Original contributionCytomegalovirus-associated cutaneous vasculopathy and scleroderma sans inclusion body change
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.
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