Elsevier

Human Pathology

Volume 38, Issue 1, January 2007, Pages 42-49
Human Pathology

Original contribution
Cytomegalovirus-associated cutaneous vasculopathy and scleroderma sans inclusion body change

https://doi.org/10.1016/j.humpath.2006.06.002Get rights and content

Summary

Viruses have long been held to be of pathogenetic importance in the evolution of autoimmune connective tissue disease. We describe 7 adults who developed cutaneous connective tissue disease stigmata in temporal association with recent cytomegalovirus (CMV) infection but without the classic cytopathic changes of CMV infection. We examined 7 adults with clinical presentations encompassing cutaneous vasculitis in 4 and scleroderma in 3. In all 7 patients, there was either IgM seropositivity for CMV and/or CMV DNA isolation from peripheral blood. Although no CMV inclusions were seen, in situ hybridization studies revealed very focal CMV RNA transcript expression with localization mainly to the endothelium. The patients with vasculitis treated with ganciclovir had improvement or resolution of symptoms, whereas only 1 patient with scleroderma received antiviral therapy, without benefit. Another scleroderma patient responded to infliximab therapy. Abortive/partial CMV reactivation can be associated with a syndrome complex mimicking and/or triggering a primary immune-based cutaneous microvascular injury syndrome. Antiviral therapy appears to be of therapeutic value in those cases associated with active necrotizing vasculitic changes. The role of tumor necrosis factor α blockers in scleroderma cases temporally associated with CMV infection requires further evaluation.

Introduction

Human cytomegalovirus (CMV) is a member of the B-Herpesviridae family, representing an enveloped double-stranded DNA. It also falls under the alternative designation of human herpesvirus 5 [1]. By the age of 35 years, most individuals have been infected with the virus. As with other herpes viruses, CMV remains in a state of latency with the possibility of reactivation occurring at any time. In latent infection, viral genome is incorporated in the cell, but there is no production of infectious virus, and hence, other viral transcripts and or viral proteins are not detectable, and the infected cells show no morphological features indicative of cytopathic effect. The latent virus is harbored in select cells that represent a permissive cell population, mainly mononuclear cells and endothelia. The circumstances which eventuate in reactivation are unclear [2], [3]. Reactivation may be incomplete, reflecting synthesis of CMV-associated immediate early and early proteins. These proteins are regulatory proteins uninvolved in viral assembly. Conversely, reactivation may proceed to full late protein expression, leading to associated inclusion body change, the classic manifestation of CMV infection [2], [3]. Usually, clinically evident CMV infection occurs in a host with an altered immune status, whereas a state of partial reactivation may be observed in patients who are relatively immunocompetent.

In light of the inherent tropism of CMV for endothelium, it is not surprising that there are many reports describing CMV endothelialitis with associated cytopathic change in immunocompromised hosts [4], [5], [6], [7], [8]. However, vasculopathic change associated with CMV infection in the absence of inclusion bodies are also described and are postulated to define the basis of rapidly progressive coronary artery disease and endothelialitis in cardiac transplant patients, coronary restenosis after angioplasty, and inflammatory aortic disease [9], [10], [11], [12], [13]. The vasculopathy is held to represent the sequelae of partial reactivation with synthesis of viral proteins that influence the cellular regulation of other genes in the infected cell but do not participate in viral synthesis. In light of its established tropism for endothelium, we have long suspected that CMV might be implicated in other immunologically mediated endothelial-based systemic disorders. We describe 7 adults who developed cutaneous vasculitis and/or a sudden onset of scleroderma, the prototypic immune microvascular injury syndrome whereby a disease onset was temporally associated with the presence of IgM and IgG anti-CMV seropositivity and/or detection of CMV DNA in peripheral blood was observed. One patient was previously reported. Potential mechanisms involved in lesional propagation are discussed. Therapeutic options are also explored.

Section snippets

Materials and methods

We prospectively encountered 7 cases with connective tissue disease (CTD)–like symptoms with prominent skin manifestations. Excluding 1 case, CMV infection was not detected or clinically suspected before biopsy. In all cases, serologic evaluation for CMV infection was performed subsequent to the biopsy. As well, in most, there were confirmatory peripheral blood CMV DNA and or bronchoalveolar lavage studies. Routine light microscopic examination was performed in each case using formalin-fixed

Results

Each of the 7 patients presented with dominant skin findings which could be subcategorized as leukocytoclastic vasculitis, lymphocytic vasculitis, pauci-inflammatory thrombogenic vasculopathy, and scleroderma with associated chronic vasculopathic changes. Each of the categories will be considered separately (see Table 1, Table 2).

Discussion

We have described 7 adult patients who developed CTD-like symptoms temporally associated with serologic and/or culture evidence of active CMV infection, whereby an integral component of their clinical presentation was skin involvement. Among the serologic features of a CTD diathesis were a high ESR, low complement levels, antiphospholipid antibodies, polyclonal hypergammaglobulinemia, positive rheumatoid factor, high C-reactive protein, lymphopenia, and thrombocytopenia. The most common

Acknowledgment

The authors thank Aimee Sisinger and Jingwei Li for their assistance. We would like to thank Drs Dean Hearne and Kelley Gallina for providing clinical information and photographs on patient 5.

References (34)

  • J.L. Melnick et al.

    Possible role of cytomegalovirus in atherogenesis

    JAMA

    (1990)
  • P.D. Sorlie et al.

    Cytomegalovirus/herpesvirus and carotid atherosclerosis: the ARIC study

    J Med Virol

    (1994)
  • W.J. Waldman et al.

    Cytolytic activity against allogeneic human endothelia: resistance of cytomegalovirus-infected cells and virally activated lysis of uninfected cells

    Transplantation

    (1998)
  • M.P. Golden et al.

    Cytomegalovirus vasculitis: case reports and review of the literature

    Medicine (Baltimore)

    (1994)
  • J. Muldoon et al.

    Ischemic colitis secondary to venous thrombosis

    Transplantation

    (1996)
  • C.A. Alford et al.
  • L.M. Rimsza et al.

    Rapid automated combined in situ hybridization and immunohistochemistry for sensitive detection of cytomegalovirus in paraffin-embedded tissue biopsies

    Am J Clin Pathol

    (1996)
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