens were routinely fixed in 10% buffered formalin and embedded in paraffin. Informed consent was obtained from all patients. Blood specimens were not available for the evaluation of viral presence in serum or PBMCs.

POLYMERASE CHAIN REACTION

DNA was extracted by proteinase K digestion according to standard procedures as previously described.18 To avoid contamination and product carryover, the microtome blade was cleaned with xylene after each cut, and DNA extraction, PCR, and gel electrophoresis were done in separate laboratories. laboratories. Successful amplification of a β-globin fragment (268 base pairs) indicated that the specimens were adequate for PCR analysis and that no inhibitors were present. The HHV-7–specific sequences were amplified by nested PCR with 2 sets of primers consisting of the HV7 and HV8 external primers and of HV10 and HV11 internal primers,19 as previously described.18 These primers were shown to amplify specifically HHV-7 DNA and not the DNA from other human herpesviruses.19 "Positive controls" consisted of DNA extracted from cord blood mononuclear cells infected with HHV-7 and skin biopsy specimens known to harbor HHV-7. The PCRs containing all PCR reagents and no DNA template and skin tissue proved previously not to contain HHV-7 DNA were included as "negative controls." The amplification products were subjected to electrophoresis in a 2% agarose gel and stained with ethidium bromide.

The sensitivity of the nested PCR system was determined to be about 1×109-ng DNA by serial 10-fold dilutions of the amplimer of the first PCR, followed by the second nested PCR and analysis by agarose gel electrophoresis. The specificity of the amplified products was confirmed by direct sequence analysis (data not shown).

IMMUNOHISTOCHEMICAL TECHNIQUE

For immunohistochemical study, we used the monoclonal antibody Mab5E1, which is directed against a phosphorylated protein (85-kd phosphoprotein [pp85]) of the virion tegument of HHV-7.15,16 The tissue sections were deparaffinized with xylene and incubated with Mab5E1 (diluted 1:50) for 90 minutes at room temperature. After the sections were washed several times with phosphate-buffered saline solution, the antibody was detected using alkaline phosphatase–antialkaline phosphatase complex (Dako Corporation, Glostrup, Denmark) according to the manufacturer's protocol. The staining reaction was developed using new fuchsin as chromogen, resulting in a red staining. For counterstaining, hematoxylin solution was briefly added. As a negative control, primary antibody was replaced by phosphate-buffered saline solution.

DETECTION OF HHV-7 DNA SEQUENCES

Human herpesvirus 7 DNA sequences were detected in only 1 (8%) of the 13 PR skin biopsy specimens by nested PCR (Figure 1) and in 2 (14%) of 14 specimens of normal skin. All specimens contained amplifiable β-globin sequences. We note that the prevalence of HHV-7 in normal skin specimens in the present study is lower than that reported previously (63%).17 The major difference in the 2 groups of specimens relates to the location of the biopsy specimens, which were collected from various body areas of both male and female persons in the present study, in contrast to the use in a previous study17 of pectoral skin biopsy specimens from women undergoing breast reduction.

Place holder to copy figure label and caption

Detection of human herpesvirus 7–specific DNA sequences in 1 of 13 skin biopsy specimens of pityriasis rosea (lane 5) by nested polymerase chain reaction (length of amplified product, 124 base pairs [bp]). M indicates DNA marker; N, negative control; and P, positive control.

Graphic Jump Location
EXPRESSION OF HHV-7–SPECIFIC ANTIGENS

The expression of HHV-7–specific antigen was detected only in the PR skin biopsy specimens that contained the viral DNA sequences and in 1 of 2 specimens of normal skin harboring the HHV-7 DNA sequence. In all cases, the cells expressing HHV-7 viral antigen pp85 were perivascular cells. Based on morphologic features, the cells expressing HHV-7 antigen represent mononuclear inflammatory cells such as lymphocytes and histiocytes.

Human herpesvirus 7 DNA sequences and cells infected with HHV-7 are present in lesional skin specimens of patients with PR and in clinically and histologically normal skin specimens of healthy persons at comparable levels (1 of 13 persons and 2 of 14 persons, respectively) and with an overall low incidence. The reliability of our experimental approach stems from the findings that PCR and immunohistochemical analysis concordantly detected HHV-7 in the same specimens—those with disease and specimens of normal skin. Current results sharply contrast with those of Drago et al,9 who found HHV-7 DNA sequences in all skin and PBMC specimens analyzed and in plasma specimens from patients with PR at a higher frequency than from healthy persons.

The reasons for the discrepancy are unclear. Whereas in our study, authenticity of the PCR data was provided by sequencing of the amplified fragments and was substantiated by immunohistochemical analysis, PCR was the only analytic technique used in the preceding study. So whether DNA sequences other than those of HHV-7 were amplified cannot be excluded, in particular because skin specimens of healthy persons were not investigated as negative controls and, furthermore, because PCR amplification products were not sequenced. The PCR is well known to produce false-positive results due to contamination. Recently, in a PCR-based study20 on the presence of human herpesvirus 8, contamination occurred even in circumstances in which the control experiments did not indicate contamination of investigated specimens. In the preceding study,8 the presence of HHV-7 in cell-free plasma specimens from patients with PR was interpreted to support a causal relationship.8,9 In our study, plasma and PBMC specimens were not available for the detection of viral sequences. For a pathogenetic association between HHV-7 and PR, however, the virus is expected to be present in the lesions. Given that in our study, HHV-7 DNA and antigens were not detected in PR specimens at a frequency compatible with a pathogenetic association, the presence of viral DNA in plasma or in PBMCs would have been indicative only of viral replication at sites other than those involved by the disease under examination rather than of a causal relationship. Alternative explanations for the presence of viral DNA in serum are conceivable. Thus, HHV-7 reactivation may be the consequence of a transient immunodepressive state, as is often observed with herpesviruses. For example, herpes labialis and herpes zoster lesions are frequently observed as a consequence of reactivation of herpes simplex and varicella-zoster viruses in persons with immunodepressive states.

Inasmuch as a consistency of findings from different groups of investigators is crucial to demonstrate a causal association between an infectious agent and a disease, current results argue strongly against a causative role for HHV-7 in the pathogenesis of PR.

Since the manuscript was submitted for publication, we became aware of a study reported by Yasukawa et al.21 In addition, anti-HHV-7 IgG levels in the serum of patients with PR were not higher than that of normal control subjects. These data confirm our findings and do not support a causal association of HHV-7 and PR.

Accepted for publication April 15, 1999.

The studies performed at University Hospital, Zurich, Switzerland, were supported by a grant from the Gertrud Rueegg Foundation, Zurich. The studies done at the University of Bologna, Bologna, Italy, were aided by grant Biomed2 BMH4 CT95 1016 from UE and the Target Project on Biotechnology.

Presented as a poster at a meeting of the Society of Investigative Dermatology, Cologne, Germany, May 13-15, 1998.

Reprints: Werner Kempf, MD, Department of Dermatology, University Hospital, Gloriastrasse 31, CH-8091 Zurich, Switzerland (e-mail: kempf@derm.unizh.ch).

Parsons  JM Pityriasis rosea update: 1986. J Am Acad Dermatol. 1986;15159- 167
Link to Article
Tschachler  EBergstresser  PRStingl  G HIV-related skin diseases. Lancet. 1996;348659- 663
Link to Article
Aoshima  TKomura  JOfuji  S Virus-like particles in the herald patch of pityriasis rosea [letter]. Dermatologica. 1981;16264- 65
Link to Article
Bonafé  JLIcart  JPerpère  MOksman  FDivoux  D Etude histopathologique et ultrastructurale, immunologique et virologique du pityriasis rosé de Gibert [Histopathologic, ultrastructural, immunologic and virologic study of Gibert's pityriasis rosea]. Ann Dermatol Venereol. 1982;109855- 861
el-Shiemy  SNassar  AMokhtar  MMabrouk  D Light and electron microscopic studies of pityriasis rosea. Int J Dermatol. 1987;26237- 239
Link to Article
Aractingi  SMorinet  FMokni  M  et al.  Absence of picornavirus genome in pityriasis rosea. Arch Dermatol Res. 1996;28960- 61
Link to Article
Lebbé  CAgbalika  F Pityriasis rosea and human herpesvirus 7, a true association [letter]? Dermatology. 1998;96275
Drago  FRanieri  EMalaguti  FLosi  ERebora  A Human herpesvirus 7 in pityriasis rosea [letter]. Lancet. 1997;3491367
Link to Article
Drago  FRanieri  EMalaguti  FBattifoglio  MLLosi  ERebora  A Human herpesvirus 7 in patients with pityriasis rosea. Dermatology. 1997;195374- 378
Link to Article
Wyatt  LSRodriguez  WJBalachandran  NFrenkel  N Human herpesvirus 7: antigenic properties and prevalence in children and adults. J Virol. 1991;656260- 6265
Tanaka  KKondo  TTorigoe  SOkada  SMukai  TYamanishi  K Human herpesvirus 7: another causal agent for roseola (exanthem subitum). J Pediatr. 1994;1251- 5
Link to Article
Hidaka  YLiu  YYamamoto  M  et al.  Frequent isolation of human herpesvirus 7 from saliva samples. J Med Virol. 1993;40343- 346
Link to Article
Chan  PKSPeiris  JSMYuen  KY Human herpesvirus 6 and human herpesvirus 7 infection in bone marrow transplant recipients. J Med Virol. 1997;53295- 305
Link to Article
Osman  HKPeiris  JSTaylor  CEKarlberg  JPMadeley  CR Correlation between the detection of viral DNA by the polymerase chain reaction in peripheral blood leukocytes and serological responses to human herpesvirus 6, human herpesvirus 7, and cytomegalovirus in renal allograft recipients. J Med Virol. 1997;53288- 294
Link to Article
Foà-Tomasi  LFiorilli  MPAvitabile  ECampadelli-Fiume  G Identification of an 85 kDa phosphoprotein as an immunodominant protein specific for human herpesvirus 7–infected cells. J Gen Virol. 1996;77 (pt 3) 511- 518
Link to Article
Stefan  ASecchiero  PBaechi  TKempf  WCampadelli-Fiume  G The 85-kilodalton phosphoprotein (pp85) of human herpesvirus 7 is encoded by open reading frame U14 and localizes to a tegument substructure in virion particles. J Virol. 1997;715758- 5763
Kempf  WAdams  VMirandola  P  et al.  Persistence of human herpesvirus 7 in normal tissues detected by expression of a structural antigen. J Infect Dis. 1998;178841- 845
Link to Article
Kempf  WAdams  VWey  N  et al.  CD68+ cells of monocyte/macrophage lineage in the environment of AIDS-associated and classic-sporadic Kaposi sarcoma are singly or doubly infected with human herpesviruses 7 and 6B. Proc Natl Acad Sci U S A. 1997;947600- 7605
Link to Article
Berneman  ZNAblashi  DVLi  G  et al.  Human herpesvirus 7 is a lymphotropic virus and is related to, but significantly different from, human herpesvirus 6 and human cytomegalovirus. Proc Natl Acad Sci U S A. 1992;8910552- 10556
Link to Article
Lin  JCLin  SCMar  EC  et al.  Is Kaposi's sarcoma–associated herpesvirus in semen of HIV-infected homosexual men? Lancet. 1998;3511365[retraction of Lin JCLin  SCMar  EC  et al. Lancet. 1995;3461601- 1602
Link to Article
Yasukawa  MSada  EMachino  HFujita  S Reactivation of human herpesvirus 6 in pityriasis rosea [letter]. Br J Dermatol. 1999;140169
Link to Article

Figures

Place holder to copy figure label and caption

Detection of human herpesvirus 7–specific DNA sequences in 1 of 13 skin biopsy specimens of pityriasis rosea (lane 5) by nested polymerase chain reaction (length of amplified product, 124 base pairs [bp]). M indicates DNA marker; N, negative control; and P, positive control.

Graphic Jump Location

Tables

References

Parsons  JM Pityriasis rosea update: 1986. J Am Acad Dermatol. 1986;15159- 167
Link to Article
Tschachler  EBergstresser  PRStingl  G HIV-related skin diseases. Lancet. 1996;348659- 663
Link to Article
Aoshima  TKomura  JOfuji  S Virus-like particles in the herald patch of pityriasis rosea [letter]. Dermatologica. 1981;16264- 65
Link to Article
Bonafé  JLIcart  JPerpère  MOksman  FDivoux  D Etude histopathologique et ultrastructurale, immunologique et virologique du pityriasis rosé de Gibert [Histopathologic, ultrastructural, immunologic and virologic study of Gibert's pityriasis rosea]. Ann Dermatol Venereol. 1982;109855- 861
el-Shiemy  SNassar  AMokhtar  MMabrouk  D Light and electron microscopic studies of pityriasis rosea. Int J Dermatol. 1987;26237- 239
Link to Article
Aractingi  SMorinet  FMokni  M  et al.  Absence of picornavirus genome in pityriasis rosea. Arch Dermatol Res. 1996;28960- 61
Link to Article
Lebbé  CAgbalika  F Pityriasis rosea and human herpesvirus 7, a true association [letter]? Dermatology. 1998;96275
Drago  FRanieri  EMalaguti  FLosi  ERebora  A Human herpesvirus 7 in pityriasis rosea [letter]. Lancet. 1997;3491367
Link to Article
Drago  FRanieri  EMalaguti  FBattifoglio  MLLosi  ERebora  A Human herpesvirus 7 in patients with pityriasis rosea. Dermatology. 1997;195374- 378
Link to Article
Wyatt  LSRodriguez  WJBalachandran  NFrenkel  N Human herpesvirus 7: antigenic properties and prevalence in children and adults. J Virol. 1991;656260- 6265
Tanaka  KKondo  TTorigoe  SOkada  SMukai  TYamanishi  K Human herpesvirus 7: another causal agent for roseola (exanthem subitum). J Pediatr. 1994;1251- 5
Link to Article
Hidaka  YLiu  YYamamoto  M  et al.  Frequent isolation of human herpesvirus 7 from saliva samples. J Med Virol. 1993;40343- 346
Link to Article
Chan  PKSPeiris  JSMYuen  KY Human herpesvirus 6 and human herpesvirus 7 infection in bone marrow transplant recipients. J Med Virol. 1997;53295- 305
Link to Article
Osman  HKPeiris  JSTaylor  CEKarlberg  JPMadeley  CR Correlation between the detection of viral DNA by the polymerase chain reaction in peripheral blood leukocytes and serological responses to human herpesvirus 6, human herpesvirus 7, and cytomegalovirus in renal allograft recipients. J Med Virol. 1997;53288- 294
Link to Article
Foà-Tomasi  LFiorilli  MPAvitabile  ECampadelli-Fiume  G Identification of an 85 kDa phosphoprotein as an immunodominant protein specific for human herpesvirus 7–infected cells. J Gen Virol. 1996;77 (pt 3) 511- 518
Link to Article
Stefan  ASecchiero  PBaechi  TKempf  WCampadelli-Fiume  G The 85-kilodalton phosphoprotein (pp85) of human herpesvirus 7 is encoded by open reading frame U14 and localizes to a tegument substructure in virion particles. J Virol. 1997;715758- 5763
Kempf  WAdams  VMirandola  P  et al.  Persistence of human herpesvirus 7 in normal tissues detected by expression of a structural antigen. J Infect Dis. 1998;178841- 845
Link to Article
Kempf  WAdams  VWey  N  et al.  CD68+ cells of monocyte/macrophage lineage in the environment of AIDS-associated and classic-sporadic Kaposi sarcoma are singly or doubly infected with human herpesviruses 7 and 6B. Proc Natl Acad Sci U S A. 1997;947600- 7605
Link to Article
Berneman  ZNAblashi  DVLi  G  et al.  Human herpesvirus 7 is a lymphotropic virus and is related to, but significantly different from, human herpesvirus 6 and human cytomegalovirus. Proc Natl Acad Sci U S A. 1992;8910552- 10556
Link to Article
Lin  JCLin  SCMar  EC  et al.  Is Kaposi's sarcoma–associated herpesvirus in semen of HIV-infected homosexual men? Lancet. 1998;3511365[retraction of Lin JCLin  SCMar  EC  et al. Lancet. 1995;3461601- 1602
Link to Article
Yasukawa  MSada  EMachino  HFujita  S Reactivation of human herpesvirus 6 in pityriasis rosea [letter]. Br J Dermatol. 1999;140169
Link to Article

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