This is a delayed type IVb hypersensitivity syndrome that presents skin eruptions, fever, lymphadenopathy, hepatitis and hematological abnormalities like eosinophilia and atypical lymphocytes. We describe 2 patients who experienced the sudden onset of severe infectious mononucleosislike illness 18 and 32 days after the initiation of therapy with sulfasalazine. Methods: PBMC from 2 patients with severe hypersensitivity syndrome to sulfasalazine, 3 patients with sulfamethoxazole allergy and 5 healthy donors were isolated and incubated with medium only (negative control), 2 concentrations (10, 100 μg/ml) of sulfapyridine, 2 concentrations (100, 200 μg/ml) of sulfamethoxazole, and tetanus toxoid (10 μg/ml) as a positive control. Mauri-Hellweg et al27 have demonstrated drug-induced activation and proliferation of PBMCs in vitro in patients with hypersensitivity syndrome. The mechanism and frequency of the reactivation of HHV-6 are unknown. This observation suggests active replication of the virus after the initiation of clinical symptoms.  TKazuhiro  |  • In infants under 2 years of age.  MEizuru Common side effects of Azulfidine include gastrointestinal disturbances, headache, allergic reactions, rash when exposed to sunlight, and changes in skin or urine color.  et al. Salazopyrin EN tablets are also used to treat rheumatoid arthritis, which is a painful joint disease. Get free access to newly published articles. Eosinophilia, atypical lymphocytosis, liver dysfunction, and renal disturbance are also frequently observed with this syndrome. An analysis of peripheral blood lymphocyte surface markers showed 35% CD4+ T cells and 30% CD8+ T cells. 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.  RPSchloemann The PCR product from HHV-6 variant A was 488 bp, and the product from variant B was 259 bp. Hernández N, Borrego L, Soler E, Hernández J. Actas Dermosifiliogr. 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. The clinical features of the syndrome appeared 18 and 32 days after administration of sulfasalazine. Han  SPGrant By the seventh week of hospitalization, the patient's condition had resolved other than symptoms of psoriatic arthritis.  SMarousek Clinical signs included a maculopapular rash progressing to exfoliative erythroderma, fever, and lymphadenopathy. 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. Conclusions: Two cases of hypersensitivity syndrome due to sulfasalazine use were associated with the reacti-vation of human herpesvirus 6, which may be a re-quired cause of hypersensitivity syndrome.  et al. The clinical symptoms of patients with HHV-6 infection should be evaluated carefully. Hypersensitivity syndrome: A severe allergic reaction called hypersensitivity syndrome has occurred for some people who take sulfasalazine.  RSTedesco 4 The liver is most commonly affected in DRESS, presenting as acute hepatitis. This case illustrates that the hemophagocytic syndrome associated with reactivation of EBV can occur as part of drug hypersensitivity reactions in RA patients taking sulfasalazine. The lavage specimen showed a … We did not observe an increase in their anti–HHV-6 IgG titers throughout their clinical courses. Our website uses cookies to enhance your experience. 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. Serum samples from the patients were stored at −80°C until use. OBSERVATIONS: We report 2 cases of hypersensitivity syndrome induced by the use of sulfasalazine. Seroconversion to human herpesvirus 6 following liver transplantation is a marker of cytomegalovirus disease.  DALaurent Severe, lifethreatening, systemic hypersensitivity reactions such as drug rash with - eosinophilia and systemic symptoms (DRESS) have been reported in patients taking various drugs including sulfasalazine. We report 2 cases of sulfasalazine-induced severe hypersensitivity syndrome associated with the reactivation of HHV-6. Sulfasalazine-induced linear immunoglobulin A bullous dermatosis with DRESS. 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. In conclusion, we demonstrate that a drug-induced hypersensitivity syndrome due to sulfasalazine use is associated with reactivation of HHV-6 and an infectious mononucleosislike illness. The antibody titers against HHV-7, Epstein-Barr virus, cytomegalovirus, measles, adenovirus, and toxoplasma were within normal ranges throughout the patient's clinical course. Results from anti–HHV-6 IgM titers were negative in these samples.  KEizuru Russler The patient was diagnosed as having hypersensitivity syndrome due to sulfasalazine use with multivisceral involvement. Shear The symptoms are often progressive for several weeks after treatment with the drug is discontinued. If acute intolerance syndrome is suspected, promptly discontinue treatment with Asacol HD. She did recover completely without any further recurrence to date, after definitively discontinuing sulfasalazine. Chou  FGreenspan Azulfidine (sulfasalazine) is an anti-inflammatory medication used to treat mild to severe ulcerative colitis and rheumatoid arthritis. A 22-year-old Japanese woman who presented with abdominal pain and bloody diarrhea was diagnosed as having ulcerative colitis.  MStenson 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. It seems likely that the reactivation of HHV-6 is specific to hypersensitivity syndrome. to download free article PDFs, Background   PLSokal Sulfasalazine has also been used for some skin conditions.  MOshima Salahuddin In 2 patients, we found an association between HHV-6 infection and hypersensitivity syndrome. 1-4 The reaction, including fever, skin rash, lymphadenopathy, and internal organ involvement, usually occurs 2 to 5 weeks after initiating treatment with sulfasalazine. We present the results of bronchoalveolar lavage in a patient with acute sulfasalazine-induced hypersensitivity pneumonitis.  RMiyazaki Mihas Sulfonamide-containing drugs are frequently implicated in allergic and non-allergic reactions. 2015 May;63(5):78-9. 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. Levy Clipboard, Search History, and several other advanced features are temporarily unavailable.  WF Inhibition of antibody secretion by 5-aminosalicylic acid. 2013 May;104(4):343-6. doi: 10.1016/j.adengl.2011.11.022. Oral sulfasalazine inhibits the absorption and metabolism of folic acid and may cause folic acid deficiency, potentially resulting in serious blood disorders (e.g. By continuing to use our site, or clicking "Continue," you are agreeing to our, 2020 American Medical Association. Secchiero Yamanishi  FJKalser  VRoujeau Associated rash usually progressed to desquamation. Sulfasalazine should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Methylprednisolone pulse therapy (1 g/d for 3 days) was administered, and the patient's general condition and liver function improved markedly. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. 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).  YYasukawa The presence of atypical lymphocytes and mononucleosislike symptoms led us to examine the possibility of viral infections.  CCMuglia  Y These drugs have a variety of uses and can be classified into antibiotics and non-antibiotic drugs.  MF  RSHoness We believe these cases represent hypersensitivity syndrome due to sulfasalazine therapy. In 2 patients, we tried to isolate HHV-6 from cultured PBMCs; however, the virus was not detected. Autoimmune disorders may also develop as a sequela of the condition. Phenobarbital has been reported to cause hypersensitivity syndrome13; therefore, the patient could have developed hypersensitivity syndrome with reactivated HHV-6 from treatment with phenobarbital.  MH Azulfidine-(sulfasalazine-) induced hepatic injury. No commercial re-use. However, 1 of the 3 patients described by Sumiyoshi et al6 had been treated with phenobarbital for 3 weeks prior to onset of the illness, and peripheral blood eosinophilia had been found on admission (Y. Sumiyoshi, written communication, June 1997). Other viral infections must be excluded, because coinfections with HHV-6 and other herpesviruses have been reported.23 The 2 patients in our study showed no increase in anti–HHV-7, anti-cytomegalovirus, and anti–Epstein-Barr virus IgG titers. Mauri-Hellweg  ECKatsafanas Callot A generalized maculopapular rash was observed over the patient's face, trunk, and extremities (Figure 1).  et al. Okuno  AAGoldenberg See rights and permissions.  CH T-cell activation is required for efficient replication of human herpesvirus 6.  BJFox : 2 Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Allergy and Clinical Immunolgy Research Group, Chulalongkorn …  K On the sixth hospital day, results from laboratory studies revealed the following values: aspartate aminotransferase, 755 U/L; alanine aminotransferase, 1058 U/L; lactate dehydrogenase, 1712 U/L; and total bilirubin, 41.04 µmol/L (2.4 mg/dL).  PD  DLennette 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. Epub 2013 Apr 4. In this report, a case of sulfasalazine- induced DRESS syndrome (the acronym for Drug Rash with Eosinophilia and Systemic Symptoms) is described. The clinical features of hypersensitivity syndrome are similar to those of infectious mononucleosis. We report a case in a 63-year-old woman who had been on sulfasalazine for 2 months to treat rheumatoid arthritis. To confirm this observation, it must be further investigated in other patients. The period from the onset of a primary symptom to the increase in anti–HHV-6 IgG titer seems too long, although the exact time from onset is unknown for reactivated HHV-6 infection. David Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome and the Rheumatologist.  DAJosephs 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′. Gopal S Arch Dermatol.  TChawla Seroepidemiology of human herpesvirus 6 infection in normal children and adults. Treatment with 0.5 g/d of sulfasalazine was started after all medications except loxoprofen had been discontinued. Clinical signs included a maculopapular rash progressing to exfoliate erythroderma, fever, and lymphadenopathy. Accessibility Statement. However, we determined that her anti–HHV-6 IgG titer had increased from 1:320 on the second hospital day to 1:2560 on the sixth hospital day when a preserved serum sample was examined.  RPNeefe This site needs JavaScript to work properly. Salazopyrin EN tablets help prevent damage to your joints. Widespread erythematous macules and papules coalesced into diffuse erythema with scaling in the forearms in patient 1. DRESS Syndrome: Drug Rash with Eosinophilia and Systemic Symptoms. Nevertheless, the patient developed a generalized eruption and was admitted to Ehime University Hospital, Ehime, Japan.  SFOnions National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. 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. 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. 1992 Jan;31(1):108-13. doi: 10.2169/internalmedicine.31.108. Sixteen days after her first hospitalisation, she was restarted on sulfasalazine and was readmitted within 10 hours with a similar but more serious presentation, requiring vasopressors. Anti–HHV-6 IgM titers were negative in these samples. Akashi Therefore, the adverse drug reaction causing hypersensitivity syndrome requires additional factors.  WJ Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. worsening of these symptoms while on treatment.  PCarrigan  JTedder Over the next 3 days, the patient's liver function worsened. The diagnosis is DRESS, also known as drug induced hypersensitivity syndrome.  JJones  KTakeshita Sulfasalazine-induced hypersensitivity syndrome (SIHS) is a serious systemic delayed adverse drug reaction that is associated with significant morbidity and mortality. Results from a physical examination revealed tender generalized lymphadenopathy. 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. Jarrett Systemic corticosteroid therapy generally improves the condition. • In patients with intestinal and urinary obstructions. Customize your JAMA Network experience by selecting one or more topics from the list below. These data indicated the reactivation of HHV-6 in the patient. It is characterised by a high fever (>38°C), a cutaneous eruption, lymphadenopathy, and single or multiorgan involvement. Human herpesvirus-6 infection in bone marrow transplantation. The skin eruption progressed to erythroderma, and the patient was diagnosed as having hypersensitivity syndrome due to sulfasalazine use with multivisceral involvement. Hepatitis associated with sulfasalazine often developed 2 to 4 weeks after therapy was initiated, although hypersensitivity hepatitis has been reported after longer periods of therapy. The expected product was 776 base pairs (bp). 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. Please enable it to take advantage of the complete set of features! 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.  RW Detection by PCR of HHV-6 and EBV DNA in blood and oropharynx of healthy adults and HIV-positives. Currently, this drug is approved by the US Food and Drug Administration (FDA) for the treatment of ulcerative colitis and rheumatoid arthritis.  DMTang Yalcin  MKobayashi A severe adverse reaction to sulfasalazine therapy has been associated with hypersensitivity syndrome, the clinical features of which are similar to infectious mononucleosis. Keywords: Drug hypersensitivity, enzyme-linked immunospot assay, sulfasalazine Yakushijin  et al.  JAFerro 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). 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). 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.  Y T-cell immune response to human herpesvirus-6 in healthy adults. We suggest that HHV-6 infection may be a required cause of hypersensitivity syndrome.  RC Interstitial pneumonitis associated with human herpesvirus-6 infection after marrow transplantation. Accordingly, the reactivation of HHV-6 did not result from coinfection with these viruses. 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