The association of pityriasis rosea with cytomegalovirus, Epstein-Barr virus and parvovirus B19 infections - A prospective case control study by polymerase chain reaction and serology

ARTICLE

The aetiology and pathogenesis of pityriasis rosea (PR) are unknown. An infectious cause for PR was supported by associations of PR with a history of respiratory tract infections [1] and unfavourable social and economic background [2], and higher incidence among workers of larger collectives [3]. Significant spatial-temporal clustering has been reported in female patients with PR in primary care settings [4].

Studies [5-14] on the association of PR with human herpesvirus 7 (HHV-7) infection have yielded conflicting results. Some studies [5-7, 14] have supported the role of HHV-7 but some do not. We have previously reported a prospective case control study [15] of chlamydia, legionella and mycoplasma infections in patients with PR. We found no evidence of active infections of these bacteria in our patients with PR.

It has been suggested in as early as 1997 that PR may be caused by reactivation rather than primary infection of a virus [5]. Cytomegalovirus (CMV) causes primary infections and reactivations, the clinical manifestations of CMV are diverse, and these infections are highly prevalent in the age group of patients with PR [17]. The age of primary Epstein-Barr virus (EBV) infection also matches that in PR. Like CMV, EBV leads to latent infection and reactivation. Bonafe et al. [18] reported that a higher percentage (42 %) of patients with PR had EBV early antigen (EA) positive compared to controls (15 %). Drago et al. [5] investigated EBV and CMV DNA by polymerase chain reaction (PCR) in the plasma and peripheral blood mononuclear cells of 12 patients with PR in 1997. They failed to find any signal.

Apart from causing erythema infectiosum, parvovirus B19 has been implicated in another exanthem suspected to be of viral aetiology, namely papular-purpuric gloves and socks syndrome [19-21]. Marcus-Farber et al. [22] detected IgG against parvovirus B19 in five (38.0 %) out of 13 patients with PR, and IgM in none of the patients. However, paired acute and convalescent serums were not collected to document significant rise in IgG titres in this study. No control subject was recruited. Moreover, DNA studies were not performed. The detection of parvovirus B19 DNA in blood by PCR has been found to be more sensitive in detecting active infection, and can reveal B19 DNA in patients who have not yet developed specific IgM and IgG [23, 24].

We report here a prospective study of patients with PR and age-and-sex-matched controls where serology against CMV, EBV and parvovirus B19 were all investigated. In addition, PCR studies were performed for EBV and parvovirus B19. Acute and convalescent blood specimens were available from all study subjects.

Objective

The objective of this study is to investigate the association of PR with CMV, EBV and parvovirus B19 infections.

Patients and methods

All patients diagnosed to have PR in a primary care setting between 1 March 2000 and 31 August 2001 (18 months) were invited to join the study. The diagnosis was based on clinical grounds by a physician with training and certifications in dermatology and paediatrics. Our diagnostic criteria were an acute eruption of discrete circular or oval lesions with peripheral collarette scaling pattern and central clearance on some or all lesions, and with some or all lesions orienting along direction of the skin cleavage lines. VDRL was investigated for all patients. Patients with atypical PR features and PR-like drug eruptions were excluded from the study.

Whole blood in acid citrate dextrose and clotted blood were collected from each patient at initial presentation. A convalescent specimen was collected four weeks later. For each patient with PR, the next patient of the same sex and comparable age (±  two calendar years) requiring blood collection for non-dermatological disease who consented to participate was recruited as a control. Informed written consent was obtained from all study and control subjects, or from the parents or legal guardians for minors. The protocol of this study was approved by the Ethics Committee, Faculty of Medicine, University of Hong Kong (EC 1497-00).

The following tests were performed for each blood specimen: CMV IgM and IgG (by enzyme immunoassay(EIA)), EBV viral capsid antigen (VCA) IgM, EBV VCA IgG, EBV EA IgG, EBV nuclear antigen (NA) IgG (by indirect fluorescent Ab), PCR EBV DNA in peripheral blood mononuclear cells in the whole blood specimens, parvovirus B19 IgM and IgG (by EIA), and PCR parvovirus B19 DNA. Tests on the acute and convalescent patient specimens and the paired control specimen were performed in parallel but results were read blinded to the clinical information.

We defined a significant rise in Ab as at least four-fold rise in titres from the acute specimen to the convalescent specimen. We used Fisher’s Exact Probability Test to analyse qualitative data (seroprevalence), and the Wilcoxon Match-Pairs Signed-Ranks Test to analyse changes in IgG titres. All p-values were calculated two-tailed.

Results

24 patients were recruited, 12 being patients with PR, and 12 being paired-matched control subjects. The patients with PR were aged between eight and 46 years (mean = 26.4 years). Three were minors aged 8, 9, and 15. Four were males and eight were females. Three were English subjects aged 15, 29 and 46. The others were Chinese. PCR HHV-6 and HHV-7 DNA results and serology findings against chlamydia, legionella and mycoplasma of some of these patients have been reported by us previously [13, 15]. All had typical features of PR. VDRL was negative for all patients. The 12 control subjects ranged in age from nine to 47 years (mean = 27.1 years). All were Chinese subjects.

The PCR and serology results are summarised in Table I. No patient had viral DNA or significant antibody rise against any of the viruses investigated. The seroprevalence of all three viruses and Ab titres in the patients with PR were insignificantly different from those of control subjects.

Two patients had IgM detected. One is a 24-year-old lady with IgM against CMV detected at 18 EIA units (reference range: less than 10 EIA units) in the acute specimen. IgM measured again on the acute specimen by indirect fluorescent Ab was positive at 1: 40 (reference range: less than 1: 10). IgM against CMV was negative in the convalescent specimen. Her IgG against CMV dropped from 49 EIA units in the acute specimen to 29 EIA units in the convalescent specimen.

The other patient is a 30-year-old lady with IgM against EBV VCA detectable at low titres of 1: 10 in the acute and convalescent specimens. Her EBV VCA IgG was at 1: 1280 in the acute specimen and 1: 640 in the convalescent specimen. Her EBV EA IgG and EBV NA IgG in the acute and convalescent specimens were all positive at 1: 80.

Discussion

No definite evidence of recent primary infection or reactivation by any of the three viruses investigated is present for any our patients with PR. The seroprevalence in our patients with PR are 61.5 % for CMV, 92.3 % for EBV and 53.8 % for parvovirus B19. These are similar to the background seroprevalence in the population, estimated to be about 60 % for CMV, [25] 95 % for EBV [26] and 60 % for parvovirus B19 [27]. For the two patients with IgM detected, cross-reactivity or an amnestic response could have accounted for the results.

The viral hypothesis of PR is mainly supported by the definite disease course of complete remission for almost
all patients within two to 12 weeks, by the absence of a second attack for most patients [28], by case reports of two or more patients with PR in the same family or intimate environment [28-31], and by epidemiological studies indicating seasonal variation [32-37] and presence of clustering [4]. The association of PR with HHV-7 infection is controversial. Drago et al. [5, 6] reported impressive findings. These findings were supported by the reports of Watanabe et al. [7, 14]. Results of other studies have been conflicting. A bacterial hypothesis of PR is mainly supported by the apparent benefit of erythromycin in PR reported by Sharma et al. [33]. However, we have reported no evidence of active chlamydia, legionella or mycoplasma infection in patients with PR [15].

We have demonstrated multiple significant temporal clusters of cases of PR, independent of seasonal variation, in a multi-centre study in primary care settings (Chuh, Lee, Molinari et al, in press). We believe that an infectious aetiology for PR is still highly likely, and would not be surprised if the final culprit is an entirely novel pathogen.

A limitation of this study is that owing to practical local constraints, the number of patients and control subjects recruited were small. However, from the seroprevalence and PCR data, we are not convinced that increasing the sample size would likely have led to different results and interpretations. Another limitation of the study is that while three patients with PR were English subjects, all control subjects were Chinese. We had difficulty in recruiting control subjects of English origin, and would have to assume that race is not an important factor in the roles of the three viruses investigated in the aetiology of PR.

CONCLUSION

Based on a prospective case control study of 12 patients with PR and 12 age-and-sex-matched control subjects, we found no evidence of active infection by CMV, EBV or parvovirus B19 in any of the patients with PR. The seroprevalence of these viruses in patients with PR are similar to the control subjects and to the background seroprevalence. We conclude that PR is not associated with CMV, EBV or parvovirus B19 infections.

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