Anadkat, Milan J

McCoy, William H

Musiek, Amy C

Otchere, Elaine

English

Digital Commons@Becker

Washington University School of MedicineDigital Commons@BeckerOpen Access Publications2018Granulomatous dermatitis as a postherpeticisotopic response in immunocompromisedpatients: A report of 5 casesWilliam H. McCoyWashington University School of Medicine in St. LouisElaine OtchereWashington University School of Medicine in St. LouisAmy C. MusiekWashington University School of Medicine in St. LouisMilan J. AnadkatWashington University School of Medicine in St. LouisFollow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubsThis Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in OpenAccess Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact engeszer@wustl.edu.Recommended CitationMcCoy, William H.; Otchere, Elaine; Musiek, Amy C.; and Anadkat, Milan J., ,"Granulomatous dermatitis as a postherpetic isotopicresponse in immunocompromised patients: A report of 5 cases." JAAD Case Reports.4,8. 752-760. (2018).https://digitalcommons.wustl.edu/open_access_pubs/7169CASE SERIESGranulomatous dermatitis as apostherpetic isotopic response inimmunocompromised patients:A report of 5 casesWilliam H. McCoy 4th, MD, PhD,a,b,c Elaine Otchere, BS,a Amy C. Musiek, MD,a,b,c andMilan J. Anadkat, MDa,b,cSaint Louis, MissouriKey words: Chronic lymphocytic leukemia; granuloma annulare; granulomatous dermatitis; immunocom-promised district; immunodeficiency; immunocompromise; immunosuppression; isotopic response; locusminoris resistentiae; postherpetic isotopic response; Wolf’s isotopic response.INTRODUCTIONGranulomatous dermatitis (GD) describes disor-ders in which mixed inflammatory infiltratescomposed primarily of histiocytes invade the skin.The pathogenesis of GD is unknown; however, GDhas been noted to occur in areas previously affectedby trauma, sun damage, or infection.1 When GDpresents at the same site of a healed, unrelated skindisease, it falls within the category of aWolf’s isotopicresponse.2 The regional restriction of a Wolf’s iso-topic response is proposed to occur due to an area oflocalized immunocompromise known as an immu-nocompromised district.3 This immunocompromiseddistrict is believed to result from various types ofcutaneous damage that hinder lymph circulation, likechronic regional lymphedema or prior herpes virusinfection (eg, varicella zoster virus [VZV] and herpessimplex virus [HSV]).3 Postherpetic isotopic response(PHIR) is the most commonly reported isotopicresponse, and more cases of PHIR-GD have beenreported than any other type of isotopic response.3 Itcan occur within the same dermatomal distributioneither immediately after primary lesion resolution(VZV[HSV) or many years later.3 Persistent VZVDNA has been detected in PHIR lesions within4 weeks after an acute episode4,5 but not after 7weeks.6,7 The presence of viral DNA in some lesionshas led to the proposal that VZV glycoproteins (gpI/II)may still be expressed at a sufficient level to initiategranuloma formation.8Since the first report of granuloma annulare (GA)as an isotopic response,9 38% of the 32 cases havebeen reported in the setting of immunocompro-mise.10 We now add 5 unreported cases and 16literature cases (not reviewed in prior meta-analyses)of immunocompromised PHIR-GD. Our review ofthe literature has also added 23 cases ofAbbreviations used:AML: acute myelogenous leukemiaCLL: chronic lymphocytic leukemiaGA: granuloma annulareGD: granulomatous dermatitisHSV: herpes simplex virusMM: multiple myelomaPHIR: postherpetic isotopic responsePHIR-GD: postherpetic isotopic response-granulomatous dermatitisPHN: postherpetic neuralgiaSCT: stem cell transplantSLE: systemic lupus erythematousSS: Sjogren syndromeVZV: varicella zoster virusFrom the Department of Medicine,b Division of Dermatology,cWashington University School of Medicine.aFunding sources: None.Conflicts of interest: Dr Anadkat has received honoraria as aspeaker and/or consultant from Aspire Bariatrics, Amgen,AstraZeneca, Biogen, Bristol-Myers Squibb, Eisai, ImClone, andTherakos. He has also served as an investigator for Biogen,Hana Biosciences, Vanda Pharmaceuticals, and Xoma. ElaineOtchere and Drs McCoy and Musiek have no conflicts todisclose.Correspondence to: William H. McCoy 4th, MD, PhD, Departmentof Medicine, Division of Dermatology, Washington University,660 S Euclid, Campus Box 8123, St. Louis, MO 63110. E-mail:mccoyw@wustl.edu.JAAD Case Reports 2018;4:752-60.2352-5126 2018 by the American Academy of Dermatology, Inc. Publishedby Elsevier, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).https://doi.org/10.1016/j.jdcr.2018.05.024752nonimmunocompromised PHIR-GD. Our analysis of33 immunocompromised and 43 immunocompetentcases highlights PHIR-GD associations with immu-nocompromise, chronic lymphocytic leukemia(CLL), and male sex.METHODSWe conducted a retrospective study of 5 immu-nocompromised PHIR-GD patients at Barnes JewishHospital in St Louis, Missouri between 2008 and2015. Through a literature search of PubMed, wereviewed all previous cases of PHIR-GD. Searchterms included Wolf’s isotopic response, postherpeticisotopic response, granulomatous dermatitis, granu-loma annulare, and perturbations of these terms.References from the identified literature were used toexpand our search.RESULTSCase 1A 53-year-old white woman with systemic lupuserythematosus (SLE), Sj€ogren syndrome (SS), andIgM deficiency on methotrexate, Plaquenil, predni-sone, and sulfasalazine presented with right V1dermatome VZV reactivation. Treatment includedvalacyclovir, tobramycin ophthalmic ointment, andgabapentin. Less than a month after the lesionsresolved, an erythematous, alopecic plaqueappeared in the same dermatome (Fig 1; SLE1SS)complicated by severe postherpetic neuralgia (PHN)and trigeminal trophic syndromewith ulceration andsuperinfection (methicillin-resistant Staphylococcusaureus, Candida keratitis). Biopsy found no viralcytopathic changes (Fig 1; SLE1SS). HSV/VZVassayswere negative. She received valacyclovir, corticoste-roids (topical, intralesional, oral), and calcineurininhibitors (tacrolimus, pimecrolimus) for her PHIR-GD. Her PHN required oral gabapentin, pregabalin,duloxetine, hydroxyzine, and topical lidocaine.Autoimmune treatments were replaced with abata-cept 6 months after PHIR-GD onset. Over 19.5months, her cutaneous disease and PHN significantlyimproved, but her PHN never resolved completely.Case 2A 56-year-old white man with a history of acutemyelogenous leukemia (AML) treated with chemo-therapy and unrelated donor stem cell transplant(SCT) later complicated by chronic graft-versus-hostdisease presented for suture removal after Mohsmicrographic surgery for squamous cell carcinomaof the left side of the forehead. He was found to haveVZV reactivation of the left V1 dermatome. Hereceived intravenous acyclovir, oral valacyclovir,and gabapentin for PHN. Less than a month later,an erythematous, sclerotic plaque developed in theFig 1. Clinical and histologic images. Four of the immunocompromised patients withgranulomatous PHIR from this case series are shown with their clinical photographs aboveand the corresponding H&E pathology immediately below. Inset images show magnified areasof rash/histology. Immunocompromise etiology and microscopic magnifications are listed. Noclinical/histologic images were available for the heart transplant subject in our case series.JAAD CASE REPORTSVOLUME 4, NUMBER 8McCoy et al 753same dermatome consistent with GD on biopsy (Fig1; AML1SCT). He was treated topically (desonide,pimecrolimus) and orally (valacyclovir, prednisone,minocycline, dicloxacillin). PHIR-GD skin lesionsand PHN persisted despite treatment at 1-yearfollow-up.Case 3A 57-year-old African-American woman with ahistory of multiple myeloma (MM) treated withchemotherapy followed by autologous SCT pre-sented with right upper extremity (dermatomes C5-C6) VZVreactivation. She was treated with high-doseacyclovir. Two weeks later, flat-topped, violaceous,polygonal papules appeared among resolving VZVlesions (Fig 1; MM1SCT). Biopsy found poorlyformed epithelioid granulomas in the superficialdermis with extension to the dermoepidermal junc-tion and no lichenoid infiltrate or viral cytopathicchange (Fig 1; MM1SCT). Grocott methenaminesilver stain, and acid-fast bacilli stains were negative.PHIR-GD treatment (hydroxyzine, high potencytopical steroids, intralesional Kenalog) resulted insignificant improvement by 5 months. Completeresolution of cutaneous findings was noted at 2-year follow-up, although PHN persisted requiringgabapentin, topical lidocaine, and epidural steroidinjections.Case 4A 73-year-old white man with a history of hearttransplant in 1985 presented with disseminated VZVreactivation (right V3 and C5 dermatomes). At pre-sentation, his immunosuppressive regimen includedcyclosporine, azathioprine, and prednisone. VZVtreatment included valacyclovir and gabapentin forPHN. Within 3 weeks, erythematous papules devel-oped interspersed within his healing VZV lesions(right C5 dermatome) with significant PHN. VZVpolymerase chain reaction was negative for bothlesions. Biopsy found a prominent interstitial gran-ulomatous process with necrobiosis and no viralcytopathic changes. Gram and Fite stains werenegative. PHIR-GD was treated with clobetasol.Case 5A 71-year-old African-American woman withCLL complicated by immune thrombocytopenicpurpura presented with VZV reactivation (left C5-T1 dermatomes) and significant PHN 1 month afterrituximab treatment and ibrutinib initiation. Sheinitially received valacyclovir, gabapentin, andacetaminophen-hydrocodone. Once the lesionsresolved, she was treated with acyclovir prophylaxis.Eight months later, firm, erythematous papules in anannular pattern developed in a left-sided C5-8 dis-tribution consistent with PHIR-GD (Fig 1; CLL).Biopsy found superficial and deep perivascularloose granulomas and lymphocytes (Fig 1; CLL).Gram, Grocott methenamine silver stain, and Fitestains were negative. Clobetasol cream improved herPHIR-GD by her follow-up at 4 months.Summary of reported casesThese 5 cases were integrated into a review of allpublished immunocompromised PHIR-GD clinicaland histologic data (Supplemental Figs 1 and 2). Forcomparison, PHIR granulomatous vasculitis andfolliculitis cases were summarized separately(Supplemental Figs 3 and 4). The average age ofPHIR-GD presentation was similar in immunocom-promised patients (656 11 years) and immunocom-petent patients (59 6 18 years). Although mostPHIR-GD cases were initiated by VZV ([96%), HSVwas identified in 9% of immunocompromised PHIR-GD cases. Similar to prior literature, herpes virusinfection occurred on average 4.2 months beforePHIR (range, 0.1 to 36), and most cases resolvedwithin 1 to 2 years with conservative GD manage-ment, although our 5 new cases all were complicatedby severe PHN.Immunocompromise analysisImmunocompromise in PHIR-GD appears morecommonly (43%) than previously reported (38%)(Fig 2, A). We have expanded the previouslyidentified immunocompromised context for PHIR-GD (chemotherapy or hematopoietic malignancy) toinclude HIV, myelodysplastic syndrome, solid organtransplant, and connective tissue disease (Fig 2, B).CLL remained the most common cause of immuno-compromise in granulomatous PHIR patients (44%all cases/48% GD). Interestingly, our work suggeststhat sex may play a role in PHIR-GD, as immuno-compromised men appeared particularly susceptibleto granulomatous PHIR independent of their higherincidence of CLL (Fig 2, C ). Conversely, granuloma-tous PHIR in immunocompetent patients is far morefrequent in women (Fig 2, C ) paralleling theincreased occurrence of GA in women.1DISCUSSIONNearly half of PHIR-GD cases (33 of 76; 43%) havebeen reported in immunocompromised patients.Immunocompromise likely worsens the regionalneuroimmune axis imbalance caused by herpeticnerve injury and thereby increases the likelihood ofPHIR-GD.11 This hypothesis is supported by recentPHIR-GD work demonstrating perineurovascularlymphohistiocytic infiltrates.12 Further, the severeJAAD CASE REPORTSSEPTEMBER 2018754 McCoy et alPHN of patients both in our study and priorpublications may reflect this proposed neuroim-mune imbalance. We recommend that practitionersaggressively manage these symptoms particularly inimmunocompromised PHIR-GD patients. Beyondlocal neuroimmune effects, the overrepresentationof CLL in our PHIR-GD patients (16 of 33; 48%)compared with baseline CLL incidence (0.5%) mayhelp illuminate what humoral and cell-mediatedimpairments led to granulomatous PHIR. Theupregulation of specific cell surface proteins onadaptive immune cells (Fig 2, D),13 immune cell-mediated hampered lymph drainage,13 andincreased tumor necrosis factor-a in CLL may helpdrive granuloma formation (Fig 2, D). Future studiesof this phenomenon are needed to determine whichfacet(s) of CLL immunocompromise favors PHIR-GD, and we believe these studies will shed light onboth PHIR (GD and other responses) and CLL.Although CLL association with PHIR-GD had beenFig 2. Immunocompromise and granulomatous PHIR. A, The presence or absence ofimmunocompromise in all published cases of granulomatous PHIR are summarized andseparated by type of inflammation. PHIR-GD granulomatous dermatitis encompasses sarcoidaland nonsarcoidal (ie, GA and GA variants). B, Cases of PHIR-GD from the most recent meta-analysis before this publication are compared with the cases added by this work. The types ofimmunocompromise are listed and highlight the predominance of CLL in both studies. C, Themale/female ratio for each type of granulomatous PHIR was calculated as a function ofimmunocompromise. Granulomatous PHIR folliculitis is not included, as there were too fewcases to include in this analysis. D, Model of how CLL immunocompromise could lead toincreased granulomatous response through both the T- and B-cell axes is shown. Theupregulated CLL B-cell factors impair immunologic synapse formation, promote Tregexpansion, and impair T cell activation/proliferation. Upregulated CLL T-cell CD30 impairsB-cell isotype switching, increases B-cell sensitivity to FasL-mediated apoptosis, and increasestumor necrosis factor-a production.JAAD CASE REPORTSVOLUME 4, NUMBER 8McCoy et al 755previously noted, male predominance in immuno-compromised PHIR-GD has not been previouslyidentified. It is particularly striking because of thereported approximately 33% increased incidence ofVZV in women over men14 and the increasedincidence of granuloma annulare in women overmen (2.5:1),1 which we also observed in our reviewof immunocompetent patients with PHIR-GD (2.9:1overall, 2.6:1 for PHIR-GD). Although the male/female ratio in CLL (1.5:1) may account for part ofthemale predominance in PHIR-GD (2.8:1), it cannotaccount entirely for this observation. Although wedo not yet understand the role of sex in PHIR-GD, werecommend screening men with PHIR-GD for im-munocompromise (particularly CLL) and aggres-sively treating PHN in these patients to improveclinical outcomes. We hope that these cases and ourliterature review will spark future investigations toimprove our understanding of PHIR, granulomatousreactions, and CLL.REFERENCES1. Muhlbauer JE. Granuloma annulare. J Am Acad Dermatol. 1980;3(3):217-230.2. Wolf R, Brenner S, Ruocco V, Filioli FG. Isotopic response. Int JDermatol. 1995;34(5):341-348.3. Ruocco V, Brunetti G, Puca RV, Ruocco E. The immunocom-promised district: a unifying concept for lymphoedematous,herpes-infected and otherwise damaged sites. J Eur AcadDermatol Venereol. 2009;23(12):1364-1373.4. Serfling U, Penneys NS, Zhu WY, Sisto M, Leonardi C.Varicella-zoster virus DNA in granulomatous skin lesionsfollowing herpes zoster. A study by the polymerase chainreaction. J Cutan Pathol. 1993;20(1):28-33.5. Gibney MD, Nahass GT, Leonardi CL. Cutaneous reactionsfollowing herpes zoster infections: report of three casesand a review of the literature. Br J Dermatol. 1996;134(3):504-509.6. Langenberg A, Yen TS, LeBoit PE. Granulomatous vasculitisoccurring after cutaneous herpes zoster despite absence ofviral genome. J Am Acad Dermatol. 1991;24(3):429-433.7. Requena K, Escalonilla O, Schaller R. Cutaneous reactions atsites of herpes zoster scars: an expanded spectrum. Br JDermatol. 1998;138(1):161-168.8. Nikkels A, Sadzot-Delvaux C, Cloes J-M, Rentier B, Pierard G.Granulomatous reactions following herpes-zoster containvaricella-zoster glycoprotein GPI. J Invest Dermatol. 1992;98(4). Available from: http://orbi.ulg.ac.be/handle/2268/62490. Accessed June 28, 2015.9. Guill MA, Goette DK. Granuloma annulare at sites of healingherpes zoster. Arch Dermatol. 1978;114(9):1383.10. Levy J, Barber D, Robertson L. Granuloma annulare as anisotopic response to herpes zoster. J Cutan Med Surg. 2014;18(6):413-419.11. Piccolo V, Russo T, Bove D, Baroni A. Segmental immunedisorders resulting from neurologic injuries. Clin Dermatol.2014;32(5):628-632.12. Kapoor R, Piris A, Saavedra AP, Duncan LM, Nazarian RM. Wolfisotopic response manifesting as postherpetic granulomaannulare: a case series. Arch Pathol Lab Med. 2013;137(2):255-258.13. Riches JC, Gribben JG. Understanding the immunodefi-ciency in chronic lymphocytic leukemia: potential clinicalimplications. Hematol Oncol Clin North Am. 2013;27(2):207-235.14. Insinga RP, Itzler RF, Pellissier JM, Saddier P, Nikas AA. Theincidence of herpes zoster in a United States administrativedatabase. J Gen Intern Med. 2005;20(8):748-753.JAAD CASE REPORTSSEPTEMBER 2018756 McCoy et alSupplemental Fig 1. Clinical summary of immunosuppressed PHIR-GD cases. Clinical dataincluding patient characteristics, immunosuppression, virus, and treatment for all reportedcases of PHIR-GD and the 5 cases reported in this manuscript are summarized.JAAD CASE REPORTSVOLUME 4, NUMBER 8McCoy et al 757Supplemental Fig 2. Histologic summary of immunosuppressed PHIR-GD cases. Patientcharacteristics (age, sex, immunosuppression) are listed next to available histologic data for allreported cases of PHIR-GD and the 5 cases reported in this manuscript.JAAD CASE REPORTSSEPTEMBER 2018758 McCoy et alSupplemental Fig 3. Clinical summary of immunosuppressed PHIR-GV/GF cases. Clinicaldata including patient characteristics, immunosuppression, virus, and treatment for all reportedcases of PHIR-GV/GF (granulomatous vasculitis/folliculitis) are summarized.JAAD CASE REPORTSVOLUME 4, NUMBER 8McCoy et al 759Supplemental Fig 4. Histologic summary of immunosuppressed PHIR-GF/GV cases. Patientcharacteristics (age, sex, immunosuppression) are listed next to available histologic data for allreported cases of PHIR-GF/GV.JAAD CASE REPORTSSEPTEMBER 2018760 McCoy et al

Granulomatous dermatitis as a postherpetic isotopic response in immunocompromised patients: A report of 5 cases

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Granulomatous dermatitis as a postherpetic isotopic response in immunocompromised patients: A report of 5 cases

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