Wolf’s isotopic response: Where and when

By Warren R. Heymann, MD, FAAD
Oct. 18, 2023
Vol. 5, No. 42

Wolf’s isotopic response (WIR) has been a mysterious and controversial dermatological sign for almost 40 years. In 1984, the Doctors Wolf (Ronni and Danny) described two cases — a 52-year-old man and a 12-year-old girl — both of whom developed tinea infection corresponding to the site of prior herpes zoster (HZ). They suggested a new term, “isoloci response,” to describe a new skin disorder appearing precisely at the site of another unrelated skin disease that has already healed. This was differentiated from the “isomorphic response” defined by Heinrich Koebner in 1877, where typical skin lesions of an existing dermatosis appear in sites of cutaneous injury. (1) Wolf et al reaffirmed this viewpoint following the description of 58 cases of what was then called an “isotopic response.” (2)

This phenomenon has been recognized for more than a century. Lichen planus was reported to develop at site of HZ in 1922; in 1925, keratosis follicularis was described at the site of previous herpetic infections. In 1955, Wyburn-Mason reported 26 cases of malignancies (basal cell carcinoma, squamous cell carcinoma, and breast cancer) appearing in the sites of prior herpetic infections (23 of 26 being HZ). (3)

The overwhelming initial rash in WIR is HZ, although other dermatoses such as tinea corporis (4) or allergic contact dermatitis (5) have been observed. Secondary disorders may appear days to months after the primary disease, including inflammatory diseases (granulomatous disorders, allergic contact dermatitis, lichen planus, lichen simplex chronicus, psoriasis, pityriasis rosea, discoid lupus, morphea, graft-versus-host disease, reactive perforating collagenosis, erythema annulare centrifugum, and bullous pemphigoid), acquired tufted angiomas, xanthomas, cutaneous infections, and malignancies (including leukemia cutis). (6,7,8)

Unusual clinical variants of WIR include concurrent WIR and reverse WIR. Toppel et al reported a case of co-occurring (concurrent) tumid lupus with documented varicella-zoster infection in a 44-year-old woman with a history of Crohn disease. (9) An excellent example of reverse WIR was reported by Kluger in which a 30+ year-old woman was treated for suspected erythema migrans (EM) with amoxicillin. A week later she developed a generalized morbilliform eruption that spared the EM site. (10) Another example is the case of a 50-year-old -man who presented with HZ; he developed a contact dermatitis that did not develop in the HZ lesions. (11)

WIR may be misdiagnosed if there is ongoing infection. Nosewicz and Nash reported the case of a 70-year-old man with a history of rheumatoid arthritis treated with rituximab, methotrexate, and prednisone. A year after experiencing HZ, he developed non-healing ulcers on the right lower abdomen (where he had HZ) and on the left hand. Biopsies demonstrated palisading necrobiotic granulomas, necrotic eccrine ducts, and herpetic viral cytopathic effects. Varicella-zoster (VZV) immunostaining was positive, confirming the diagnosis of chronic VZV infection in an immunocompromised host. The lesions responded to therapy with valacyclovir. If this case were WIR, there would have been no evidence of ongoing infection. (12)

We reported the case of an immunosuppressed 19-year-old woman with a history of systemic lupus erythematosus (SLE) with discoid lupus erythematosus (DLE). Four months after a bout of HZ on her left chest and back, she developed lesions of DLE at those sites. In our estimation this represented an isomorphic response (Koebner reaction) because she already carried the diagnosis of lupus. (13)

The etiology of WIR is enigmatic and remains a source of debate as to whether it is a variant of the isomorphic response (Koebner phenomenon) or a distinct entity. The term “locus minoris resistentiae” (“place of least resistance’) espouses the concept that once tissue has been inflamed, it is altered in some way carrying a memory of the event, so that it may subsequently react in a modified fashion. (14) Yao and Liu state, “Some hypotheses intimate that the aetiology of WIR arises from type III/IV hypersensitivity reactions resulting from the stimulation of continuous viral residual antigens, peripheral nerve damage and the release of neuropeptides and the dysregulation of angiogenesis.” (15) While Happle and Kluger contend that the WIR is not distinct from the Koebner reaction labelling it a “historical error” (16), this view is not shared by Nwabudike and Tatu, who suggest that WIR is a variant of the Koebner phenomenon, and propose that it could be considered a type V response. (17)

The debate will rage on until we understand the pathophysiology of the Koebner phenomenon and WIR. Personally, if I see a rash develop at the site of trauma in a patient who already has that disease (psoriasis, for example), I will call it an isomorphic response. If a new rash appears at the site of a previously healed eruption (such as lichen planus in healed HZ), I will consider that a WIR. This reminds me that if Rodgers and Hart were dermatologists, they would use the lyrics from “Where or When” — Some things that happened for the first time seem to be happening again.

One day we will understand WIR’s where, when, and why.

Point to Remember: Although the nature of Wolf’s isotopic response may be debated among dermatologists, clinicians must recognize that new rashes and tumors may appear in sites of previously healed sites from other disorders, most frequently herpes zoster.

Our expert’s viewpoint

Ronni Wolf, MD
Associate Clinical Professor of Dermatology
The School of Medicine, Hebrew University and Hadassah, Jerusalem

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The creation of a unique publication that prioritizes practical and clinically relevant information about cutaneous medicine and surgery by Dr. Heymann and the editorial board of Dermatology World Insights and Inquiries comes as a breath of fresh air in an era in which molecular biology, genetics, and sophisticated laser surgery dominate most of the journal space. The publication’s focus on descriptive clinical dermatology and morphology, and diagnosis and treatment of real-live patients is a welcome change from reports on skin specimens, cells, and mediators. By bridging the gap between bench and bedside, academic theoretical and clinical practice, and “skin specialists/scientists” and general primary care physicians, the publication provides valuable insights for an all-encompassing clinical readership. I am humbled that such a distinguished leader of the dermatologic community found the phenomenon “Wolf’s Isotopic Response” worthy of inclusion, fully aware that mine is joined by distinguished works of wide interest by our most knowledgeable colleagues.

The present commentary, “Wolf’s Isotopic Response: Where and When,” is an excellent example of the publication’s praiseworthy policy.

My opinion/perception of WIR hasn’t changed considerably since our initial publication. Our viewpoint is as expressed in the attached paper (18) and is similar to what is written in Dr. Heymann’s commentary. Personally, if I see a rash develop at the site of trauma in a patient who already has that disease (psoriasis, for example), I will call it an isomorphic response. If a new rash appears at the site of a previously healed eruption (such as lichen planus in healed HZ), I will consider that a WIR.

1. Wolf R, Wolf D. Tinea in a site of healed herpes zoster (isoloci response?). Int J Dermatol. 1985 Oct;24(8):539. doi: 10.1111/j.1365-4362.1985.tb05844.x. PMID: 4066096.

2. Wolf R, Brenner S, Ruocco V, Filioli FG. Isotopic response. Int J Dermatol. 1995 May;34(5):341-8. doi: 10.1111/j.1365-4362.1995.tb03616.x. PMID: 7607796.

3. Wyburn-Mason R. Malignant change arising in tissues affected by herpes. Br Med J. 1955 Nov 5;2(4948):1106-9. doi: 10.1136/bmj.2.4948.1106. PMID: 13260671; PMCID: PMC1981341.

4. Suzuki R, Numata T, Hiruma J, Maeda T, Tsuboi R, Harada K. Wolf's isotopic response after tinea corporis caused by Microsporum canis. J Dermatol. 2023 Jan 5. doi: 10.1111/1346-8138.16685. Epub ahead of print. PMID: 36606296.

5. Pollard B, McCoy WH 4th, Leonardi CL, Martin AG. Wolf's isotopic response of lichen planus following contact dermatitis. JAAD Case Rep. 2022 Jul 16;27:128-130. doi: 10.1016/j.jdcr.2022.07.010. PMID: 36046802; PMCID: PMC9421081.

6. Samaan CB, Rohr BR, Maroon M, Chandler W. Cutaneous Lupus Erythematosus-like Isotopic Response to Herpes Zoster Infection. Cutis. 2022 May;109(5):E22-E24. doi: 10.12788/cutis.0529. PMID: 35856756.

7. Kim YS, Lee YS, Han TY, Lee J, Choi JE. Post-Zoster Eosinophilic Dermatosis and Acquired Tufted Angioma: Isotopic Response. Indian J Dermatol. 2022 Sep-Oct;67(5):614-615. doi: 10.4103/ijd.ijd_44_21. PMID: 36865826; PMCID: PMC9971777.

8. Li CN, Lee WR, Tseng JT. Dystrophic xanthomatization as a type of Wolf's isotopic response: eruptive xanthomata at a herpes zoster site. J Am Acad Dermatol. 2013 Feb;68(2):e53-5. doi: 10.1016/j.jaad.2012.08.017. PMID: 23317991.

9. Tappel A, Kozak M, Flowers R, Saavedra A. Concurrent presentation of tumid lupus with herpes zoster infection: A variant of Wolf isotopic response? JAAD Case Rep. 2019 Jul 12;5(7):612-613. doi: 10.1016/j.jdcr.2019.04.022. PMID: 31341938; PMCID: PMC6629916.

10. Kluger N. Isotopic sparing phenomenon on an area of erythema migrans in amoxicillin-induced exanthema. Ann Dermatol Venereol. 2022 Nov 22:S0151-9638(22)00090-4. doi: 10.1016/j.annder.2022.09.005. Epub ahead of print. PMID: 36428123.

11. Ma Y, Hu W, Xu AE, Wang P. A report of reverse-Wolf's isotopic response. Br J Dermatol. 2022 Sep;187(3):e78. doi: 10.1111/bjd.21620. Epub 2022 May 16. PMID: 35575447.

12. Nosewicz J, Nash J. Resolution of post-zoster granulomatous dermatitis with valacyclovir. Int J Dermatol. 2023 Apr;62(4):e205-e207. doi: 10.1111/ijd.16426. Epub 2022 Sep 13. PMID: 36097979.

13. Anyanwu CO, Sommer LL, Kuzyshyn H, Camacho JM, Eid HM, Heymann WR. Discoid lupus erythematosus following herpes zoster. Cutis. 2018 May;101(5):370-372. PMID: 29894527.

14. Miller RA. Locus minoris resistentiae and the Koebner Phenomenon. Int J Dermatol. 1990 Apr;29(3):223-4. doi: 10.1111/j.1365-4362.1990.tb03808.x. PMID: 2335420.

15. Yao QH, Liu ZH. Postherpetic psoriasis: a Wolf's isotopic response. QJM. 2022 Aug 13;115(8):537-538. doi: 10.1093/qjmed/hcac134. PMID: 35640991.

16. Happle R, Kluger N. Koebner's sheep in Wolf's clothing: does the isotopic response exist as a distinct phenomenon? J Eur Acad Dermatol Venereol. 2018 Apr;32(4):542-543. doi: 10.1111/jdv.14664. Epub 2017 Nov 22. PMID: 29080318.

17. Happle R, Kluger N. Koebner's sheep in Wolf's clothing: does the isotopic response exist as a distinct phenomenon? J Eur Acad Dermatol Venereol. 2018 Apr;32(4):542-543. doi: 10.1111/jdv.14664. Epub 2017 Nov 22. PMID: 29080318.

18. Wolf R, Wolf D. “Wolf’s isotopic response”: the originators speak their mind and set the record straight. Clin Dermatol. 2017 Jul-Aug;35(4):416-418. doi: 10.1016/j.clindermatol.2017.02.003. Epub 2017 Feb 24. PMID: 28709573.

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