Report
Eosinophilic folliculitis occurring after stem cell transplant for acute lymphoblastic leukemia: a case report and review Kristine Zitelli1, MD, Neil Fernandes1, MD, and Brian B. Adams1,2, MD, MPH
1 Department of Dermatology, University of Cincinnati, Cincinnati, OH, USA, and 2 Section of Dermatology, Veterans Affairs Medical Center, Cincinnati, OH, USA
Correspondence Brian B. Adams, MD, MPH Department of Dermatology University of Cincinnati PO Box 670592 Cincinnati, OH 45267-0592, USA E-mail: [email protected] Funding: None. Conflicts of interest: None.
Abstract Background Eosinophilic folliculitis (EF) comprises classic eosinophilic pustular folliculitis (EPF), human immunodeficiency virus (HIV)-related EF, and infantile EPF subtypes. A fourth proposed subtype describes EF associated with hematologic malignancy. Recently, EF has occurred after bone marrow or stem cell transplantation (SCT). Objectives We report a unique case of EF after haploidentical allogeneic SCT for acute lymphoblastic leukemia (ALL) and review the literature for similar cases. Methods A 56-year-old, HIV-negative ALL patient presented with an intensely pruritic papulopustular eruption. He had undergone haploidentical allogeneic SCT 65 days earlier, which he had tolerated well. Histopathology revealed a moderately dense perifollicular and perivascular lymphocytic infiltrate with many eosinophils extending from the superficial dermis to the subcutaneous fat. Fungal stains were negative. These findings were highly consistent with EF. Results Therapy with a class II topical corticosteroid ointment, oral doxepin, and emollients achieved near-resolution of the lesions within eight weeks. Transition to topical tacrolimus 0.1% ointment applied twice daily to residual lesions yielded complete clearance by 12 weeks with mild post-inflammatory hyperpigmentation. The patient’s ALL remains in remission. Conclusions A fourth proposed subtype of EF is associated with HIV-negative hematologic disease. This subtype is distinguished by a predictable timeframe to presentation and a relatively rapid response to therapy. Although EF is an important consideration in all patients with hematologic malignancy, clinically heightened suspicion is warranted during the 2–3 months after transplant.
Introduction Ofuji et al.1 first described eosinophilic pustular folliculitis (EPF) as pruritic, sterile, follicular, papulopustular crops that extend peripherally and resolve with dyspigmentation. Three well-known subtypes exist, including classic EPF (Ofuji’s disease), human immunodeficiency virus (HIV)-related eosinophilic folliculitis, and infantile EPF.2 More recently, unique cases of eosinophilic folliculitis (EF) have emerged. Some newer associations with EF refer to medications, such as carbamazepine3 and allopurinol,4,5 pregnancy,6 and hematologic malignancies including acute myeloid leukemia (AML),7 chronic lymphocytic leukemia (CLL),7 B cell CLL,8 Hodgkin lymphoma,9 non-Hodgkin lymphoma (NHL),10 and myelodysplastic syndrome.11 Keida et al.12 suggest a fourth EF subtype for HIV-negative patients with hematologic disease. Previous reviews additionally describe other EF cases occurring after bone marrow transplantation (BMT) or stem cell transplantation ª 2014 The International Society of Dermatology
(SCT).13,14 Accordingly, in the setting of malignancy and immunosuppression, EF is likely to represent a manifestation of immune dysregulation.15 Thirteen previously reported cases depict EF in patients with hematologic malignancy specifically following BMT or SCT.12–14,16–21 Affected patients share similar characteristics. Perhaps most interesting is the finding that although EF may occur at any time during the course of a hematologic malignancy, transplant-related EF typically presents approximately 60 days after BMT or SCT. To our knowledge, we report the first case of EF following haploidentical allogeneic SCT for acute lymphoblastic leukemia (ALL). We additionally review the literature for similar cases of transplant-related EF. Materials and Methods A 56-year-old, HIV-negative man presented with an intensely pruritic papulopustular eruption, initially involving the face, which progressed over two weeks to involve the chest and upper International Journal of Dermatology 2015, 54, 785–789
785
786
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Zitelli et al.
Transplant-related eosinophilic folliculitis
back. His past medical history was significant for ALL. Notably, approximately 65 days prior to presentation, he had undergone definitive treatment with haploidentical allogeneic SCT. His SCT conditioning regimen included cyclophosphamide, tacrolimus, and mycophenolate mofetil. Current medications included
kemia cutis or lymphoma), or other nonspecific reactions (e.g. Sweet’s syndrome, erythema nodosum, or EF).22 This case of EF following haplo-identical allogeneic SCT for ALL parallels 13 other transplant-related EF cases with different hematological malignancies (Table 1).12–14,16–21
dapsone, clarithromycin, valacyclovir, fluconazole, and tacrolimus. Other previous chemotherapy regimens included hyperCVAD (i.e. cyclophosphamide, vincristine, doxorubicin, and dexamethasone, followed by methotrexate and cytarabine) plus imatinib initially with remission, followed by inotuzumab ozogamicin (anti-CD22-calicheamicin conjugate) after relapse. He had tolerated SCT well and had engrafted successfully within the expected time period. Physical examination revealed numerous erythematous and dark brown papules and scattered pustules measuring 2–4 mm in diameter involving the face, chest and upper back (Fig. 1). The initial differential diagnosis included graft-versus-host disease (GVHD), EF, bacterial folliculitis and atypical drug eruption with focal secondary impetiginization. Histopathologic examination revealed a moderately dense perifollicular and perivascular predominantly lymphocytic infiltrate with many eosinophils extending from the superficial dermis to the subcutaneous fat (Fig. 2). The eosinophils extended into the affected follicles (Fig. 2c). Fungal stains were negative. These findings were highly consistent with EF. The epidermal basal vacuolar changes typically seen in acute GVHD were not present and the lack of microorganisms or neutrophils in the perifollicular infiltrate made infectious folliculitis unlikely. The perivascular infiltrate of lymphocytes and eosinophils raised suspicion of dermal hypersensitivity reactions such as urticaria or arthropod assault, but the folliculocentric nature of the infiltrate and presence of follicular spongiosis were more specific for EF.
(a)
Prior to SCT, the patient’s relative eosinophil count had been 0.1% (normal range: 0.0–8.0%) of 2400/ll leukocytes (normal range: 3800–10 800/ll). A chemistry panel at the time of the eruption revealed 6.4% eosinophils of 7500/ll leukocytes (absolute count: 480/ll), indicating a new relative peripheral eosinophilia.
Results Therapy with a class II topical corticosteroid ointment, oral doxepin taken nightly, and emollients achieved nearresolution of the lesions and pruritus within eight weeks. Transition to topical tacrolimus 0.1% ointment applied twice daily to residual lesions yielded complete clearance by 12 weeks with mild post-inflammatory hyperpigmentation. The patients ALL remains in remission. Discussion Cutaneous eruptions following transplant may include transplant-related disorders (e.g. GVHD, drug eruptions, or neoplasms), underlying disease manifestations (e.g. leuInternational Journal of Dermatology 2015, 54, 785–789
(b) Figure 1 (a) Eosinophilic folliculitis involving the face, chest, and upper back after haploidentical allogeneic stem cell transplantation for acute lymphoblastic leukemia in a 56-year-old, HIV-negative man. (b) Clinical morphology of erythematous, dark brown papules and scattered pustules involving the chest ª 2014 The International Society of Dermatology
Zitelli et al.
(a)
(b)
(c) Figure 2 (a) Histology of a biopsy of a representative lesion showing a moderately dense perifollicular and, to a lesser extent, perivascular infiltrate. (b) The infiltrate extends from the superficial dermis to the available subcutaneous tissue. (c) Higher magnification reveals a dense infiltrate of lymphocytes and numerous eosinophils extending into hair follicles. [Hematoxylin and eosin stain; original magnification (a) 940, (b) 940, (c) 9200]
ª 2014 The International Society of Dermatology
Transplant-related eosinophilic folliculitis
Report
Analysis of these 13 previous patients and the present patient (n = 14) reveals that EF occurred in HIV-negative patients after autologous BMT (n = 5, 35.7%), allogeneic BMT (n = 3, 21.4%), autologous SCT (n = 2, 14.3%), allogeneic SCT (n = 2, 14.3%), and mini-allogeneic SCT (n = 2, 14.3%). Transplant indications included NHL (n = 4, 28.6%), AML (n = 3, 21.4%), myeloma (n = 2, 14.3%), ALL (n = 2, 14.3%), and one case each (n = 1, 7.1%) of chronic myelogenous leukemia, aplastic anemia, and eosinophilic acute leukemia. Patient ages ranged from 12 years to 59 years (median: 37 years), and the male to female ratio was 8 : 6. Notably, the median approximate time from transplant to cutaneous eruption was 60 days (range: 20–90 days). Lesions commonly involved the head, neck, upper extremities, and trunk. Histopathologic examination revealed a mixed (usually eosinophil-rich) perivascular, periadnexal, and/or perifollicular infiltrate with or without specific folliculitis pathology or spongiosis. Thirteen patients had a peripheral eosinophilia. In transplant-related EF, lesions resolved at a median of eight weeks (range: 1–32 weeks) with various treatments including oral and topical steroids, dapsone, antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs; e.g. indomethacin), antihistamines, and/or emollients. The collective data suggest a distinct entity in which HIV-negative patients with hematologic malignancy develop EF approximately 60 days after BMT or SCT, which initially resolves with minimal therapy. Eosinophilic folliculitis reflects multifactorial aberrations in eosinophil regulation and is likely to represent a Th2 predominant condition,23 although the mRNA profiles for Th1, Th2, and Th17 cells are not fully delineated.24 Recent research shows that prostaglandin D2 induces considerable eosinophil infiltrates via sebocyte production of eotaxin-3.25 Accordingly, NSAIDs (e.g. indomethacin) would effectively treat EF through cyclooxygenase inhibition and thus decreased prostaglandin production. Other research supports interplay between indomethacin and the prostaglandin D2 receptor (i.e. chemoattractant receptor homologous molecule expressed on Th2 cells) for EF pathogenesis.26 Notably, a peripheral eosinophilia often occurs in EF12–14,16–21 and may transpire after preparative transplant regimens with busulfan, cyclophosphamide, or total body irradiation.27 Further research may reveal the degree to which BMT or SCT and associated medication regimens alter either these inflammatory pathways or the induction of eosinophil chemotaxis. New data likewise support immune dysregulation in EF pathogenesis. A recent review of the Japanese literature from 1980 to 2010 classified 113 EF cases into classic EPF, immunosuppression-associated EF, or infantile EF
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Table 1 Transplant-related eosinophilic folliculitis (EF)
References
Patient age, years
Days to EF
PE
Treatment
Outcome
Patrizi et al.16 Bull et al.19 Bull et al.19 Bull et al.19
BMT BMT BMT BMT
40 70 60 90
Yes Yes Yes Yes
Lymphoma relapse Resolved/8 weeks Resolved/8 weeks Resolved/8 weeks
B cell NHL
Autologous BMT
73
Yes
M
ALL
Autologous SCT
60
Yes
Oral steroid, antihistamines Oral and topical steroids Dapsone, topical steroid Dapsone, topical steroid, antihistamines Minocycline, oral and topical steroids Oral steroid
41
M
NHL
Autologous SCT
30
Yes
Resolved/8 weeks
Bull et al.19 Ota et al.13 Ogawa et al.21
39 22 12
F F F
MDS/AML CML AA
Allogeneic BMT Allogeneic BMT Allogeneic BMT
60 90 42
Yes Yes Yes
Fraser et al.14
45
F
Myeloma
Mini-allogeneic SCT
60
Yes
Fraser et al.14
55
M
AML
Mini-allogeneic SCT
90
No
Goiriz et al.17 Present case
26 56
F M
EAL ALL
Allogeneic SCT Allogeneic SCT
20 65
Yes Yes
Oral and topical NSAIDs, topical steroid Oral and topical steroids Topical steroid NSAIDs, topical steroid, antihistamines Topical steroid, antihistamines, emollients Topical steroid, antihistamines Oral steroid Topical steroid, antihistamine, emollients
Gender
Hematologic malignancy
Transplant
31 35 40 59
F M M M
NHL B cell NHL AML IgG myeloma
Autologous Autologous Autologous Autologous
Evans et al.20
35
M
Takiwaki & Wantanabe18 Keida et al.12
16
Resolved/6 weeks Resolved/32 weeks
Resolved/3 weeks Resolved/5 weeks Resolved/2 weeks Gradual improvement Slow response Resolved/1 week Resolved/10 weeks
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; AA, aplastic anemia; BMT, bone marrow transplant; CML, chronic myeloid leukemia; EAL, eosinophilic acute leukemia; F, female; IgG, immunoglobulin G; M, male; MDS, myelodysplasia; NHL, non-Hodgkin lymphoma; NSAIDs, nonsteroidal anti-inflammatory drugs; PE, peripheral eosinophilia; SCT, stem cell transplant.
subtypes.28 Data revealed that, in Japan, the incidence of immunosuppression-associated EF increased from the late 1990s in line with the rising number of HIV-positive patients.28 Interestingly, EF may develop in HIV patients at 3–6 months after the initiation of highly active antiretroviral therapy (HAART),29 thus implying a consequence of immune reconstitution.28 We also consider that treatment with BMT or SCT for hematologic malignancy may result in immune reconstitution-type reactions. Conclusions Eosinophilic folliculitis historically comprises classic, HIV-related, and infantile forms. A fourth proposed subtype refers to EF associated with HIV-negative hematologic disease and a self-limiting course. Among patients with hematologic malignancy, EF occurred approximately 60 days after BMT or SCT in at least 14 patients. This subset of transplant-related EF is distinguished by a predictable timeframe to presentation and a relatively rapid response to therapy. Although EF is an important consideration in all patients with hematologic malignancy, clinically heightened suspicion is warranted during the initial 2–3 months following transplant. International Journal of Dermatology 2015, 54, 785–789
Acknowledgment Dr. Miguel A. Islas, Internal Medicine and Oncology Hematology Care, Jewish Hospital, is thanked for his contribution in the care of this patient. References 1 Ofuji S, Ogino A, Horio T, et al. Eosinophilic pustular folliculitis. Acta Derm Venereol 1970; 50: 195–203. 2 Moritz DL, Elmets CA. Eosinophilic pustular folliculitis. J Am Acad Dermatol 1991; 24: 903–907. 3 Mizoguchi S, Setoyama M, Higashi Y, et al. Eosinophilic pustular folliculitis induced by carbamazepine. J Am Acad Dermatol 1998; 38: 641–643. 4 Ooi CG, Walker P, Sidhu SK, et al. Allopurinol-induced generalized eosinophilic pustular folliculitis. Australas J Dermatol 2006; 47: 270–273. 5 Maejima H, Mukai H, Hikaru E. Eosinophilic pustular folliculitis induced by allopurinol and timepidium bromide. Acta Derm Venereol 2002; 82: 316–317. 6 Mabuchi T, Matsuyama T, Ozawa A. Case of eosinophilic pustular folliculitis associated with pregnancy. J Dermatol 2011; 38: 1191–1193. ª 2014 The International Society of Dermatology
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7 Patrizi A, Chieregato C, Visani G, et al. Leukemiaassociated eosinophilic folliculitis (Ofujis disease). J Eur Acad Dermatol Venereol 2004; 18: 596–598. 8 Lambert J, Berneman Z, Dockx P, et al. Eosinophilic pustular folliculitis and B cell chronic lymphatic leukemia. Dermatology 1994; 189: 58–59. 9 Vassallo C, Ciocca O, Arcaini L, et al. Eosinophilic folliculitis occurring in a patient affected by Hodgkin lymphoma. Int J Dermatol 2002; 41: 298–300. 10 Barkley A, Shall I, Millard LG. Simultaneous onset of eosinophilic pustular dermatosis and non-Hodgkin lymphoma. Abstracts of the First Congress of the European Academy of Dermatology and Venereology, September 25–28, 1989, Firenze: 210. 11 Jang KA, Chung ST, Choi JH, et al. Eosinophilic pustular folliculitis (Ofujis disease) in myelodysplastic syndrome. J Dermatol 1998; 25: 742–746. 12 Keida T, Hayashi N, Kawashima M. Eosinophilic pustular folliculitis following autologous peripheral blood stem-cell transplantation. J Dermatol 2004; 31: 21–26. 13 Ota M, Shimizu T, Hashino S, et al. Eosinophilic folliculitis in a patient after allogeneic bone marrow transplantation: case report and review of the literature. Am J Hematol 2004; 76: 295–296. 14 Fraser SJ, Benton EC, Roddie PH, et al. Eosinophilic folliculitis: an important differential diagnosis after allogeneic bone marrow transplant. Clin Exp Dermatol 2009; 34: 369–371. 15 Magro CM, Crowson AN. Eosinophilic pustular follicular reaction: a paradigm of immune dysregulation. Int J Dermatol 1994; 33: 172–178. 16 Patrizi A, Di Lernia V, Neri I, et al. Eosinophilic pustular folliculitis (Ofujis disease) and non-Hodgkin lymphoma. Acta Derm Venereol 1992; 72: 146–147. 17 Goiriz R, Guhl-Millan G, Penas PF, et al. Eosinophilic folliculitis following allogeneic peripheral blood stem cell transplantation: case report and review. J Cutan Pathol 2007; 34: 33–36. 18 Takiwaki H, Wantanabe T. Eosinophilic folliculitis occurred in an HIV-negative patient treated for leukemia. Hifuka No Rinsho 2001; 55: 485–487. 19 Bull RH, Harland CA, Fallowfield ME, et al. Eosinophilic folliculitis: a self-limiting illness in patients
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21
22
23
24
25
26
27
28
29
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being treated for hematological malignancy. Br J Dermatol 1993; 129: 178–182. Evans TR, Mansi JL, Bull R, et al. Eosinophilic folliculitis occurring after bone marrow autograft in a patient with non-Hodgkins lymphoma. Cancer 1994; 73: 2512–2514. Ogawa E, Okuyama R, Niizuma H, et al. Eosinophilic pustular folliculitis occurring after bone marrow transplantation in a child with aplastic anemia. Acta Derm Venereol 2009; 89: 200–201. Canninga-van Dijk MR, Sanders CJ, Verdonck LF, et al. Differential diagnosis of skin lesions after allogeneic hematopoietic stem cell transplantation. Histopathology 2003; 42: 313–330. Fushimi M, Tokura Y, Sachi Y, et al. Eosinophilic pustular folliculitis effectively treated with recombinant interferon-gamma: suppression of mRNA expression of interleukin 5 in peripheral blood mononuclear cells. Br J Dermatol 1996; 134: 766–772. Otsuka A, Doi H, Miyachi Y, et al. Treatment of eosinophilic pustular folliculitis with cyclosporin: suppression of mRNA expression of IL-4 and IL-13. J Eur Acad Dermatol Venereol 2010; 24: 1489–1491. Nakahigashi K, Doi H, Otsuka A, et al. PGD2 induces eotaxin-3 via PPARc from sebocytes: a possible pathogenesis of eosinophilic pustular folliculitis. J Allergy Clin Immunol 2012; 129: 536–543. Satoh T, Shimura C, Miyagishi C, et al. Indomethacin-induced reduction in CRTH2 in eosinophilic pustular folliculitis (Ofujis disease): a proposed mechanism of action. Acta Derm Venereol 2010; 90: 18–22. Kalaycioglu ME, Bolwell BJ. Eosinophilia after allogeneic bone marrow transplantation using the busulfan and cyclophosphamide preparative regimen. Bone Marrow Transplant 1994; 14: 113–115. Katoh M, Nomura T, Miyachi Y, et al. Eosinophilic pustular folliculitis: a review of the Japanese published works. J Dermatol 2013; 40: 15–20. Rajendran PM, Dolev JC, Heaphy MR Jr, et al. Eosinophilic folliculitis: before and after the introduction of antiretroviral therapy. Arch Dermatol 2005; 141: 1227–1231.
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Eosinophilic folliculitis occurring after stem cell transplant for acute lymphoblastic leukemia: a case report and review Kristine Zitelli1, MD, Neil Fernandes1, MD, and Brian B. Adams1,2, MD, MPH
1 Department of Dermatology, University of Cincinnati, Cincinnati, OH, USA, and 2 Section of Dermatology, Veterans Affairs Medical Center, Cincinnati, OH, USA
Correspondence Brian B. Adams, MD, MPH Department of Dermatology University of Cincinnati PO Box 670592 Cincinnati, OH 45267-0592, USA E-mail: [email protected] Funding: None. Conflicts of interest: None.
Abstract Background Eosinophilic folliculitis (EF) comprises classic eosinophilic pustular folliculitis (EPF), human immunodeficiency virus (HIV)-related EF, and infantile EPF subtypes. A fourth proposed subtype describes EF associated with hematologic malignancy. Recently, EF has occurred after bone marrow or stem cell transplantation (SCT). Objectives We report a unique case of EF after haploidentical allogeneic SCT for acute lymphoblastic leukemia (ALL) and review the literature for similar cases. Methods A 56-year-old, HIV-negative ALL patient presented with an intensely pruritic papulopustular eruption. He had undergone haploidentical allogeneic SCT 65 days earlier, which he had tolerated well. Histopathology revealed a moderately dense perifollicular and perivascular lymphocytic infiltrate with many eosinophils extending from the superficial dermis to the subcutaneous fat. Fungal stains were negative. These findings were highly consistent with EF. Results Therapy with a class II topical corticosteroid ointment, oral doxepin, and emollients achieved near-resolution of the lesions within eight weeks. Transition to topical tacrolimus 0.1% ointment applied twice daily to residual lesions yielded complete clearance by 12 weeks with mild post-inflammatory hyperpigmentation. The patient’s ALL remains in remission. Conclusions A fourth proposed subtype of EF is associated with HIV-negative hematologic disease. This subtype is distinguished by a predictable timeframe to presentation and a relatively rapid response to therapy. Although EF is an important consideration in all patients with hematologic malignancy, clinically heightened suspicion is warranted during the 2–3 months after transplant.
Introduction Ofuji et al.1 first described eosinophilic pustular folliculitis (EPF) as pruritic, sterile, follicular, papulopustular crops that extend peripherally and resolve with dyspigmentation. Three well-known subtypes exist, including classic EPF (Ofuji’s disease), human immunodeficiency virus (HIV)-related eosinophilic folliculitis, and infantile EPF.2 More recently, unique cases of eosinophilic folliculitis (EF) have emerged. Some newer associations with EF refer to medications, such as carbamazepine3 and allopurinol,4,5 pregnancy,6 and hematologic malignancies including acute myeloid leukemia (AML),7 chronic lymphocytic leukemia (CLL),7 B cell CLL,8 Hodgkin lymphoma,9 non-Hodgkin lymphoma (NHL),10 and myelodysplastic syndrome.11 Keida et al.12 suggest a fourth EF subtype for HIV-negative patients with hematologic disease. Previous reviews additionally describe other EF cases occurring after bone marrow transplantation (BMT) or stem cell transplantation ª 2014 The International Society of Dermatology
(SCT).13,14 Accordingly, in the setting of malignancy and immunosuppression, EF is likely to represent a manifestation of immune dysregulation.15 Thirteen previously reported cases depict EF in patients with hematologic malignancy specifically following BMT or SCT.12–14,16–21 Affected patients share similar characteristics. Perhaps most interesting is the finding that although EF may occur at any time during the course of a hematologic malignancy, transplant-related EF typically presents approximately 60 days after BMT or SCT. To our knowledge, we report the first case of EF following haploidentical allogeneic SCT for acute lymphoblastic leukemia (ALL). We additionally review the literature for similar cases of transplant-related EF. Materials and Methods A 56-year-old, HIV-negative man presented with an intensely pruritic papulopustular eruption, initially involving the face, which progressed over two weeks to involve the chest and upper International Journal of Dermatology 2015, 54, 785–789
785
786
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Zitelli et al.
Transplant-related eosinophilic folliculitis
back. His past medical history was significant for ALL. Notably, approximately 65 days prior to presentation, he had undergone definitive treatment with haploidentical allogeneic SCT. His SCT conditioning regimen included cyclophosphamide, tacrolimus, and mycophenolate mofetil. Current medications included
kemia cutis or lymphoma), or other nonspecific reactions (e.g. Sweet’s syndrome, erythema nodosum, or EF).22 This case of EF following haplo-identical allogeneic SCT for ALL parallels 13 other transplant-related EF cases with different hematological malignancies (Table 1).12–14,16–21
dapsone, clarithromycin, valacyclovir, fluconazole, and tacrolimus. Other previous chemotherapy regimens included hyperCVAD (i.e. cyclophosphamide, vincristine, doxorubicin, and dexamethasone, followed by methotrexate and cytarabine) plus imatinib initially with remission, followed by inotuzumab ozogamicin (anti-CD22-calicheamicin conjugate) after relapse. He had tolerated SCT well and had engrafted successfully within the expected time period. Physical examination revealed numerous erythematous and dark brown papules and scattered pustules measuring 2–4 mm in diameter involving the face, chest and upper back (Fig. 1). The initial differential diagnosis included graft-versus-host disease (GVHD), EF, bacterial folliculitis and atypical drug eruption with focal secondary impetiginization. Histopathologic examination revealed a moderately dense perifollicular and perivascular predominantly lymphocytic infiltrate with many eosinophils extending from the superficial dermis to the subcutaneous fat (Fig. 2). The eosinophils extended into the affected follicles (Fig. 2c). Fungal stains were negative. These findings were highly consistent with EF. The epidermal basal vacuolar changes typically seen in acute GVHD were not present and the lack of microorganisms or neutrophils in the perifollicular infiltrate made infectious folliculitis unlikely. The perivascular infiltrate of lymphocytes and eosinophils raised suspicion of dermal hypersensitivity reactions such as urticaria or arthropod assault, but the folliculocentric nature of the infiltrate and presence of follicular spongiosis were more specific for EF.
(a)
Prior to SCT, the patient’s relative eosinophil count had been 0.1% (normal range: 0.0–8.0%) of 2400/ll leukocytes (normal range: 3800–10 800/ll). A chemistry panel at the time of the eruption revealed 6.4% eosinophils of 7500/ll leukocytes (absolute count: 480/ll), indicating a new relative peripheral eosinophilia.
Results Therapy with a class II topical corticosteroid ointment, oral doxepin taken nightly, and emollients achieved nearresolution of the lesions and pruritus within eight weeks. Transition to topical tacrolimus 0.1% ointment applied twice daily to residual lesions yielded complete clearance by 12 weeks with mild post-inflammatory hyperpigmentation. The patients ALL remains in remission. Discussion Cutaneous eruptions following transplant may include transplant-related disorders (e.g. GVHD, drug eruptions, or neoplasms), underlying disease manifestations (e.g. leuInternational Journal of Dermatology 2015, 54, 785–789
(b) Figure 1 (a) Eosinophilic folliculitis involving the face, chest, and upper back after haploidentical allogeneic stem cell transplantation for acute lymphoblastic leukemia in a 56-year-old, HIV-negative man. (b) Clinical morphology of erythematous, dark brown papules and scattered pustules involving the chest ª 2014 The International Society of Dermatology
Zitelli et al.
(a)
(b)
(c) Figure 2 (a) Histology of a biopsy of a representative lesion showing a moderately dense perifollicular and, to a lesser extent, perivascular infiltrate. (b) The infiltrate extends from the superficial dermis to the available subcutaneous tissue. (c) Higher magnification reveals a dense infiltrate of lymphocytes and numerous eosinophils extending into hair follicles. [Hematoxylin and eosin stain; original magnification (a) 940, (b) 940, (c) 9200]
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Transplant-related eosinophilic folliculitis
Report
Analysis of these 13 previous patients and the present patient (n = 14) reveals that EF occurred in HIV-negative patients after autologous BMT (n = 5, 35.7%), allogeneic BMT (n = 3, 21.4%), autologous SCT (n = 2, 14.3%), allogeneic SCT (n = 2, 14.3%), and mini-allogeneic SCT (n = 2, 14.3%). Transplant indications included NHL (n = 4, 28.6%), AML (n = 3, 21.4%), myeloma (n = 2, 14.3%), ALL (n = 2, 14.3%), and one case each (n = 1, 7.1%) of chronic myelogenous leukemia, aplastic anemia, and eosinophilic acute leukemia. Patient ages ranged from 12 years to 59 years (median: 37 years), and the male to female ratio was 8 : 6. Notably, the median approximate time from transplant to cutaneous eruption was 60 days (range: 20–90 days). Lesions commonly involved the head, neck, upper extremities, and trunk. Histopathologic examination revealed a mixed (usually eosinophil-rich) perivascular, periadnexal, and/or perifollicular infiltrate with or without specific folliculitis pathology or spongiosis. Thirteen patients had a peripheral eosinophilia. In transplant-related EF, lesions resolved at a median of eight weeks (range: 1–32 weeks) with various treatments including oral and topical steroids, dapsone, antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs; e.g. indomethacin), antihistamines, and/or emollients. The collective data suggest a distinct entity in which HIV-negative patients with hematologic malignancy develop EF approximately 60 days after BMT or SCT, which initially resolves with minimal therapy. Eosinophilic folliculitis reflects multifactorial aberrations in eosinophil regulation and is likely to represent a Th2 predominant condition,23 although the mRNA profiles for Th1, Th2, and Th17 cells are not fully delineated.24 Recent research shows that prostaglandin D2 induces considerable eosinophil infiltrates via sebocyte production of eotaxin-3.25 Accordingly, NSAIDs (e.g. indomethacin) would effectively treat EF through cyclooxygenase inhibition and thus decreased prostaglandin production. Other research supports interplay between indomethacin and the prostaglandin D2 receptor (i.e. chemoattractant receptor homologous molecule expressed on Th2 cells) for EF pathogenesis.26 Notably, a peripheral eosinophilia often occurs in EF12–14,16–21 and may transpire after preparative transplant regimens with busulfan, cyclophosphamide, or total body irradiation.27 Further research may reveal the degree to which BMT or SCT and associated medication regimens alter either these inflammatory pathways or the induction of eosinophil chemotaxis. New data likewise support immune dysregulation in EF pathogenesis. A recent review of the Japanese literature from 1980 to 2010 classified 113 EF cases into classic EPF, immunosuppression-associated EF, or infantile EF
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Table 1 Transplant-related eosinophilic folliculitis (EF)
References
Patient age, years
Days to EF
PE
Treatment
Outcome
Patrizi et al.16 Bull et al.19 Bull et al.19 Bull et al.19
BMT BMT BMT BMT
40 70 60 90
Yes Yes Yes Yes
Lymphoma relapse Resolved/8 weeks Resolved/8 weeks Resolved/8 weeks
B cell NHL
Autologous BMT
73
Yes
M
ALL
Autologous SCT
60
Yes
Oral steroid, antihistamines Oral and topical steroids Dapsone, topical steroid Dapsone, topical steroid, antihistamines Minocycline, oral and topical steroids Oral steroid
41
M
NHL
Autologous SCT
30
Yes
Resolved/8 weeks
Bull et al.19 Ota et al.13 Ogawa et al.21
39 22 12
F F F
MDS/AML CML AA
Allogeneic BMT Allogeneic BMT Allogeneic BMT
60 90 42
Yes Yes Yes
Fraser et al.14
45
F
Myeloma
Mini-allogeneic SCT
60
Yes
Fraser et al.14
55
M
AML
Mini-allogeneic SCT
90
No
Goiriz et al.17 Present case
26 56
F M
EAL ALL
Allogeneic SCT Allogeneic SCT
20 65
Yes Yes
Oral and topical NSAIDs, topical steroid Oral and topical steroids Topical steroid NSAIDs, topical steroid, antihistamines Topical steroid, antihistamines, emollients Topical steroid, antihistamines Oral steroid Topical steroid, antihistamine, emollients
Gender
Hematologic malignancy
Transplant
31 35 40 59
F M M M
NHL B cell NHL AML IgG myeloma
Autologous Autologous Autologous Autologous
Evans et al.20
35
M
Takiwaki & Wantanabe18 Keida et al.12
16
Resolved/6 weeks Resolved/32 weeks
Resolved/3 weeks Resolved/5 weeks Resolved/2 weeks Gradual improvement Slow response Resolved/1 week Resolved/10 weeks
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; AA, aplastic anemia; BMT, bone marrow transplant; CML, chronic myeloid leukemia; EAL, eosinophilic acute leukemia; F, female; IgG, immunoglobulin G; M, male; MDS, myelodysplasia; NHL, non-Hodgkin lymphoma; NSAIDs, nonsteroidal anti-inflammatory drugs; PE, peripheral eosinophilia; SCT, stem cell transplant.
subtypes.28 Data revealed that, in Japan, the incidence of immunosuppression-associated EF increased from the late 1990s in line with the rising number of HIV-positive patients.28 Interestingly, EF may develop in HIV patients at 3–6 months after the initiation of highly active antiretroviral therapy (HAART),29 thus implying a consequence of immune reconstitution.28 We also consider that treatment with BMT or SCT for hematologic malignancy may result in immune reconstitution-type reactions. Conclusions Eosinophilic folliculitis historically comprises classic, HIV-related, and infantile forms. A fourth proposed subtype refers to EF associated with HIV-negative hematologic disease and a self-limiting course. Among patients with hematologic malignancy, EF occurred approximately 60 days after BMT or SCT in at least 14 patients. This subset of transplant-related EF is distinguished by a predictable timeframe to presentation and a relatively rapid response to therapy. Although EF is an important consideration in all patients with hematologic malignancy, clinically heightened suspicion is warranted during the initial 2–3 months following transplant. International Journal of Dermatology 2015, 54, 785–789
Acknowledgment Dr. Miguel A. Islas, Internal Medicine and Oncology Hematology Care, Jewish Hospital, is thanked for his contribution in the care of this patient. References 1 Ofuji S, Ogino A, Horio T, et al. Eosinophilic pustular folliculitis. Acta Derm Venereol 1970; 50: 195–203. 2 Moritz DL, Elmets CA. Eosinophilic pustular folliculitis. J Am Acad Dermatol 1991; 24: 903–907. 3 Mizoguchi S, Setoyama M, Higashi Y, et al. Eosinophilic pustular folliculitis induced by carbamazepine. J Am Acad Dermatol 1998; 38: 641–643. 4 Ooi CG, Walker P, Sidhu SK, et al. Allopurinol-induced generalized eosinophilic pustular folliculitis. Australas J Dermatol 2006; 47: 270–273. 5 Maejima H, Mukai H, Hikaru E. Eosinophilic pustular folliculitis induced by allopurinol and timepidium bromide. Acta Derm Venereol 2002; 82: 316–317. 6 Mabuchi T, Matsuyama T, Ozawa A. Case of eosinophilic pustular folliculitis associated with pregnancy. J Dermatol 2011; 38: 1191–1193. ª 2014 The International Society of Dermatology
Zitelli et al.
7 Patrizi A, Chieregato C, Visani G, et al. Leukemiaassociated eosinophilic folliculitis (Ofujis disease). J Eur Acad Dermatol Venereol 2004; 18: 596–598. 8 Lambert J, Berneman Z, Dockx P, et al. Eosinophilic pustular folliculitis and B cell chronic lymphatic leukemia. Dermatology 1994; 189: 58–59. 9 Vassallo C, Ciocca O, Arcaini L, et al. Eosinophilic folliculitis occurring in a patient affected by Hodgkin lymphoma. Int J Dermatol 2002; 41: 298–300. 10 Barkley A, Shall I, Millard LG. Simultaneous onset of eosinophilic pustular dermatosis and non-Hodgkin lymphoma. Abstracts of the First Congress of the European Academy of Dermatology and Venereology, September 25–28, 1989, Firenze: 210. 11 Jang KA, Chung ST, Choi JH, et al. Eosinophilic pustular folliculitis (Ofujis disease) in myelodysplastic syndrome. J Dermatol 1998; 25: 742–746. 12 Keida T, Hayashi N, Kawashima M. Eosinophilic pustular folliculitis following autologous peripheral blood stem-cell transplantation. J Dermatol 2004; 31: 21–26. 13 Ota M, Shimizu T, Hashino S, et al. Eosinophilic folliculitis in a patient after allogeneic bone marrow transplantation: case report and review of the literature. Am J Hematol 2004; 76: 295–296. 14 Fraser SJ, Benton EC, Roddie PH, et al. Eosinophilic folliculitis: an important differential diagnosis after allogeneic bone marrow transplant. Clin Exp Dermatol 2009; 34: 369–371. 15 Magro CM, Crowson AN. Eosinophilic pustular follicular reaction: a paradigm of immune dysregulation. Int J Dermatol 1994; 33: 172–178. 16 Patrizi A, Di Lernia V, Neri I, et al. Eosinophilic pustular folliculitis (Ofujis disease) and non-Hodgkin lymphoma. Acta Derm Venereol 1992; 72: 146–147. 17 Goiriz R, Guhl-Millan G, Penas PF, et al. Eosinophilic folliculitis following allogeneic peripheral blood stem cell transplantation: case report and review. J Cutan Pathol 2007; 34: 33–36. 18 Takiwaki H, Wantanabe T. Eosinophilic folliculitis occurred in an HIV-negative patient treated for leukemia. Hifuka No Rinsho 2001; 55: 485–487. 19 Bull RH, Harland CA, Fallowfield ME, et al. Eosinophilic folliculitis: a self-limiting illness in patients
ª 2014 The International Society of Dermatology
Transplant-related eosinophilic folliculitis
20
21
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being treated for hematological malignancy. Br J Dermatol 1993; 129: 178–182. Evans TR, Mansi JL, Bull R, et al. Eosinophilic folliculitis occurring after bone marrow autograft in a patient with non-Hodgkins lymphoma. Cancer 1994; 73: 2512–2514. Ogawa E, Okuyama R, Niizuma H, et al. Eosinophilic pustular folliculitis occurring after bone marrow transplantation in a child with aplastic anemia. Acta Derm Venereol 2009; 89: 200–201. Canninga-van Dijk MR, Sanders CJ, Verdonck LF, et al. Differential diagnosis of skin lesions after allogeneic hematopoietic stem cell transplantation. Histopathology 2003; 42: 313–330. Fushimi M, Tokura Y, Sachi Y, et al. Eosinophilic pustular folliculitis effectively treated with recombinant interferon-gamma: suppression of mRNA expression of interleukin 5 in peripheral blood mononuclear cells. Br J Dermatol 1996; 134: 766–772. Otsuka A, Doi H, Miyachi Y, et al. Treatment of eosinophilic pustular folliculitis with cyclosporin: suppression of mRNA expression of IL-4 and IL-13. J Eur Acad Dermatol Venereol 2010; 24: 1489–1491. Nakahigashi K, Doi H, Otsuka A, et al. PGD2 induces eotaxin-3 via PPARc from sebocytes: a possible pathogenesis of eosinophilic pustular folliculitis. J Allergy Clin Immunol 2012; 129: 536–543. Satoh T, Shimura C, Miyagishi C, et al. Indomethacin-induced reduction in CRTH2 in eosinophilic pustular folliculitis (Ofujis disease): a proposed mechanism of action. Acta Derm Venereol 2010; 90: 18–22. Kalaycioglu ME, Bolwell BJ. Eosinophilia after allogeneic bone marrow transplantation using the busulfan and cyclophosphamide preparative regimen. Bone Marrow Transplant 1994; 14: 113–115. Katoh M, Nomura T, Miyachi Y, et al. Eosinophilic pustular folliculitis: a review of the Japanese published works. J Dermatol 2013; 40: 15–20. Rajendran PM, Dolev JC, Heaphy MR Jr, et al. Eosinophilic folliculitis: before and after the introduction of antiretroviral therapy. Arch Dermatol 2005; 141: 1227–1231.
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