Generalized granuloma annulare after varicella infection: Wolf isotopic response? (2014)

To the Editor: The etiopathogenesis of granuloma annulare (GA) is unknown, but a delayed-type hypersensitivity reaction to an unknown antigen has been hypothesized. Several inciting factors have been reported, including trauma, ultraviolet radiation, and viral infections.1Thornsberry L.A. English 3rd., J.C. Etiology, diagnosis, and therapeutic management of granuloma annulare: an update.Am J Clin Dermatol. 2013; 14: 279-290Crossref PubMed Scopus (117) Google Scholar Among the latter, GA developing at the site of previous herpes zoster (HZ) has frequently been reported in a Wolf isotopic response (WIR).1Thornsberry L.A. English 3rd., J.C. Etiology, diagnosis, and therapeutic management of granuloma annulare: an update.Am J Clin Dermatol. 2013; 14: 279-290Crossref PubMed Scopus (117) Google Scholar, 2Kapoor R. Piris A. Saavedra A.P. Duncan L.M. Nazarian R.M. Wolf isotopic response manifesting as postherpetic granuloma annulare: a case series.Arch Pathol Lab Med. 2013; 137: 255-258Crossref PubMed Scopus (31) Google Scholar, 3Ruocco E. Baroni A. Cutrì F.T. Filioli F.G. Granuloma annulare in a site of healed herpes zoster: Wolf's isotopic response.J Eur Acad Dermatol Venereol. 2003; 17: 686-688Crossref PubMed Scopus (29) Google Scholar However, GA developing after varicella infection, to the best of our knowledge, has not been reported except in a single report of localized GA developing 6 weeks after uncomplicated varicella in a 4-year-old child.4Klein P. Levy R.S. Granuloma annulare.Arch Dermatol. 1984; 120: 578Crossref PubMed Scopus (14) Google Scholar Here we report generalized GA developing in previously healed lesions of varicella 2 months after infection clearance. A 5-year-old girl presented with a 2-month history of an asymptomatic skin eruption on her trunk and extremities. This eruption was preceded by an uncomplicated varicella infection that occurred 2 months earlier and resolved spontaneously. The parents indicated that the new lesions may have arisen at the same sites of previous varicella lesions. The patient was otherwise healthy. Skin examination revealed multiple firm skin-colored papules on trunk and extremities, some of which were grouped in a “herpetiform” arrangement (Fig 1). Punch biopsy revealed a palisaded granulomatous dermatitis with focal collagen degeneration and mucin deposition (Fig 2). These features were diagnostic of generalized GA, which probably developed at the sites of previous varicella lesions. Systemic workup was negative. The parents elected not to treat, and the lesions resolved spontaneously in 11 months.Fig 2Granuloma annulare. Histopathology showed a palisaded granulomatous dermatitis with focal collagen degeneration and mucin deposition mainly in the upper dermis. Perineurovascular lymphohistiocytic infiltrate with multinucleated giant cells was also noted. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×4; B, ×20.)View Large Image Figure ViewerDownload Hi-res image Download (PPT) WIR is characterized by the development of a distinctive cutaneous disease at the site of another unrelated and healed disease after a variable period ranging from days to years.1Thornsberry L.A. English 3rd., J.C. Etiology, diagnosis, and therapeutic management of granuloma annulare: an update.Am J Clin Dermatol. 2013; 14: 279-290Crossref PubMed Scopus (117) Google Scholar, 2Kapoor R. Piris A. Saavedra A.P. Duncan L.M. Nazarian R.M. Wolf isotopic response manifesting as postherpetic granuloma annulare: a case series.Arch Pathol Lab Med. 2013; 137: 255-258Crossref PubMed Scopus (31) Google Scholar, 3Ruocco E. Baroni A. Cutrì F.T. Filioli F.G. Granuloma annulare in a site of healed herpes zoster: Wolf's isotopic response.J Eur Acad Dermatol Venereol. 2003; 17: 686-688Crossref PubMed Scopus (29) Google Scholar, 4Klein P. Levy R.S. Granuloma annulare.Arch Dermatol. 1984; 120: 578Crossref PubMed Scopus (14) Google Scholar, 5Barksdale S.K. Perniciaro C. Halling K.C. Strickler J.G. Granuloma annulare in patients with malignant lymphoma: clinicopathologic study of thirteen new cases.J Am Acad Dermatol. 1994; 31: 42-48Abstract Full Text PDF PubMed Scopus (97) Google Scholar All described cases have occurred after herpes simplex or zoster infections and usually manifest as granulomatous reactions including GA, sarcoidosis, foreign-body reactions, and infections. However, viral DNA in these reactions is rare and typically documented in cases in which the interval between the 2 diseases is short. Several hypotheses exist on WIR development following herpetic infection, including delayed-type hypersensitivity reaction to incompletely degraded viral envelope glycoproteins or virally induced neural alteration resulting in neuropeptide release that locally modulates immune and angiogenic responses. The latter hypothesis may even be the explanation why the WIR is seen more frequently in herpes zoster than varicella, because nerve damage is probably more pronounced in herpes zoster. Our case is peculiar in that generalized GA occurred after varicella infection. In addition to occasional association with malignancies, generalized GA has been associated with viral infections, including hepatitis B and human immunodeficiency virus. Although a previous GA case that developed after varicella has been described, that case reported localized GA variant and the lesions did not affect sites of healed varicella lesions. In occurring shortly after varicella infection and most probably at the sites of healed varicella lesions as supported by the history and the “herpetiform” arrangement of the lesions, our case probably represents a generalized Wolf isotopic response. This is supported by the microscopic finding of perineurovascular lymphohistiocytic infiltrate with multinucleated giant cells in our case, which are features reported to be peculiar to post-herpetic GA.