- Email: [email protected]
Toxic epidermal necrolysis in the absence of circulating T cells: A possible role for resident memory T cells
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patient was treated with prednisone (1 mg/kg/day). Myalgias, impaired renal function, and leucopenia developed. Even though treatment was discontinued 13 days later, skin lesions progressively improved. Two months later the patient died due to progression of the lymphoproliferative process. SS is a primary cutaneous T-cell lymphoma associated with dysregulation of both cellular and humoral immunity.1 Staphylococcus aureus has been identified as the most common pathogenic organism in cutaneous infections and bacteremias in patients with SS. Disseminated herpes infections are also frequently found with progressive cell-mediated immunity decline.1 Leishmaniasis due to L. infantum is endemic in Spain, both in immunocompetent and in immunosuppressed patients, and is transmitted by mosquitoes.2 Disseminated cutaneous leishmaniasis is rarely seen in SS. To our knowledge, there is only one report of cutaneous leishmaniasis in a patient with SS.3 Cutaneous leishmaniasis caused by dermotropic species may disseminate in immunosuppressed patients and present different clinical characteristics. Poor response to treatment is common and relapses are frequent,4 depending on the Leishmania strain.5 Differential diagnosis of disseminated cutaneous eruptions in immunocompromised patients must include other infectious diseases such as leishmaniasis, histoplasmosis, sporotrichosis, and paracoccidioidomycosis. Histopathologic examination is necessary for the diagnosis of cutaneous leishmaniasis, although the parasites may not be found. If clinical suspicion is high, polymerase chain reaction may be useful.5
NOVEMBER 2014
2.
3.
4.
5.
United States Cutaneous Lymphoma Consortium (USCLC). J Am Acad Dermatol 2011;64:352-404. Cortes S, Chicharro C, Cruz I, Cristov~ao JM, Ca~ navate C, Campino L. Genetic diversity of human zoonotic leishmaniasis in Iberian peninsula. Zoonoses Public Health 2011;58:234-7. Mahe A, Gessain A, Huerre M, Pratlong F, Dedet JP. Erythrodermic diffuse cutaneous leishmaniasis with S ezary syndrome. Lancet 1996;348:405-6. Van Griensven J, Carrillo E, L opez-Velez R, Lynen L, Moreno J. Leishmaniasis in immunosuppressed individuals. Clin Microbiol Infect 2014;20:286-99. Masmoudi A, Hariz W, Marrekchi S, Amouri M, Turki H. Old World cutaneous leishmaniasis: diagnosis and treatment. J Dermatol Case Rep 2013;7:31-41. http://dx.doi.org/10.1016/j.jaad.2014.07.010
Toxic epidermal necrolysis in the absence of circulating T cells: A possible role for resident memory T cells To the Editor: Toxic epidermal necrolysis (TEN) is a life-threatening mucocutaneous disease with high mortality, mainly induced by drugs. Although the pathogenesis of TEN remains elusive, reports have suggested the importance of T lymphocytes.1,2 Here, we report a case of TEN that occurred in the absence of circulating leukocytes but in the presence of resident memory T cells (TRM), suggesting key role(s) for TRM in the pathogenesis of TEN.
Priscila Giavedoni, MD,a Ignasi Pau-Charles, MD,a Jose M. Mascar o, Jr, MD,a Merce Alsina-Gibert, a MD, Adriana Garcıa-Herrera, MD,b and Teresa Estrach, MDa Departments of Dermatologya and Pathology,b Hospital Clınic, IDIBAPS, Universitat de Barcelona, Spain Funding sources: None. Conflicts of interest: None declared. Correspondence to: Teresa Estrach, MD, Department of Dermatology, Hospital Clınic, UB, C/ Villarroel 170, 08036 Barcelona, Spain E-mail: [email protected] REFERENCES 1. Olsen EA, Rook AH, Zic J, Kim Y, Porcu P, Querfeld C, et al. S ezary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the
Fig 1. Toxic epidermal necrolysis. A, Clinical presentation on day 30 after initial chemotherapy. Skin lesions on the back showed exudative erythema with positive Nikolsky sign. B, Histopathologic findings of skin biopsy specimen taken from area of erythema on the left arm. Hematoxylineosin staining showed interface dermatitis and exocytosis of mononuclear cells with individual cell necrosis of keratinocytes. Scale bar: 300 m.
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Fig 2. A to D, Two-color immunofluorescence images of frozen skin sections from the left arm were obtained for CD4/CD8 (green) and CD45RO/CD69 (red ). The majority of CD41 T cells and CD81 T cells are costained with CD45RO and CD69. T cells that co-express both molecules (arrowheads). Scale bars: 20 m.
A 60-year-old Japanese man with natural killer cell leukemia underwent SMILE chemotherapy (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide). On day 19 after initiation of chemotherapy, erythema appeared on the whole body associated with a fever of 398C. Targetoid lesions and erosions developed on the trunk and extremities. Erosions extended to the oral and genital mucosa, and covered more than 60% of the body surface by day 25 (Fig 1, A). Blood work on day 18 showed profound leukocytopenia (\1.0 3 102/L, with absence of lymphocytes on blood smear), which persisted thereafter. Hemoglobin was 8.0 g/dL and platelet count was 2.1 3 103/L. Histopathologic examination of a skin biopsy specimen on day 23 revealed interface dermatitis with individual cell necrosis (Fig 1, B). Infiltrating cells were mostly CD41 and CD81 T cells (Fig 2). Upon diagnosis of TEN, all drugs were either discontinued or changed. High-dose intravenous immunoglobulin (400 mg/kg/d) was given for 5 days and intravenous methylprednisolone (1000 mg/d) for 3 days followed by oral prednisone (2 mg/kg/d). Although the TEN subsided, he died of cerebral hemorrhage on day 39. The culprit drug remained undetermined.
This case of TEN occurred in the absence of circulating T cells. As recently reported, skin contains a large number of TRM.3,4 To determine whether TRM was involved, a necropsy skin specimen was analyzed via immunofluorescence microscopy for the expression of CD45RO (memory T-cell marker) and CD69 (resident T-cell marker).4 The majority of CD41 and CD81 T cells expressed CD45RO and CD69 (Fig 2). These results indicated that lesional T cells were of TRM phenotype, and because TRM were the only lesional T cells, it was suggested that they played a major role in the pathogenesis of this case. Expression of granzyme B indicated that lesional TRM were activated (data not shown). TRM in this patient’s skin presumably arose in response to previous inflammatory events. Why such TRM with irrelevant antigen specificity attacked the epidermis in the presence of drugs to which the patient had not previously been exposed remains unclear. Interestingly, Ostrov et al5 reported that abacavir binds to a major histocompatibility complex groove, which alters the repertoire of self-peptide ligands bound, thereby allowing self-reactivity of T cells. Application of this concept to our case would suggest that the culprit drug generated a self-peptide/drug/major histocompatibility complex as a neo-epitope on the keratinocytes.
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TRM then initiated cytotoxic responses against keratinocytes that resulted in epidermal necrolysis. Further analyses are needed to reveal the precise mechanisms. This case shows that TEN can be evoked even in the absence of circulating T cells, and emphasizes the importance of TRM during skin inflammation including drug hypersensitivity. Hisato Iriki, MD,a Takeya Adachi, MD,a Mariko Mori, MD,a Keiji Tanese, MD, PhD,a Takeru Funakoshi, MD, PhD,a Daiki Karigane, MD,b Takayuki Shimizu, MD, PhD,b Shinichiro Okamoto, MD, PhD,b and Keisuke Nagao, MD, PhDa Departments of Dermatologya and Hematology,b Keio University School of Medicine, Tokyo, Japan This work was partly supported by Health and Labour Sciences Research Grants (Research on Intractable Diseases) from the Ministry of Health, Labour and Welfare of Japan (H22-nanchiippan-003). Disclosure: Dr Okamoto reports receiving grants and honoraria from Novartis and Bristol-Myers Squibb and receiving grants, honoraria, and residency or fellowship program from Kyowa Kirin. Drs Iriki, Adachi, Mori, Tanese, Funakoshi, Karigane, Shimizu, and Nagao have no conflicts of interest to declare.
Varicella zoster viruseassociated generalized pustular psoriasis in a baby with heterozygous IL36RN mutation To the Editor: A 2-month-old otherwise healthy boy presented with erythema and pustules without vesicles on the face, trunk, and all limbs. There was no improvement following treatment with oral antibiotics 3 weeks earlier. On admission to our hospital he had a slight fever and a generalized crusted pustular eruption (Fig 1). Laboratory data showed the following abnormal values: white blood cell count 19.14 3 109/L (normal range: 7-15 3 109/L); C-reactive protein level 108.5 mg/L (normal range: \3 mg/L). Bacterial culture of the pustules and microscopy for fungal infection were negative. Histopathologic examination of a skin biopsy specimen revealed spongiosis with neutrophil infiltration in the upper epidermis (Fig 2). The pustulosis did not improve with application of a potent topical steroid and vitamin D3-containing ointment. Oral cyclosporine was started and gradually increased to 4 mg/kg at 64 days from the disease onset. One week later, the pustules had almost cleared. Administration of 4 mg/kg cyclosporine was continued for more than 9 months. Extensive pustules reappeared with development of an upper respiratory tract infection
Correspondence to: Keisuke Nagao, MD, PhD, Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bldg 10, Rm 12N238, 9000 Rockville Pike, Bethesda, MD 20892 E-mail: [email protected] REFERENCES 1. Nassif A, Bensussan A, Dorothee G, Mami-Chouaib F, Bachot N, Bagot M, et al. Drug-specific cytotoxic T cells in the skin lesions of a patient with toxic epidermal necrolysis. J Invest Dermatol 2002;118:728-33. 2. Pereira FA, Mudgil AV, Rosmarin DM. Toxic epidermal necrolysis. J Am Acad Dermatol 2007;56:181-200. 3. Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, Dowgiert RK, et al. The vast majority of CLA1 T cells are resident in normal skin. J Immunol 2006;176:4431-9. 4. Sathaliyawala T, Kubota M, Yudanin N, Turner D, Camp P, Thome JJ, et al. Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity 2013;38:187-97. 5. Ostrov DA, Grant BJ, Pompeu YA, Sidney J, Harndahl M, Southwood S, et al. Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire. Proc Natl Acad Sci U S A 2012;109:9959-64. http://dx.doi.org/10.1016/j.jaad.2014.07.013
Fig 1. Varicella zoster viruseinduced generalized pustular psoriasis in an infant. Pustulosis and crusts on the face, trunk, and limbs are seen.
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patient was treated with prednisone (1 mg/kg/day). Myalgias, impaired renal function, and leucopenia developed. Even though treatment was discontinued 13 days later, skin lesions progressively improved. Two months later the patient died due to progression of the lymphoproliferative process. SS is a primary cutaneous T-cell lymphoma associated with dysregulation of both cellular and humoral immunity.1 Staphylococcus aureus has been identified as the most common pathogenic organism in cutaneous infections and bacteremias in patients with SS. Disseminated herpes infections are also frequently found with progressive cell-mediated immunity decline.1 Leishmaniasis due to L. infantum is endemic in Spain, both in immunocompetent and in immunosuppressed patients, and is transmitted by mosquitoes.2 Disseminated cutaneous leishmaniasis is rarely seen in SS. To our knowledge, there is only one report of cutaneous leishmaniasis in a patient with SS.3 Cutaneous leishmaniasis caused by dermotropic species may disseminate in immunosuppressed patients and present different clinical characteristics. Poor response to treatment is common and relapses are frequent,4 depending on the Leishmania strain.5 Differential diagnosis of disseminated cutaneous eruptions in immunocompromised patients must include other infectious diseases such as leishmaniasis, histoplasmosis, sporotrichosis, and paracoccidioidomycosis. Histopathologic examination is necessary for the diagnosis of cutaneous leishmaniasis, although the parasites may not be found. If clinical suspicion is high, polymerase chain reaction may be useful.5
NOVEMBER 2014
2.
3.
4.
5.
United States Cutaneous Lymphoma Consortium (USCLC). J Am Acad Dermatol 2011;64:352-404. Cortes S, Chicharro C, Cruz I, Cristov~ao JM, Ca~ navate C, Campino L. Genetic diversity of human zoonotic leishmaniasis in Iberian peninsula. Zoonoses Public Health 2011;58:234-7. Mahe A, Gessain A, Huerre M, Pratlong F, Dedet JP. Erythrodermic diffuse cutaneous leishmaniasis with S ezary syndrome. Lancet 1996;348:405-6. Van Griensven J, Carrillo E, L opez-Velez R, Lynen L, Moreno J. Leishmaniasis in immunosuppressed individuals. Clin Microbiol Infect 2014;20:286-99. Masmoudi A, Hariz W, Marrekchi S, Amouri M, Turki H. Old World cutaneous leishmaniasis: diagnosis and treatment. J Dermatol Case Rep 2013;7:31-41. http://dx.doi.org/10.1016/j.jaad.2014.07.010
Toxic epidermal necrolysis in the absence of circulating T cells: A possible role for resident memory T cells To the Editor: Toxic epidermal necrolysis (TEN) is a life-threatening mucocutaneous disease with high mortality, mainly induced by drugs. Although the pathogenesis of TEN remains elusive, reports have suggested the importance of T lymphocytes.1,2 Here, we report a case of TEN that occurred in the absence of circulating leukocytes but in the presence of resident memory T cells (TRM), suggesting key role(s) for TRM in the pathogenesis of TEN.
Priscila Giavedoni, MD,a Ignasi Pau-Charles, MD,a Jose M. Mascar o, Jr, MD,a Merce Alsina-Gibert, a MD, Adriana Garcıa-Herrera, MD,b and Teresa Estrach, MDa Departments of Dermatologya and Pathology,b Hospital Clınic, IDIBAPS, Universitat de Barcelona, Spain Funding sources: None. Conflicts of interest: None declared. Correspondence to: Teresa Estrach, MD, Department of Dermatology, Hospital Clınic, UB, C/ Villarroel 170, 08036 Barcelona, Spain E-mail: [email protected] REFERENCES 1. Olsen EA, Rook AH, Zic J, Kim Y, Porcu P, Querfeld C, et al. S ezary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the
Fig 1. Toxic epidermal necrolysis. A, Clinical presentation on day 30 after initial chemotherapy. Skin lesions on the back showed exudative erythema with positive Nikolsky sign. B, Histopathologic findings of skin biopsy specimen taken from area of erythema on the left arm. Hematoxylineosin staining showed interface dermatitis and exocytosis of mononuclear cells with individual cell necrosis of keratinocytes. Scale bar: 300 m.
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Fig 2. A to D, Two-color immunofluorescence images of frozen skin sections from the left arm were obtained for CD4/CD8 (green) and CD45RO/CD69 (red ). The majority of CD41 T cells and CD81 T cells are costained with CD45RO and CD69. T cells that co-express both molecules (arrowheads). Scale bars: 20 m.
A 60-year-old Japanese man with natural killer cell leukemia underwent SMILE chemotherapy (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide). On day 19 after initiation of chemotherapy, erythema appeared on the whole body associated with a fever of 398C. Targetoid lesions and erosions developed on the trunk and extremities. Erosions extended to the oral and genital mucosa, and covered more than 60% of the body surface by day 25 (Fig 1, A). Blood work on day 18 showed profound leukocytopenia (\1.0 3 102/L, with absence of lymphocytes on blood smear), which persisted thereafter. Hemoglobin was 8.0 g/dL and platelet count was 2.1 3 103/L. Histopathologic examination of a skin biopsy specimen on day 23 revealed interface dermatitis with individual cell necrosis (Fig 1, B). Infiltrating cells were mostly CD41 and CD81 T cells (Fig 2). Upon diagnosis of TEN, all drugs were either discontinued or changed. High-dose intravenous immunoglobulin (400 mg/kg/d) was given for 5 days and intravenous methylprednisolone (1000 mg/d) for 3 days followed by oral prednisone (2 mg/kg/d). Although the TEN subsided, he died of cerebral hemorrhage on day 39. The culprit drug remained undetermined.
This case of TEN occurred in the absence of circulating T cells. As recently reported, skin contains a large number of TRM.3,4 To determine whether TRM was involved, a necropsy skin specimen was analyzed via immunofluorescence microscopy for the expression of CD45RO (memory T-cell marker) and CD69 (resident T-cell marker).4 The majority of CD41 and CD81 T cells expressed CD45RO and CD69 (Fig 2). These results indicated that lesional T cells were of TRM phenotype, and because TRM were the only lesional T cells, it was suggested that they played a major role in the pathogenesis of this case. Expression of granzyme B indicated that lesional TRM were activated (data not shown). TRM in this patient’s skin presumably arose in response to previous inflammatory events. Why such TRM with irrelevant antigen specificity attacked the epidermis in the presence of drugs to which the patient had not previously been exposed remains unclear. Interestingly, Ostrov et al5 reported that abacavir binds to a major histocompatibility complex groove, which alters the repertoire of self-peptide ligands bound, thereby allowing self-reactivity of T cells. Application of this concept to our case would suggest that the culprit drug generated a self-peptide/drug/major histocompatibility complex as a neo-epitope on the keratinocytes.
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NOVEMBER 2014
TRM then initiated cytotoxic responses against keratinocytes that resulted in epidermal necrolysis. Further analyses are needed to reveal the precise mechanisms. This case shows that TEN can be evoked even in the absence of circulating T cells, and emphasizes the importance of TRM during skin inflammation including drug hypersensitivity. Hisato Iriki, MD,a Takeya Adachi, MD,a Mariko Mori, MD,a Keiji Tanese, MD, PhD,a Takeru Funakoshi, MD, PhD,a Daiki Karigane, MD,b Takayuki Shimizu, MD, PhD,b Shinichiro Okamoto, MD, PhD,b and Keisuke Nagao, MD, PhDa Departments of Dermatologya and Hematology,b Keio University School of Medicine, Tokyo, Japan This work was partly supported by Health and Labour Sciences Research Grants (Research on Intractable Diseases) from the Ministry of Health, Labour and Welfare of Japan (H22-nanchiippan-003). Disclosure: Dr Okamoto reports receiving grants and honoraria from Novartis and Bristol-Myers Squibb and receiving grants, honoraria, and residency or fellowship program from Kyowa Kirin. Drs Iriki, Adachi, Mori, Tanese, Funakoshi, Karigane, Shimizu, and Nagao have no conflicts of interest to declare.
Varicella zoster viruseassociated generalized pustular psoriasis in a baby with heterozygous IL36RN mutation To the Editor: A 2-month-old otherwise healthy boy presented with erythema and pustules without vesicles on the face, trunk, and all limbs. There was no improvement following treatment with oral antibiotics 3 weeks earlier. On admission to our hospital he had a slight fever and a generalized crusted pustular eruption (Fig 1). Laboratory data showed the following abnormal values: white blood cell count 19.14 3 109/L (normal range: 7-15 3 109/L); C-reactive protein level 108.5 mg/L (normal range: \3 mg/L). Bacterial culture of the pustules and microscopy for fungal infection were negative. Histopathologic examination of a skin biopsy specimen revealed spongiosis with neutrophil infiltration in the upper epidermis (Fig 2). The pustulosis did not improve with application of a potent topical steroid and vitamin D3-containing ointment. Oral cyclosporine was started and gradually increased to 4 mg/kg at 64 days from the disease onset. One week later, the pustules had almost cleared. Administration of 4 mg/kg cyclosporine was continued for more than 9 months. Extensive pustules reappeared with development of an upper respiratory tract infection
Correspondence to: Keisuke Nagao, MD, PhD, Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bldg 10, Rm 12N238, 9000 Rockville Pike, Bethesda, MD 20892 E-mail: [email protected] REFERENCES 1. Nassif A, Bensussan A, Dorothee G, Mami-Chouaib F, Bachot N, Bagot M, et al. Drug-specific cytotoxic T cells in the skin lesions of a patient with toxic epidermal necrolysis. J Invest Dermatol 2002;118:728-33. 2. Pereira FA, Mudgil AV, Rosmarin DM. Toxic epidermal necrolysis. J Am Acad Dermatol 2007;56:181-200. 3. Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, Dowgiert RK, et al. The vast majority of CLA1 T cells are resident in normal skin. J Immunol 2006;176:4431-9. 4. Sathaliyawala T, Kubota M, Yudanin N, Turner D, Camp P, Thome JJ, et al. Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity 2013;38:187-97. 5. Ostrov DA, Grant BJ, Pompeu YA, Sidney J, Harndahl M, Southwood S, et al. Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire. Proc Natl Acad Sci U S A 2012;109:9959-64. http://dx.doi.org/10.1016/j.jaad.2014.07.013
Fig 1. Varicella zoster viruseinduced generalized pustular psoriasis in an infant. Pustulosis and crusts on the face, trunk, and limbs are seen.