JEADV
LETTER TO THE EDITOR
Syndrome of inappropriate secretion of antidiuretic hormone in a patient with druginduced hypersensitivity syndrome Editor Drug-induced hypersensitivity syndrome (DIHS)⁄drug rash with eosinophilia and systemic symptoms (DRESS) is a severe multiorgan reaction related to drugs and to reactivation of herpes
viruses, particularly HHV6. The most frequent incriminated drugs are the aromatic anticonvulsants and sulphonamides.1 Symptoms typically develop 4–6 weeks after the administration of the causative drug and include fever, maculopapular rash, facial oedema, leucocytosis with eosinophilia along with visceral dysfunction.1 The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with limbic encephalitis was reported once with DRESS2 and is a rare but well-recognized complications of GVHD, a very close entity to DRESS.3,4 We present a case of SIADH following DRESS and HHV 6 reactivation with no evidence of limbic encephalitis.
Figure 1 Marked facial edema with generalized erythematous to violaceous maculopapular rash.
JEADV 2015
© 2015 European Academy of Dermatology and Venereology
Letter to the Editor
2
A 30-year-old woman was started on Lamotrigine 50 mg/day for somatization disorder. On day 35 of treatment, she developed morbilliform rash that started all from her trunk and spread to her face, her arms and legs within a few days, along with high-grade fever, malaise and facial oedema with marked periorbital involvement (Fig. 1). A skin biopsy specimen taken from the trunk revealed exocytosis of lymphoid cells into the epidermis, as well as perivascular and perifollicular lymphoid and eosinophilic infiltrates in the upper dermis (Fig. 2). Physical examination and blood tests revealed cervical lymphadenopathy, leucocytosis with eosinophilia and abnormal liver tests. The diagnosis of DIHS⁄DRESS was made, and treatment with oral corticosteroids (prednisolone, 60 mg⁄day) was started. The blood samples simultaneously collected contained HHV-6 DNA. One week later, serum sodium that was initially been normal declined to 118 mmol⁄L; potassium and chloride were within the normal range. By the following day, serum sodium had fallen to 115 mmol⁄L. Urine osmolarity was of 705 mOsm⁄L (50–1300) and serum was 242 mOsm⁄L (275–290). The increased urine osmolarity and decreased serum osmolarity, together with normal renal and adrenocortical functions, were suggestive of SIADH. No neurological sign was found. Progressive normalization of natremia was achieved a few days after therapy with hypertonic saline infusion and water restriction. This is the first reported case to our knowledge of concomitant SIADH and DIHS⁄ DRESS with no sign of limbic encephalitis or neurological deterioration. One case of concomitant SIADH and DIHS/DRESS with limbic encephalitis was described by Sakuma et al.2 and suggested that the limbic encephalitis was secondarily caused by reactivation of latent HHV6 which caused inappropriately increased release of antidiuretic hormone from the posterior pituitary gland and hyponatremia. Mechanisms that have been implicated in DRESS include genetic predisposition and association with HLA, virus reactivation, particularly HHV6 and accumulation of reactive drug metabolites.5,6 Limbic encephalitis which developed 2–4 weeks after onset of DRESS syndrome was also associated with a skin rash suggestive of GVHD4 and with reactivation of HHV 6 after stem-cell transplantation.7 The absence of encephalitis in our case suggest that SIADH following DHIS/DRESS may be related to subtle immune response generated upon reactivation of HHV6 or due to the inflammatory reaction and cytokine milieu occurring in DHIS/DRESS, rather than from a severe central neurologic insult like limbic encephalitis. In particular levels of tumour necrosis factor-alpha and interleukin-6, which are typical pro-inflammatory cytokines, are elevated in this syndrome before the reactivation of HHV-6.8 Similar findings could likewise be expected with other pituitary hormones like PRL, ACTH, TSH and GH, and should be detected in the setting of DRESS. In conclusion, DRESS/DIHS can lead to SIADH and severe hyponatremia even
JEADV 2015
Figure 2 Perivascular and perifollicular lymphoid infiltrate with epidermotropism.
without limbic encephalitis. Clinicians must be aware about this rare but recently well-documented severe complication to enable early diagnosis and appropriate management. R. Haber,1,2,* F. Stephan,1,2 F. Kamar,3 R. Tomb1,2 1
Department of Dermatology, Hotel Dieu de France University Hospital, Beirut, 2Faculty of Medicine, Saint Joseph University, Beirut, 3Department of Oncology, Belle-Vue Medical Center, Beirut, Lebanon *Correspondence: R. Haber. E-mail: [email protected]
References 1 Ichiche M, Kiesch N, De Bels D. DRESS syndrome associated with HHV-6 reactivation. Eur J Intern Med 2003; 14: 498–500. 2 Sakuma K, Kano Y, Fukuhara Y, Shiohara T. Syndrome of inappropriate secretion of antidiuretic hormone associated with limbic encephalitis in a patient with drug-induced hypersensitivity syndrome. Clin Exp Dermatol 2008; 33: 287–290. 3 Ito T, Ooishi C, Chiba A, Sakuta M, Sakuma K, Shiohara T. Limbic encephalitis associated with drug-induced hypersensitivity syndrome due to phenobarbital: a case report. Rinsho Shinkeigaku 2005; 45: 495–501. 4 Chik KW, Chan PK, Li CK et al. Human herpesvirus-6 encephalitis after unrelated umbilical cord blood transplant in children. Bone Marrow Transplant 2002; 29: 991–994. 5 Criado PR, Avancini J, Santi CG, Medrado AT, Rodrigues CE, de Carvalho JF. Drug reaction with eosinophilia and systemic symptoms (DRESS): a complex interaction of drugs, viruses and the immune system. Isr Med Assoc J 2012; 14: 577–582. 6 Ang CC, Wang YS, Yoosuff EL, Tay YK. Retrospective analysis of drug induced hypersensitivity syndrome: a study of 27 patients. J Am Acad Dermatol 2010; 63: 219–227. 7 Wainwright MS, Martin PL, Morse RP et al. Human herpesvirus 6 limbic encephalitis after stem cell transplantation. Ann Neurol 2001; 50: 612–619. 8 Yoshikawa T, Fujita A, Yagami A et al. Human herpesvirus 6 reactivation and inflammatory cytokine production in patients with drug-induced hypersensitivity syndrome. J Clin Virol 2006; 37 (suppl. 1): 92–96. DOI: 10.1111/jdv.13037
© 2015 European Academy of Dermatology and Venereology
LETTER TO THE EDITOR
Syndrome of inappropriate secretion of antidiuretic hormone in a patient with druginduced hypersensitivity syndrome Editor Drug-induced hypersensitivity syndrome (DIHS)⁄drug rash with eosinophilia and systemic symptoms (DRESS) is a severe multiorgan reaction related to drugs and to reactivation of herpes
viruses, particularly HHV6. The most frequent incriminated drugs are the aromatic anticonvulsants and sulphonamides.1 Symptoms typically develop 4–6 weeks after the administration of the causative drug and include fever, maculopapular rash, facial oedema, leucocytosis with eosinophilia along with visceral dysfunction.1 The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with limbic encephalitis was reported once with DRESS2 and is a rare but well-recognized complications of GVHD, a very close entity to DRESS.3,4 We present a case of SIADH following DRESS and HHV 6 reactivation with no evidence of limbic encephalitis.
Figure 1 Marked facial edema with generalized erythematous to violaceous maculopapular rash.
JEADV 2015
© 2015 European Academy of Dermatology and Venereology
Letter to the Editor
2
A 30-year-old woman was started on Lamotrigine 50 mg/day for somatization disorder. On day 35 of treatment, she developed morbilliform rash that started all from her trunk and spread to her face, her arms and legs within a few days, along with high-grade fever, malaise and facial oedema with marked periorbital involvement (Fig. 1). A skin biopsy specimen taken from the trunk revealed exocytosis of lymphoid cells into the epidermis, as well as perivascular and perifollicular lymphoid and eosinophilic infiltrates in the upper dermis (Fig. 2). Physical examination and blood tests revealed cervical lymphadenopathy, leucocytosis with eosinophilia and abnormal liver tests. The diagnosis of DIHS⁄DRESS was made, and treatment with oral corticosteroids (prednisolone, 60 mg⁄day) was started. The blood samples simultaneously collected contained HHV-6 DNA. One week later, serum sodium that was initially been normal declined to 118 mmol⁄L; potassium and chloride were within the normal range. By the following day, serum sodium had fallen to 115 mmol⁄L. Urine osmolarity was of 705 mOsm⁄L (50–1300) and serum was 242 mOsm⁄L (275–290). The increased urine osmolarity and decreased serum osmolarity, together with normal renal and adrenocortical functions, were suggestive of SIADH. No neurological sign was found. Progressive normalization of natremia was achieved a few days after therapy with hypertonic saline infusion and water restriction. This is the first reported case to our knowledge of concomitant SIADH and DIHS⁄ DRESS with no sign of limbic encephalitis or neurological deterioration. One case of concomitant SIADH and DIHS/DRESS with limbic encephalitis was described by Sakuma et al.2 and suggested that the limbic encephalitis was secondarily caused by reactivation of latent HHV6 which caused inappropriately increased release of antidiuretic hormone from the posterior pituitary gland and hyponatremia. Mechanisms that have been implicated in DRESS include genetic predisposition and association with HLA, virus reactivation, particularly HHV6 and accumulation of reactive drug metabolites.5,6 Limbic encephalitis which developed 2–4 weeks after onset of DRESS syndrome was also associated with a skin rash suggestive of GVHD4 and with reactivation of HHV 6 after stem-cell transplantation.7 The absence of encephalitis in our case suggest that SIADH following DHIS/DRESS may be related to subtle immune response generated upon reactivation of HHV6 or due to the inflammatory reaction and cytokine milieu occurring in DHIS/DRESS, rather than from a severe central neurologic insult like limbic encephalitis. In particular levels of tumour necrosis factor-alpha and interleukin-6, which are typical pro-inflammatory cytokines, are elevated in this syndrome before the reactivation of HHV-6.8 Similar findings could likewise be expected with other pituitary hormones like PRL, ACTH, TSH and GH, and should be detected in the setting of DRESS. In conclusion, DRESS/DIHS can lead to SIADH and severe hyponatremia even
JEADV 2015
Figure 2 Perivascular and perifollicular lymphoid infiltrate with epidermotropism.
without limbic encephalitis. Clinicians must be aware about this rare but recently well-documented severe complication to enable early diagnosis and appropriate management. R. Haber,1,2,* F. Stephan,1,2 F. Kamar,3 R. Tomb1,2 1
Department of Dermatology, Hotel Dieu de France University Hospital, Beirut, 2Faculty of Medicine, Saint Joseph University, Beirut, 3Department of Oncology, Belle-Vue Medical Center, Beirut, Lebanon *Correspondence: R. Haber. E-mail: [email protected]
References 1 Ichiche M, Kiesch N, De Bels D. DRESS syndrome associated with HHV-6 reactivation. Eur J Intern Med 2003; 14: 498–500. 2 Sakuma K, Kano Y, Fukuhara Y, Shiohara T. Syndrome of inappropriate secretion of antidiuretic hormone associated with limbic encephalitis in a patient with drug-induced hypersensitivity syndrome. Clin Exp Dermatol 2008; 33: 287–290. 3 Ito T, Ooishi C, Chiba A, Sakuta M, Sakuma K, Shiohara T. Limbic encephalitis associated with drug-induced hypersensitivity syndrome due to phenobarbital: a case report. Rinsho Shinkeigaku 2005; 45: 495–501. 4 Chik KW, Chan PK, Li CK et al. Human herpesvirus-6 encephalitis after unrelated umbilical cord blood transplant in children. Bone Marrow Transplant 2002; 29: 991–994. 5 Criado PR, Avancini J, Santi CG, Medrado AT, Rodrigues CE, de Carvalho JF. Drug reaction with eosinophilia and systemic symptoms (DRESS): a complex interaction of drugs, viruses and the immune system. Isr Med Assoc J 2012; 14: 577–582. 6 Ang CC, Wang YS, Yoosuff EL, Tay YK. Retrospective analysis of drug induced hypersensitivity syndrome: a study of 27 patients. J Am Acad Dermatol 2010; 63: 219–227. 7 Wainwright MS, Martin PL, Morse RP et al. Human herpesvirus 6 limbic encephalitis after stem cell transplantation. Ann Neurol 2001; 50: 612–619. 8 Yoshikawa T, Fujita A, Yagami A et al. Human herpesvirus 6 reactivation and inflammatory cytokine production in patients with drug-induced hypersensitivity syndrome. J Clin Virol 2006; 37 (suppl. 1): 92–96. DOI: 10.1111/jdv.13037
© 2015 European Academy of Dermatology and Venereology
