sulfasalazine hypersensitivity syndrome

Conclusions  Sulfasalazine therapy was discontinued 4 days later. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. 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). to download free article PDFs, The patients showed similar clinical courses associated with reactivated HHV-6 infection. 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. 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. The symptoms are often progressive for several weeks after treatment with the drug is discontinued.  WJ Activation of drug-specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. Mihas  SMukai  YYasukawa Chou Sulfasalazine has been reported to induce pulmonary eosinophilia and hypersensitivity with symptoms of dyspnea and fever. Phenobarbital has been reported to cause hypersensitivity syndrome13; therefore, the patient could have developed hypersensitivity syndrome with reactivated HHV-6 from treatment with phenobarbital. The investigation for infectious mononucleosis yielded negative results and a diagnosis of sulfasalazine-induced hypersensitivity syndrome was confirmed using enzyme-linked immunospot assays. We suggest that HHV-6 infection may be a required cause of hypersensitivity syndrome. Please enable it to take advantage of the complete set of features! • In patients with intestinal and urinary obstructions. 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. This case demonstrates the importance of recognising SIHS early in patients to prevent re-exposure to sulfasalazine and to ensure timely initiation of appropriate treatment. Several methods may be used to confirm HHV-6 infection, including measurement of anti–HHV-6 titers, PCR analysis, and isolation of HHV-6. 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. Salazopyrin EN tablets help prevent damage to your joints. Cessation of sulfasalazine and administration of steroids led to dramatic improvement.  GI Analysis of interstrain variation in a putative immediate-early region of human herpesvirus 6 DNA and definition of variant-specific sequences.  MAKnox  TShiraki The presence of atypical lymphocytes and mononucleosislike symptoms led us to examine the possibility of viral infections. Epub 2013 Apr 4.  DJ Primary human herpesvirus 6 infection in an adult. DRESS Syndrome: Drug Rash with Eosinophilia and Systemic Symptoms. All Rights Reserved.  MJNash  et al. Autoimmune disorders may also develop as a sequela of the condition. A skin biopsy specimen obtained from the upper portion of the patient's right arm showed lymphocytic infiltration in the epidermis with necrotic keratinocytes, partial liquefaction degeneration of basal cells, and perivascular lymphocytic infiltration in the dermis (Figure 2). By the seventh week of hospitalization, the patient's condition had resolved other than symptoms of psoriatic arthritis. Fulminant hepatitis in primary human herpesvirus-6 infection. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not This is a delayed type IVb hypersensitivity syndrome that presents skin eruptions, fever, lymphadenopathy, hepatitis and hematological abnormalities like eosinophilia and atypical lymphocytes. Get free access to newly published articles.  RSHoness  DALaurent The clinical features of hypersensitivity syndrome are similar to those of infectious mononucleosis.  RMiyazaki Salazopyrin is used to treat and manage ulcerative colitis and Crohn's disease which are inflammatory bowel diseases. The lavage specimen showed a … [DRESS syndrome following sulfasalazine treatment]. Medium-to-long-term follow-up is required even after complete resolution of the condition. This reaction involves a number of organs in the body and may be fatal if not treated quickly. Oral sulfasalazine inhibits the absorption and metabolism of folic acid and may cause folic acid deficiency, potentially resulting in serious blood disorders (e.g.  SKTapper 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. J Assoc Physicians India. We report 2 cases of sulfasalazine-induced severe hypersensitivity syndrome associated with the reactivation of HHV-6. Clinical signs included a maculopapular rash progressing to exfoliate erythroderma, fever, and lymphadenopathy.  Y 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). 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. Clinical signs included a maculopapular rash progressing to exfoliative erythroderma, fever, and lymphadenopathy. It has also been used “off label” for Crohn's disease and ankylosing spondylitis. 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.  GSPeters 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.  PD Currently, this drug is approved by the US Food and Drug Administration (FDA) for the treatment of ulcerative colitis and rheumatoid arthritis. Results from a physical examination revealed a high fever (body temperature, 39.7°C), tonsillar pharyngitis, bilateral cervical lymphadenopathy, and hepatosplenomegaly. NLM A severe adverse reaction to sulfasalazine has been identified as a type of hypersensitivity syndrome.  JAFerro Sobue 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. 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. However, these proposed pathomechanisms do not fully explain the phenomenon of hypersensitivity syndrome, which is induced by only a select group of medications. 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. Interestingly, it has been considered that the reactivation of HHV-6 from latently infected PBMCs requires T-cell activation.28 On investigation of 4 patients who developed adverse drug reactions but not hypersensitivity syndrome, an increase in anti–HHV-6 IgG titer was not found and the virus was not isolated.  MStenson The dosage was increased to 2 g/d several weeks later. 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. All Rights Reserved, Challenges in Clinical Electrocardiography, Clinical Implications of Basic Neuroscience, Health Care Economics, Insurance, Payment, Scientific Discovery and the Future of Medicine, United States Preventive Services Task Force, 1998;134(9):1113-1117. doi:10.1001/archderm.134.9.1113. COVID-19 is an emerging, rapidly evolving situation. Sulfasalazine is considered to be generally safer than other DMARDS such as MTX and Leflunomide. 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. Terms of Use| It should be noted that the patients' clinical conditions improved with the use of systemic corticosteroids.  RSTedesco In 2 patients, we tried to isolate HHV-6 from cultured PBMCs; however, the virus was not detected. Over the next 3 days, the patient's liver function worsened. 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.  RMBroods Eosinophilia, atypical lymphocytosis, liver dysfunction, and renal disturbance are also frequently observed with this syndrome. Accessibility Statement.  TSuga Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome and the Rheumatologist. We examined HHV-6 DNA from skin biopsy specimens of patient 1 using PCR. Carrigan  NSchirmer  et al.  et al.  KKAsh Frenkel  KEizuru An analysis of peripheral blood lymphocyte surface markers showed 35% CD4+ T cells and 30% CD8+ T cells. Results from anti–HHV-6 IgM titers were negative in these samples. 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. The DNA was detected from frozen skin specimens obtained on the patient's 19th hospital day, but not from paraffin-embedded skin specimens obtained on the 6th day. Medium-to-long-term follow-up is required even after complete resolution of the condition. Keywords: In addition, the increase in the anti–HHV-6 IgG titers was observed more than 2 weeks after the onset of disease. Autoimmune disorders may also develop as a sequela of the condition.  CH T-cell activation is required for efficient replication of human herpesvirus 6. 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.  et al. Treatment with 60 mg/d of oral prednisolone was begun on the patient's ninth day at the hospital and tapered with improvement of clinical symptoms. Sulfonamide-containing drugs are frequently implicated in allergic and non-allergic reactions. We are indebted to Mark R. Pittelkow, MD, for his helpful comments. In immunocompromised patients, it appears that the reactivation of HHV-6 is not infrequent.15-17 Human herpesvirus 6 was first isolated from immunocompromised patients with lymphoproliferative disease.18 One of these patients experienced drug-induced dermatopathologic lymphadenopathy with skin eruption. Salazopyrin EN tablets are also used to treat rheumatoid arthritis, which is a painful joint disease. Yalcin Human herpesvirus 6 infection in renal transplantation.  KShiraki  M  THigashi We believe these cases represent hypersensitivity syndrome due to sulfasalazine therapy.  M  SFOnions Yakushijin Severe infectious mononucleosis-like syndrome and primary human herpesvirus 6 infection in an adult. Systemic corticosteroid therapy generally improves the condition. 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. Treatment with 0.5 g/d of sulfasalazine was started after all medications except loxoprofen had been discontinued.  et al. 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). Liver and renal dysfunction were found, with increased serum creatinine levels of 141.44 µmol/L (1.6 mg/dL), aspartate aminotransferase levels of 88 U/L, alanine aminotransferase levels of 148 U/L, and lactate dehydrogenase levels of 1892 U/L. Morris 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. Sulfasalazine has also been used for some skin conditions.  KBalachandra Vittorio 4 The liver is most commonly affected in DRESS, presenting as acute hepatitis. 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. S Arch Dermatol.  |  Background   SMarousek David Curr Rheumatol Rep. 2017 Jan;19(1):3. doi: 10.1007/s11926-017-0626-z.  |   DBettens Yamanishi  DJSlaughter Widespread erythematous macules and papules coalesced into diffuse erythema with scaling in the forearms in patient 1. Then, HHV-6 latently infects monocytes and salivary glands. To confirm this observation, it must be further investigated in other patients. 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. The antibody titers against HHV-7, Epstein-Barr virus, cytomegalovirus, measles, adenovirus, and toxoplasma were within normal ranges throughout the patient's clinical course. Pulmonary infiltration and eosinophilia associated with sulfasalazine therapy for ulcerative colitis: a case report and review of literature. Published by BMJ. 1998;134(9):1113–1117. Therefore, sulfasalazine is contraindicated in patients with sulfasalazine hypersensitivity, salicylate hypersensitivity, sulfonamide hypersensitivity, and 5-aminosalicylates hypersensitivity. 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. Okuno Liver and renal functions were within normal limits.  YSumiyoshi Many drugs may cause allergic reactions via T-cell activation, but the reactions do not always develop into hypersensitivity syndrome. 1998;134:1113-1117 ULFASALAZINE IS a common therapeuticdrugusedtotreat inflammatory bowel dis-ease, rheumatoid arthritis,  et al. Sulfasalazine is contraindicated in: Infants under the age of 2 years.  AAGoldenberg We report 2 cases of hypersensitivity syndrome induced by the use of sulfasalazine. If acute intolerance syndrome is suspected, promptly discontinue treatment with Asacol HD.  NHSpielberg Mauri-Hellweg et al27 have demonstrated drug-induced activation and proliferation of PBMCs in vitro in patients with hypersensitivity syndrome.  VRoujeau Danis  YKikuchi It is characterised by a high fever (>38°C), a cutaneous eruption, lymphadenopathy, and single or multiorgan involvement. 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. Accordingly, the reactivation of HHV-6 did not result from coinfection with these viruses. Isolated virus was identified with immunofluorescence assay using anti–HHV-6 monoclonal antibody and polymerase chain reaction (PCR) assay.  LIRudzki The skin eruption progressed to erythroderma, and the patient was diagnosed as having hypersensitivity syndrome due to sulfasalazine use with multivisceral involvement. No serologic evidence of Epstein-Barr virus, cytomegalovirus, or other viral infections have been reported in hypersensitivity syndrome, although HHV-6 infection has not been specifically investigated.  DE Detection of human herpesvirus-6 DNA in peripheral blood and saliva. Seroepidemiology of human herpesvirus 6 infection in normal children and adults. Kanner  DAJosephs  Y DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) is a drug-induced hypersensitivity syndrome that can mimic malignant lymphoma. Anti–HHV-6 IgM titers were negative in these samples. Leukocytosis, atypical lymphocytes, liver dysfunction, and renal disturbance were also observed. We report 2 cases of hypersensitivity syndrome induced by the use of sulfasalazine. © BMJ Publishing Group Limited 2020.  SP Anticonvulsant hypersensitivity syndrome. M indicates the molecular weight standard marker; P, positive control; and N, umbilical cord-blood mononuclear cells (negative control). She did recover completely without any further recurrence to date, after definitively discontinuing sulfasalazine.  SZAblashi Sotolongo Patients with a known hypersensitivity to sulfasalazine, its metabolites or any of the excipients as well as sufonamides or salicylates.  FGreenspan Sulfasalazine-induced hypersensitivity syndrome (SIHS) is a serious systemic delayed adverse drug reaction that is associated with significant morbidity and mortality.  ECKatsafanas A severe adverse reaction to sulfasalazine therapy has been associated with hypersensitivity syndrome, the clinical features of which are similar to infectious mononucleosis. Seroconversion to human herpesvirus 6 following liver transplantation is a marker of cytomegalovirus disease. Severe Hypersensitivity Syndrome Due to Sulfasalazine Associated With Reactivation of Human Herpesvirus 6. 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. A Case of Sulfasalazine-Induced Hypersensitivity Syndrome Confirmed by Enzyme-Linked Immunospot Assay Parkpoom Phatharacharukul, 1 and Jettanong Klaewsongkram 2 1 Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.  JE Sulfapyridine-induced serum-sickness-like syndrome associated with plasmacytosis, lymphocytosis and multiclonal gamma-globulinopathy. 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. Associated rash usually progressed to desquamation.  KG Hypersensitivity reaction to sulfasalazine with severe hepatotoxicity. Hypersensitivity syndrome: A severe allergic reaction called hypersensitivity syndrome has occurred for some people who take sulfasalazine. Human herpesvirus 6 has been identified as the cause of exanthem subitum.14 Most people are infected with HHV-6 in early childhood. The clinical symptoms of patients with HHV-6 infection should be evaluated carefully. 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. The expected product was 776 base pairs (bp).  KOkuno Drug-induced pseudolymphoma and hypersensitivity syndrome.  RC Interstitial pneumonitis associated with human herpesvirus-6 infection after marrow transplantation. 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. This is a delayed type IVb hypersensitivity syndrome that presents skin eruptions, fever, lymphadenopathy, hepatitis and hematological abnormalities like eosinophilia and atypical lymphocytes. See rights and permissions.  et al. Okuno  PLSokal Treatment with all medications except ketotifen fumarate was discontinued.  TTakahashi Red papules appeared on her abdominal skin and rapidly progressed over her whole body.  Y A case of human herpesvirus-6 lymphadenitis with infectious mononucleosis-like syndrome.  TKazuhiro  et al. Effects on folic acid.  MKobayashi The clinical features of the syndrome appeared 18 and 32 days after administration of sulfasalazine. 2015 May;63(5):78-9. Secchiero Laboratory data showed a white blood cell count of 14.4 × 109/L (48% lymphocytes and 3% atypical lymphocytes).  FJKalser It seems likely that the reactivation of HHV-6 is specific to hypersensitivity syndrome. 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. And immunosuppressed patients by polymerase chain reaction assay for the HHV-6 genome was performed as described previously.9 the primers 5′-GTGTTTCCATTGTACTGAAACCGGT-3′... ” for Crohn 's disease which are inflammatory bowel diseases known hypersensitivity to with... Bowel disease, rheumatoid arthritis, and high seroprevalence of the reactivation of HHV-6 not! Lymphoproliferative disorders administration of sulfasalazine in addition, the clinical features of the syndrome appeared 18 32... 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