The Many Faces of α-Herpesviridae Infections

To the Editor: We read with interest the article by Boer and coworkers entitled “Herpes incognito most commonly is herpes zoster and its histopathologic pattern is distinctive.”1 This paper underlines the difficulty to recognize by conventional microscopy herpesvirus infections lacking the usual histopathologic features of an α-herpesvirus infection. It also stresses the need of complementary diagnostic testing such as polymerase chain reaction to achieve a correct diagnosis in these instances. In the introduction of their article, the authors state that little work has been done so far searching for a correlation between the results of complementary diagnostic testing and the histopathologic patterns of atypical or ingocnito herpesvirus infections. This assertion is perhaps too strong because a number of publications have already addressed these aspects leading to the description of a wide spectrum of histologic patterns related to the diverse α-herpesviridae viral behaviors, including those of the herpes simplex virus (HSV) types I and II, and the varicella zoster virus (VZV). Furthermore, precise correlations existing between the histopathologic alterations and the distribution of HSV and VZV specific antigens and nucleic acids have been previously described in the skin2-4 and systemic infections.5 In fact, the classic pathogenic concept of α-herpesviridae infections distinguishes latent and productive viral infections. This represents the cornerstone of the understanding of the pathomechanisms of the α-herpesviridae-associated diseases, mainly represented by orolabial and genital herpes as well as varicella and herpes zoster. There is evidence that beside the classic pathogenic concepts, other mechanisms exist including the low-productive and semiproductive viral infections. These infections are associated with a large variety of atypical skin manifestations attributed to the α-herpesviridae. Tables 1 and 2 summarize some of the major features of these low-productive and semiproductive α-herpesviridae infections.TABLE 1: Characteristics of the Low-productive Infection of α-HerpesviridaeTABLE 2: Characteristics of the Semiproductive Infection by α-HerpesviridaeA biological continuum probably exists in humans between the latent and productive infections. This continuum can be described starting from the nonproductive condition to end with the productive one. First, the latent infection is solely encountered in the dorsal root ganglia cells, a situation where viral protein production is absent (HSV) or only restricted to certain IE and E proteins (VZV). There are no histocytologic clues suggesting a latent viral infection.6 Due to the absence of major immunogenic antigens no inflammatory reaction is observed.6 This situation of latent infection is never encountered in the skin. In other cases, one encounters the low-productive α-herpesviridae infection in keratinocytes. The infected cells do not display any histocytologic signs suggesting a conventional α-herpesviridae infection. The chronic verrucous VZV lesions in HIV-infected patients represent a typical example of this type of infection.7,8 The absence or the weak and sporadic production of viral immunogenic proteins on the host cell membranes, explains the almost absence of an inflammatory reaction. The semiproductive infection is a further step on the ladder of α-herpesviridae manifestations. In this condition, viral antigens are present in the cytoplasm and eventually on the cell membrane of the infected keratinocytes. This condition may be responsible for the induction of unusual inflammatory responses, corresponding to α-herpesviridae-associated lichenoid reactions.9 In these instances, cytohistologic alterations are only sparsely expressed. By contrast, the full-blown manifestation of the productive infection is associated with marked cytopathologic alterations. The clinical expressions of this type of infection are the typical vesicular orolabial and genital herpes, as well as varicella and herpes zoster. Other clinicopathologic features of some atypical α-herpesviridae-associated entities have also been described, including atypical recurrent varicella in the immunocompromised adult patient,10 herpes zoster folliculitis,11,12 and the median herpetic glossitis.13 The authors further describe the differential diagnosis of several histologic patterns and state that herpes incognito exhibits a distinctive histopathology. Our own experience is at variance indicating that these histological features may only suggest the possibility of α-herpesviridae infections. All these cases should be further examined by specific immunohistochemistry, in situ hybridization, and polymerase chain reaction techniques to prove their viral origin. Hence, the paper by Boer and coworkers1 and our previous publications underline the fact that the classical histologic features of α-herpesviridae skin infections only identify with confidence the usual infections. Complementary diagnostic methods, including immunohistochemsitry, in situ hybridization, and polymerase chain reaction, are mandatory to reveal the viral origin of a large series of atypical α-herpesviridae-associated cutaneous manifestations. Arjen F. Nikkels MD, PhD Gérald E. Piérard MD, PhD Department of Dermatopathology, University Medical Center, CHU du Sart Tilman, B-4000 Liège, Belgium