PCarrigan A drug-associated hypersensitivity syndrome has been reported with administration of sulfasalazine, anticonvulsants, dapsone, allopurinol, and several other medications.1-4,12,13 Its clinical features resemble those of infectious mononucleosis and appear 2 to 5 weeks after administration of the drugs.  YYasukawa  RL Sulfasalazine toxic reactions. Shear Sulfonamide antimicrobials are commonly reported as causing drug allergy and have been implicated in a variety of hypersensitivity reactions including immediate IgE-mediated reactions, benign T-cell-mediated rashes, and severe cutaneous adverse reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms.  et al. Mauri-Hellweg et al27 have demonstrated drug-induced activation and proliferation of PBMCs in vitro in patients with hypersensitivity syndrome.  MH Azulfidine-(sulfasalazine-) induced hepatic injury. : 2 Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Allergy and Clinical Immunolgy Research Group, Chulalongkorn … Detection of human herpesvirus 6 in plasma of children with primary infection and immunosuppressed patients by polymerase chain reaction.  SAsano Our website uses cookies to enhance your experience. However, PCR analysis is more sensitive, detecting HHV-6 DNA in 49% to 88% of PBMCs in healthy seropositive adults.19,20 A recent study suggested that the detection of HHV-6 DNA in serum by quantitative PCR defined the border between latency and active viral replication.21 In contrast, isolating the virus is the most reliable method of proving infection, because HHV-6 is rarely isolated from the PBMCs of healthy subjects.22 Our observations of the isolation of HHV-6 from PBMCs and the remarkable increase in anti–HHV-6 IgG titers without the appearance of IgM antibodies indicated reactivated HHV-6 infection. Secchiero Serum samples from the patients were stored at −80°C until use. It has also been used “off label” for Crohn's disease and ankylosing spondylitis. 5.3 Hypersensitivity Reactions . Anti–HHV-6 IgM titers were negative in these samples. Sulfonamide-containing drugs are frequently implicated in allergic and non-allergic reactions. We are indebted to Mark R. Pittelkow, MD, for his helpful comments. Vittorio  GJune Sulfasalazine has been reported to induce pulmonary eosinophilia and hypersensitivity with symptoms of dyspnea and fever. COVID-19 is an emerging, rapidly evolving situation. Seroepidemiology of human herpesvirus 6 infection in normal children and adults.  MAKnox The presence of atypical lymphocytes and mononucleosislike symptoms led us to examine the possibility of viral infections. Edema of the face was also present. It seems likely that the reactivation of HHV-6 is specific to hypersensitivity syndrome. We would like to suggest possible treatment with an antiviral drug such as ganciclovir for hypersensitivity syndrome, since our observations indicate that HHV-6 infection occurs in a late stage of hypersensitivity syndrome.31. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) is a drug-induced hypersensitivity syndrome that can mimic malignant lymphoma. To confirm this observation, it must be further investigated in other patients.  CH T-cell activation is required for efficient replication of human herpesvirus 6. Human herpesvirus-6 infection in bone marrow transplantation.  K Akashi Tohyama M, Yahata Y, Yasukawa M, et al. Seven days after the onset of the disease, sulfasalazine therapy was discontinued, and the patient was treated with 50 mg/d of oral prednisolone for 4 days.  DBrander The mechanism and frequency of the reactivation of HHV-6 are unknown.  DLennette  FMauri  ECKatsafanas  RFClark The patient was diagnosed as having hypersensitivity syndrome due to sulfasalazine use with multivisceral involvement. Oral sulfasalazine inhibits the absorption and metabolism of folic acid and may cause folic acid deficiency, potentially resulting in serious blood disorders (e.g. Experimental infection of cynomolgus and African green monkeys with human herpesvirus 6. Okuno Okuno Sulfasalazine is contraindicated in patients with porphyria, urinary or intestinal obstruction, and hypersensitivity to sulfasalazine, its metabolites, sulfonamides, or salicylates. doi:10.1001/archderm.134.9.1113, © 2020 American Medical Association.  WRRussler Yakushijin  NHSpielberg  MKobayashi We describe a new case of sulfasalazine-induced hypersensitivity syndrome associated with HHV-6 reactivation and the induction of anticardiolipin and anti-thyroid peroxidase antibodies. Callot Autoimmune disorders may also develop as a sequela of the condition.  MJNash Here, we report the first case, to our knowledge, of a patient with previously unidentified SIHS who developed a significantly more rapid and extreme recurrence on re-exposure to sulfasalazine.  DR Susceptibility of human herpesvirus-6 to acyclovir and ganciclovir. 1998;134:1113-1117 ULFASALAZINE IS a common therapeuticdrugusedtotreat inflammatory bowel dis-ease, rheumatoid arthritis, In this report, a case of sulfasalazine- induced DRESS syndrome (the acronym for Drug Rash with Eosinophilia and Systemic Symptoms) is described.  BJFox  K Antibody titers against HHV-7, Epstein-Barr virus, cytomegalovirus, rubella, adenovirus, and toxoplasma did not change throughout the clinical course. One explanation for this finding might be that the corticosteroids suppressed an excessive immune response to drug metabolites and/or inhibited the production of cytokines caused by massive replicated viruses, which in turn induced severe illness. These findings led us to hypothesize that severe drug-induced hypersensitivity syndromes have a 2-stage course: first, T-cell activation develops as an immune response to reactive drug metabolites and second, HHV-6 reactivated by activated T cells affects the general condition of the patients and causes infectious mononucleosislike symptoms. Therefore, sulfasalazine is contraindicated in patients with sulfasalazine hypersensitivity, salicylate hypersensitivity, sulfonamide hypersensitivity, and 5-aminosalicylates hypersensitivity.  HOkamoto Clinical signs include a maculopapular rash that often progresses to exfoliative erythroderma, fever, lymphadenopathy, and multivisceral involvement. Hypersensitivity syndrome due to the use of sulfonamides and anticonvulsants may be related to individual genetic polymorphisms in the enzymes involved in the metabolism cascade of these drugs.25,26 It is hypothesized that the reactive metabolite binds to tissue macromolecules and causes cell damage or acts as a hapten and elicits an immune response. Salazopyrin is used to treat and manage ulcerative colitis and Crohn's disease which are inflammatory bowel diseases. Eosinophilia, atypical lymphocytosis, liver dysfunction, and renal disturbance are also frequently observed with this syndrome.  TShiraki We describe a new case of sulfasalazine-induced hypersensitivity syndrome associated with HHV-6 reactivation and the induction of anticardiolipin and anti-thyroid peroxidase antibodies. The clinical features of the syndrome appeared 18 and 32 days after administration of sulfasalazine. The symptoms are often progressive for several weeks after treatment with the drug is discontinued. DNA from peripheral blood mononuclear cells (Pt) showed amplified human herpesvirus 6 DNA product with 776 base pairs (bp) using common primers for variant A and variant B (left), and with 259 bp using variant B–specific primers (right). MacDermott Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. Yalcin  FGreenspan  GMRathjen The dosage was increased to 2 g/d several weeks later. Hypersensitivity syndrome: A severe allergic reaction called hypersensitivity syndrome has occurred for some people who take sulfasalazine.  MStenson A 22-year-old Japanese woman who presented with abdominal pain and bloody diarrhea was diagnosed as having ulcerative colitis. M indicates the molecular weight standard marker; P, positive control; and N, umbilical cord-blood mononuclear cells (negative control). Recently, a severe infectious mononucleosislike syndrome caused by HHV-6 infection was reported in immunocompetent adults.5-7 Clinical signs included high fever, skin rash, generalized lymphadenopathy, liver dysfunction, and leukocytosis with the appearance of atypical lymphocytes.  et al. In general, the appearance of anti–HHV-6 IgM antibodies suggests primary infection, while a remarkable increase in IgG titers without IgM antibodies indicates reactivated HHV-6 infection. Drug-induced pseudolymphoma and hypersensitivity syndrome.  SMukai Sulfasalazine should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. worsening of these symptoms while on treatment. The clinical features of the syndrome appeared 18 and 32 days after administration of sulfasalazine. Background  pms-SULFASALAZINE and pms-SULFASALAZINE-E. C. (sulfasalazine) are contraindicated: • In patients with hypersensitivity to sulfasalazine, its metabolites, or any other component of the product (See Composition), sulfonamides, or salicylates. To exclude the possibility that the adverse drug reaction was nonspecifically associated with HHV-6 reactivation, we investigated 4 patients who developed adverse drug reactions due to oral administration of phenytoin, allopurinol, and acetaminophen.  RMBroods Some patients may have a similar reaction to Asacol HD tablets or to other compounds that Hernández N, Borrego L, Soler E, Hernández J. Actas Dermosifiliogr. The evaluation of HHV-6 antibody titers is controversial. A 58-year-old woman with rheumatoid arthritis (RA) developed fever, skin eruptions, leukocytopenia, and thrombocytopenia, 3 weeks after treatment with  MEizuru SULFASALAZINE IS a common therapeutic drug used to treat inflammatory bowel disease, rheumatoid arthritis, and psoriatic arthritis. Isolated virus was identified with immunofluorescence assay using anti–HHV-6 monoclonal antibody and polymerase chain reaction (PCR) assay. She did recover completely without any further recurrence to date, after definitively discontinuing sulfasalazine.  |  Clinical signs included a maculopapular rash progressing to exfoliative erythroderma, fever, and lymphadenopathy. Phenobarbital has been reported to cause hypersensitivity syndrome13; therefore, the patient could have developed hypersensitivity syndrome with reactivated HHV-6 from treatment with phenobarbital. Associated rash usually progressed to desquamation. It is one of the “go to” DMARDs when a patient is considering pregnancy.  DMTang Sulfasalazine is contraindicated in: Infants under the age of 2 years. Here, we report the first case, to our knowledge, of a patient with previously unidentified SIHS who developed a significantly more rapid and extreme recurrence on re-exposure to sulfasalazine.  et al.  MOshima This observation suggests active replication of the virus after the initiation of clinical symptoms. Drug Hypersensitivity Syndrome, also known as Drug Rash with Eosinophilia and Systemic Symptoms is a severe adverse reaction characterized by clinical manifestations including fever, skin eruption, lymphoadenopathy, associated with eosinophilia, leukocytosis and multiple visceral involvement, with 10% of mortality due to development of multiple organ failure. If acute intolerance syndrome is suspected, promptly discontinue treatment with Asacol HD. Two cases of hypersensitivity syndrome due to sulfasalazine use were associated with the reactivation of human herpesvirus 6, which may be a required cause of hypersensitivity syndrome. Nevertheless, the patient developed a generalized eruption and was admitted to Ehime University Hospital, Ehime, Japan. Salazopyrin EN tablets are also used to treat rheumatoid arthritis, which is a painful joint disease.  |  In 1 patient, human herpesvirus 6 variant B was isolated from peripheral blood mononuclear cells, and in both patients anti–human herpesvirus 6 IgG titers increased considerably. Cessation of sulfasalazine We describe a previously unreported association of and administration of steroids led to dramatic improvement. Methylprednisolone pulse therapy (1 g/d for 3 days) was administered, and the patient's general condition and liver function improved markedly. • In infants under 2 years of age. Recently, a severe infectious mononucleosislike syndrome was reported to be caused by human herpesvirus 6 (HHV-6) infection in immunocompetent adults.5-7 Its clinical features are characterized by skin rash, generalized lymphadenopathy, high fever, liver dysfunction, leukocytosis, and atypical lymphocytosis. Fulminant hepatitis in primary human herpesvirus-6 infection. Many drugs may cause allergic reactions via T-cell activation, but the reactions do not always develop into hypersensitivity syndrome. Currently, this drug is approved by the US Food and Drug Administration (FDA) for the treatment of ulcerative colitis and rheumatoid arthritis. Sulfasalazine is broken down to sulfapyridine (a sulfonamide) and 5-aminosalicylic acid (mesalamine). We report 2 cases of sulfasalazine-induced severe hypersensitivity syndrome associated with the reactivation of HHV-6. Conclusions   SPGrant © 2020 American Medical Association. We did not observe an increase in their anti–HHV-6 IgG titers throughout their clinical courses. The skin eruption progressed to erythroderma, and the patient was diagnosed as having hypersensitivity syndrome due to sulfasalazine use with multivisceral involvement. Treatment with 1.5 g/d of sulfasalazine and 1 mg/d of betamethasone suppository was commenced, and the patient's symptoms resolved 2 weeks later. No serologic evidence of viral infections has been reported with this syndrome; however, human herpesvirus 6 infection has not been specifically investigated, which could cause an infectious mononucleosislike syndrome. Polymerase chain reaction assay for the HHV-6 genome was performed as described previously.9 The primers were 5′-GTGTTTCCATTGTACTGAAACCGGT-3′ and 5′-TAAACATCAATGCGTT-GCATACAGT-3′. Azulfidine (sulfasalazine) is an anti-inflammatory medication used to treat mild to severe ulcerative colitis and rheumatoid arthritis. A severe adverse reaction to sulfasalazine has been identified as a type of hypersensitivity syndrome. Seroconversion to human herpesvirus 6 following liver transplantation is a marker of cytomegalovirus disease.  DRDrobyski  RPSchloemann 1998;134(9):1113–1117.  VRoujeau Effects on folic acid. We report 2 cases of hypersensitivity syndrome induced by the use of sulfasalazine.  Y Please enable it to take advantage of the complete set of features! Kanner  et al. The patient's skin was covered with erythematous macules and papules and scattered petechiae. The lavage specimen showed a … They showed skin rash, fever, and mild liver dysfunction, but no mononucleosislike reactions.  NHSpielberg Reprints: Mikiko Tohyama, MD, Department of Dermatology, Ehime University School of Medicine, Shitsukawa, Shigenobucho, Onsengun, Ehime 791-0295, Japan (e-mail: tohm@m.ehime-u.ac.jp). The antibody titers against HHV-7, Epstein-Barr virus, cytomegalovirus, measles, adenovirus, and toxoplasma were within normal ranges throughout the patient's clinical course.  Y Widespread erythematous macules and papules coalesced into diffuse erythema with scaling in the forearms in patient 1.  THigashi to download free article PDFs, From the Department of Dermatology (Drs Tohyama, Yahata, and Hashimoto) and the First Department of Internal Medicine (Dr Yasukawa), Ehime University School of Medicine, Ehime, the Department of Microbiology, Osaka University Medical School, Osaka (Drs Inagi and Yamanishi), and the Department of Dermatology, Tokushima University School of Medicine, Tokushima (Dr Urano), Japan. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Patients with porphyria. Gopal Danis Published by BMJ. Han Observations  USA.gov. Jarrett Autoimmune disorders may also develop as a sequela of the condition. Results from a physical examination revealed a high fever (body temperature, 39.7°C), tonsillar pharyngitis, bilateral cervical lymphadenopathy, and hepatosplenomegaly.  CCMuglia This reaction involves a number of organs in the body and may be fatal if not treated quickly. Although the 3 reported cases were described as primary HHV-6 infection, the possibility of reactivated HHV-6 could not be excluded because of an absent or low anti–HHV-6 IgM response.24 If the infectious mononucleosislike syndrome was precipitated by reactivated HHV-6 infection, possible causes of the reactivation were not delineated.  RW Detection by PCR of HHV-6 and EBV DNA in blood and oropharynx of healthy adults and HIV-positives. 1-4 The reaction, including fever, skin rash, lymphadenopathy, and internal organ involvement, usually occurs 2 to 5 weeks after initiating treatment with sulfasalazine. On the patient's third hospital day, 30 mg/d of oral prednisolone was readministered because of high fever (body temperature, 39.5°C), erythroderma, progressive facial edema, and increasing levels of aspartate aminotransferase and alanine aminotransferase. Sulfa drugs (also called sulphur drugs or sulfonamide-containing drugs) is an imprecise term that generally refers to drugs that contain a sulfonamide functional group in their chemical structure. In 1 patient, human herpesvirus 6 variant B was isolated from peripheral blood mononuclear cells, and in both patients anti–human herpesvirus 6 IgG titers increased considerably. Cessation of sulfasalazine and administration of steroids led to dramatic improvement. Sulfasalazine-induced hypersensitivity syndrome (SIHS) is a serious systemic delayed adverse drug reaction that is associated with significant morbidity and mortality.  et al. The patient is a 58-year-old woman with asymptomatic Crohn's disease who, 10 days after initiating sulfasalazine, developed fevers, diffuse rash, pancytopenia, hypotension and hepatitis without a definitive source of infection. Human herpesvirus 6 infection in renal transplantation. A marked increase in anti–HHV-6 IgG titers strongly indicates a primary or reactivated infection of HHV-6. These findings support the relevance of HHV-6 infection in their clinical diseases. Sulfasalazine has been reported to modulate the immune response by inhibiting the secretion of IgA and the production of interleukin 1 and tumor necrosis factor α.29,30 These effects of sulfasalazine on the immune system may facilitate the reactivation of HHV-6 by activated T cells and induce the constellation of symptoms and signs of hypersensitivity syndrome. Sobue Customize your JAMA Network experience by selecting one or more topics from the list below. Clinical signs included a maculopapular rash progressing to exfoliative erythroderma, fever, and lymphadenopathy.  KG Hypersensitivity reaction to sulfasalazine with severe hepatotoxicity. Keywords:  RSHoness  et al. Shear Furthermore, an anti–HHV-6 IgG titer of 1:160 two days before admission and on the 6th hospital day increased to 1:1280 on the 16th day and 1:5120 on the 22nd day. Several methods may be used to confirm HHV-6 infection, including measurement of anti–HHV-6 titers, PCR analysis, and isolation of HHV-6. Mihas  SMarousek  et al. Human herpesvirus 6 has been identified as the cause of exanthem subitum.14 Most people are infected with HHV-6 in early childhood. It is characterised by a high fever (>38°C), a cutaneous eruption, lymphadenopathy, and single or multiorgan involvement. Sulfasalazine has also been used for some skin conditions.  et al. A severe adverse reaction to sulfasalazine therapy has been associated with hypersensitivity syndrome, the clinical features of which are similar to infectious mononucleosis.  MACarrigan Thirty-two days after treatment with sulfasalazine was initiated, the patient developed a sore throat, nausea, vomiting, diarrhea, and high fever. However, these proposed pathomechanisms do not fully explain the phenomenon of hypersensitivity syndrome, which is induced by only a select group of medications. Peripheral blood mononuclear cells (PBMCs) were separated and cultured with umbilical cord blood mononuclear cells as described previously.8 The cytopathic effect of HHV-6 was examined with an inverted microscope. Findings from a microscopic examination of a skin lesion on the upper portion of the right arm of patient 1 shows infiltration of lymphocytic cells in the epidermis with necrotic keratinocytes, partial liquefaction degeneration of basal cells, and perivascular infiltration of lymphocytic cells in the dermis (hematoxylin-eosin, original magnification ×100). Keywords: Drug hypersensitivity, enzyme-linked immunospot assay, sulfasalazine Treatment with 0.5 g/d of sulfasalazine was started after all medications except loxoprofen had been discontinued.  KOkuno Laboratory data showed a white blood cell count of 14.4 × 109/L (48% lymphocytes and 3% atypical lymphocytes). 4 The liver is most commonly affected in DRESS, presenting as acute hepatitis.  LIRudzki David Prednisolone, 40 mg/d, was continued and tapered with improvement of clinical symptoms. 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Borrego L, Soler E, hernández J. Actas Dermosifiliogr leukocytosis, atypical lymphocytes, liver,... Symptoms resembling infectious mononucleosis 31 ( 1 ):108-13. doi: 10.2169/internalmedicine.31.108 and. And the patient was diagnosed as having hypersensitivity syndrome ( SIHS ) is a serious systemic delayed adverse reaction... Azulfidine ( sulfasalazine ) is a serious systemic delayed adverse drug reaction is... Were stored at −80°C until use recover completely without any further recurrence date. P, positive control ; and N, Borrego L, Soler,. Cutaneous eruption, lymphadenopathy, and lymphadenopathy:343-6. doi: 10.2169/internalmedicine.31.108 DRESS syndrome: drug rash with and... Experience by selecting one or more topics from the list below was started after all medications ketotifen... Sulfasalazine has been identified as the cause of hypersensitivity T cells and 30 % CD8+ cells. Included a white blood cell count of 23.6 × 109/L ( 48 % lymphocytes mononucleosislike! And rheumatoid arthritis showed a white blood cell count of 23.6 × 109/L ( 48 % lymphocytes and 3 atypical. Proliferation of PBMCs in vitro in patients with HHV-6 infection may be fatal if not treated quickly forearms in 1! 5′-Gtgtttccattgtactgaaaccggt-3′ and 5′-TAAACATCAATGCGTT-GCATACAGT-3′ more than 2 weeks later prevent re-exposure to sulfasalazine also! Reactions have been reported in patients to prevent re-exposure to sulfasalazine and 1 mg/d of betamethasone suppository was,!