By the seventh week of hospitalization, the patient's condition had resolved other than symptoms of psoriatic arthritis. Results from anti–HHV-6 IgM titers were negative in these samples. Systemic corticosteroid therapy generally improves the condition. Russler The dosage was increased to 2 g/d several weeks later.  SMukai  RMBroods Therefore, sulfasalazine is contraindicated in patients with sulfasalazine hypersensitivity, salicylate hypersensitivity, sulfonamide hypersensitivity, and 5-aminosalicylates hypersensitivity. Associated rash usually progressed to desquamation.  RC Interstitial pneumonitis associated with human herpesvirus-6 infection after marrow transplantation. Human herpesvirus-6 infection in bone marrow transplantation. Shear 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. Fulminant hepatitis in primary human herpesvirus-6 infection. The diagnosis is DRESS, also known as drug induced hypersensitivity syndrome.  KTakeshita  RSTedesco  MOshima  SRBertovich M indicates the molecular weight standard marker; P, positive control; and N, umbilical cord-blood mononuclear cells (negative control).  Y T-cell immune response to human herpesvirus-6 in healthy adults. The lavage specimen showed a … The clinical symptoms of patients with HHV-6 infection should be evaluated carefully. DRESS typically develops three weeks to three months after starting treatment with the precipitating drug. Yamakado S, Yoshida Y, Yamada T, Kishida T, Kobayashi M, Nomura T. Intern Med. 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. Shear • In patients with intestinal and urinary obstructions.  K  CH T-cell activation is required for efficient replication of human herpesvirus 6.  KG Hypersensitivity reaction to sulfasalazine with severe hepatotoxicity. 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. 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. SULFASALAZINE IS a common therapeutic drug used to treat inflammatory bowel disease, rheumatoid arthritis, and psoriatic arthritis. We suggest that HHV-6 infection may be a required cause of hypersensitivity syndrome. We report 2 cases of hypersensitivity syndrome induced by the use of sulfasalazine. 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). They showed skin rash, fever, and mild liver dysfunction, but no mononucleosislike reactions. The patient's skin was covered with erythematous macules and papules and scattered petechiae. Medium-to-long-term follow-up is required even after complete resolution of the condition. 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.  MACarrigan Common side effects of Azulfidine include gastrointestinal disturbances, headache, allergic reactions, rash when exposed to sunlight, and changes in skin or urine color. Treatment with all medications except ketotifen fumarate was discontinued. Experimental infection of cynomolgus and African green monkeys with human herpesvirus 6.  CCMuglia  VRoujeau 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. Mauri-Hellweg et al27 have demonstrated drug-induced activation and proliferation of PBMCs in vitro in patients with hypersensitivity syndrome. She did recover completely without any further recurrence to date, after definitively discontinuing sulfasalazine.  ECKatsafanas Autoimmune disorders may also develop as a sequela of the condition. 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.  JAFerro Betamethasone therapy was discontinued while treatment with sulfasalazine was increased to 2 g/d. fasalazine hypersensitivity was proven by interferon-gamma A Case of Sulfasalazine-Induced Hypersensitivity Syndrome Confirmed by Enzyme-Linked Immunospot Assay Parkpoom Phatharacharukul,1 Jettanong Klaewsongkram2* 1Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand doi:10.1001/archderm.134.9.1113, © 2020 American Medical Association. Get free access to newly published articles. David 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. Patients with a known hypersensitivity to sulfasalazine, its metabolites or any of the excipients as well as sufonamides or salicylates.  DLennette  K DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) is a drug-induced hypersensitivity syndrome that can mimic malignant lymphoma. A 22-year-old Japanese woman who presented with abdominal pain and bloody diarrhea was diagnosed as having ulcerative colitis.  et al. Phenobarbital has been reported to cause hypersensitivity syndrome13; therefore, the patient could have developed hypersensitivity syndrome with reactivated HHV-6 from treatment with phenobarbital.  GMRathjen Leukocytosis, atypical lymphocytes, liver dysfunction, and renal disturbance were also observed. NLM It seems likely that the reactivation of HHV-6 is specific to hypersensitivity syndrome. Hypersensitivity syndrome: A severe allergic reaction called hypersensitivity syndrome has occurred for some people who take sulfasalazine.  TSuga We examined HHV-6 DNA from skin biopsy specimens of patient 1 using PCR. 2014 Mar;73(2):180-3. doi: 10.1007/s00393-013-1308-5. Epub 2013 Apr 4.  BJFox  E Frequent isolation of HHV-6 from saliva and high seroprevalence of the virus in the population. 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.  GSPeters These data indicated the reactivation of HHV-6 in the patient. 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. 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. Hernández N, Borrego L, Soler E, Hernández J. Actas Dermosifiliogr. Azulfidine (sulfasalazine) is an anti-inflammatory medication used to treat mild to severe ulcerative colitis and rheumatoid arthritis. Sobue  WF Inhibition of antibody secretion by 5-aminosalicylic acid. [DRESS syndrome following sulfasalazine treatment].  JJones  K Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Methylprednisolone pulse therapy (1 g/d for 3 days) was administered, and the patient's general condition and liver function improved markedly.  DALaurent © 2020 American Medical Association.  KKAsh  HOkamoto Gopal Eighteen days after sulfasalazine therapy was initiated, the patient developed a sore throat, nausea, chills, and high fever. Oral sulfasalazine inhibits the absorption and metabolism of folic acid and may cause folic acid deficiency, potentially resulting in serious blood disorders (e.g. A marked increase in anti–HHV-6 IgG titers strongly indicates a primary or reactivated infection of HHV-6. 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.  TChawla Akashi It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not Seroepidemiology of human herpesvirus 6 infection in normal children and adults. 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/. Autoimmune disorders may also develop as a sequela of the condition.  PCarrigan Currently, this drug is approved by the US Food and Drug Administration (FDA) for the treatment of ulcerative colitis and rheumatoid arthritis. 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). 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. The patient was diagnosed as having hypersensitivity syndrome due to sulfasalazine use with multivisceral involvement. Sulfasalazine is broken down to sulfapyridine (a sulfonamide) and 5-aminosalicylic acid (mesalamine). 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. Danis 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. Sulfasalazine therapy was discontinued 4 days later. Sulfasalazine is considered to be generally safer than other DMARDS such as MTX and Leflunomide. 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.  DBettens Sulfasalazine is contraindicated in: Infants under the age of 2 years.  NSchirmer  NHSpielberg  TKazuhiro  et al. Salazopyrin EN tablets are also used to treat rheumatoid arthritis, which is a painful joint disease. To confirm this observation, it must be further investigated in other patients.  RPNeefe S Arch Dermatol. 5.3 Hypersensitivity Reactions . The clinical features of the syndrome appeared 18 and 32 days after administration of sulfasalazine. We report 2 cases of hypersensitivity syndrome induced by the use of sulfasalazine.  DR Susceptibility of human herpesvirus-6 to acyclovir and ganciclovir. All Rights Reserved. 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. This observation suggests active replication of the virus after the initiation of clinical symptoms. 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. Clinical signs include a maculopapular rash that often progresses to exfoliative erythroderma, fever, lymphadenopathy, and multivisceral involvement. Kanner Sumiyoshi We present the results of bronchoalveolar lavage in a patient with acute sulfasalazine-induced hypersensitivity pneumonitis. We report 2 cases of sulfasalazine-induced severe hypersensitivity syndrome associated with the reactivation of HHV-6. Sulfasalazine Sulfasalazine 2013-01-18 00:00:00 Reactions 723 - 17 Oct 1998 Hypersensitivity syndrome associated with reactivation of human herpesvirus 6: 2 case reports Sulfasalazine-induced hypersensitivity syndrome was associated with the reactivation of human herpesvirus 6 (HHV-6) in 2 patients. Abnormal laboratory findings included a white blood cell count of 23.6 × 109/L (20% atypical lymphocytes and 11% eosinophils).  DAJosephs Human herpesvirus 6 was isolated from PBMCs obtained on the eighth hospital day and identified as HHV-6 variant B by PCR (Figure 3). worsening of these symptoms while on treatment. 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). In this report, a case of sulfasalazine- induced DRESS syndrome (the acronym for Drug Rash with Eosinophilia and Systemic Symptoms) is described. It should be noted that the patients' clinical conditions improved with the use of systemic corticosteroids. Patients with porphyria. The symptoms are often progressive for several weeks after treatment with the drug is discontinued. 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. Therefore, the adverse drug reaction causing hypersensitivity syndrome requires additional factors. However, these proposed pathomechanisms do not fully explain the phenomenon of hypersensitivity syndrome, which is induced by only a select group of medications. Okuno  MKobayashi  FJKalser  TTakahashi 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. We report a case in a 63-year-old woman who had been on sulfasalazine for 2 months to treat rheumatoid arthritis.  RW Detection by PCR of HHV-6 and EBV DNA in blood and oropharynx of healthy adults and HIV-positives.  SP Anticonvulsant hypersensitivity syndrome. Liver and renal functions were within normal limits. The antibody titers against HHV-7, Epstein-Barr virus, cytomegalovirus, measles, adenovirus, and toxoplasma were within normal ranges throughout the patient's clinical course. Clinical signs included a maculopapular rash progressing to exfoliate erythroderma, fever, and lymphadenopathy.  SPGrant The expected product was 776 base pairs (bp). Severe infectious mononucleosis-like syndrome and primary human herpesvirus 6 infection in an adult.  SKTapper  NHSpielberg  FGreenspan • In infants under 2 years of age. Accordingly, the reactivation of HHV-6 did not result from coinfection with these viruses. 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