Diagnosis Of Drug-induced Hypersensitivity Syndrome Research Articles

Clinical features of drug-induced hypersensitivity syndrome to BRAF inhibitors with and without previous immune checkpoint inhibition: a review.

Cutaneous reactions to BRAF inhibitors are common, but severe reactions resembling or consistent with drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) are relatively rare. Several reports suggest that cutaneous reactions including DRESS/DIHS to BRAF inhibitors are more frequent and severe in the setting of previous immune checkpoint inhibition (ICI). To characterize existing literature on these reports, we queried the PubMed/MEDLINE database for cases of DIHS/DRESS to BRAF inhibitors. We identified 23 cases of DIHS to BRAF inhibitors following checkpoint inhibition and 14 cases without prior checkpoint inhibitor therapy. In both cohorts, DIHS occurred relatively early, with median time to onset from drug exposure of 8-10days. Patients who received prior ICI were less likely to have peripheral eosinophilia (26% vs 71%), atypical lymphocytes (9% vs 50%), renal involvement (61% vs 79%), hepatic involvement (52% vs 86%), and lymphadenopathy (9% vs 43%) compared to patients who did not receive prior ICI. Thrombocytopenia was more common with prior ICI (17% vs 7%). Only patients who received prior ICI experienced hypotension (26%) during the course of their DIHS. All cases of BRAF-induced DIHS generally improved on systemic steroids/supportive care, and no cases of death were identified. Dermatologists should consider a diagnosis of DIHS following BRAF inhibitor initiation, particularly in the setting of past checkpoint inhibition, with atypical features including relatively rapid onset and steroid responsiveness, lack of peripheral eosinophilia, lymphocytosis, or lymphadenopathy, and increased risk of thrombocytopenia and hypotension.

Drug-induced hypersensitivity syndrome with human herpesvirus-6 reactivation

A 45-year-old man, on carbamazepine for the past 3 months, was referred as a case of atypical measles. On examination, he had high-grade fever, generalized itchy rash, cough, vomiting and jaundice. A provisional diagnosis of drug hypersensitivity syndrome to carbamazepine was made with a differential diagnosis of viral exanthema with systemic complications. Laboratory investigations revealed leukocytosis with eosnophilia and elevated liver enzymes. Real-time multiplex polymerase chain reaction (PCR) on throat swab and blood was suggestive of human herpesvirus-6 (HHV-6). Measles was ruled out by PCR and serology. The diagnosis of drug-induced hypersensitivity syndrome (DIHS) was confirmed, which could explain all the features manifested by the patient. HHV-6 infects almost all humans by age 2 years. It infects and replicates in CD4 T lymphocytes and establishes latency in human peripheral blood monocytes or macrophages and early bone marrow progenitors. In DIHS, allergic reaction to the causative drug stimulates T cells, which leads to reactivation of the herpesvirus genome. DIHS is treated by withdrawal of the culprit drug and administration of systemic steroids. Our patient responded well to steroids and HHV-6 was negative on repeat real-time multiplex PCR at the end of treatment.

A Case of Drug-induced Hypersensitivity Syndrome due to Carbamazepine

The patient was a 51-year-old man who had been prescribed carbamazepine for right third-branch trigeminal neuralgia. He had stopped taking the medication after the neuralgia resolved. When the neuralgia recurred, he resumed medication, and about 1 month later he developed fever, fatigue, cervical lymphadenopathy, generalized skin flushing, facial edema and perioral vesicles, and was admitted to Ichikawa General Hospital, Tokyo Dental College. Oral findings showed reddening and erosion of the buccal mucosa. Routine laboratory examination revealed leukocytosis and hepatic dysfunction. Human herpesvirus 6 antibody titer remarkably increased during development of eruptions. These findings led to a diagnosis of drug-induced hypersensitivity syndrome. Carbamazepine was discontinued, and prednisolone (30 mg/day) was started and tapered based on improvement of symptoms. Because skin symptoms recurred after he was discharged 15 days after admission, the dose of prednisolone was increased and the symptoms finally disappeared. The patient has experienced no further recurrence.

Drug-Induced Hypersensitivity Syndrome: A Literature Review and A Case Report

Drug-induced hypersensitivity syndrome (DIHS) is characterized by fever, rash and internal organ involvement, mostly in form of hepatitis, myocarditis, nephritis or pneumonitis, which may occur 1-8 weeks after medicine exposure. Fever is an early feature, usually preceding a widespread erythematous skin eruption, but the severity of the skin-related changes does not correlate with the extent of internal organ involvement. It is considered that anticonvulsants (particularly carbamazepine), antibiotics, allopurinol are the most frequent causative agents of DIHS. The underlying mechanisms causing DIHS are poorly understood--defective detoxification of the reactive drug's metabolites or genetic predisposition have been implicated. Diagnosis of DIHS is based on clinical presentation connected with drug intake, supported by a finding of eosinophilia, increased concentration of inflammation markers and abnormal biochemical parameters, mainly liver function tests. Treatment consists of immediate withdrawal of all suspected medicines, followed by supportive systemic corticosteroids. We describe a case of a 72-years-old female who developed symptoms of drug-induced hypersensitivity syndrome after approximately 4 weeks of taking anticonvulsant (Amizepin) due to sensual axonal polyneuropathy. Withdrawal of drug and treatment with systemic corticosteroids caused clinical improvement rapidly.

Stevens-Johnson syndrome and toxic epidermal necrolysis due to anticonvulsants share certain clinical and laboratory features with drug-induced hypersensitivity syndrome, despite differences in cutaneous presentations

Drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is characterized by late disease onset, fever, rash, hepatic dysfunction, haematological abnormalities, lymphadenopathy and often, human herpesvirus (HHV) reactivation. The diagnosis of DIHS is based on the combined presence of these findings. Anticonvulsants are a major cause of DIHS and may also cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We examined whether SJS/TEN due to anticonvulsants display similar clinical and laboratory features seen in DIHS. Patients diagnosed with SJS or TEN due to anticonvulsants (n = 8) were examined and their clinical features and laboratory findings were compared with patients with anticonvulsant-related DIHS (n = 6). Seven of the eight patients with SJS/TEN developed symptoms > 3 weeks after starting anticonvulsants. Hepatic dysfunction was present in six patients with SJS/TEN and five patients with DIHS. Leucocytosis and/or eosinophilia was noted in seven patients with SJS/TEN and four patients with DIHS. Only one patient in the SJS/TEN group had atypical lymphocytosis; this was present in four patients with DIHS. Reactivation of HHV-6 was detected in one of the four patients tested in the SJS/TEN group, although it was seen in five of the six patients with DIHS. TSJS/TEN due to anticonvulsants may exhibit some clinical and laboratory features of DIHS. The nature of the cutaneous involvement should be emphasized in the diagnosis of DIHS.

Retrospective analysis of drug-induced hypersensitivity syndrome: A study of 27 patients

Previous reports regarding the characteristics of patients with drug-induced hypersensitivity syndrome (DIHS) are mostly limited to small case reports and drug-specific case series, mainly involving Caucasian patients. We describe the trends in the clinical presentation and laboratory findings of our patients with DIHS and their response to therapy. This is a retrospective case series. Clinical records of patients treated in the Department of Dermatology, Changi General Hospital, Singapore, with a diagnosis of DIHS from January 2003 to January 2008 were retrieved and analyzed. In all, 27 patients were analyzed. The 3 most consistent features in our patients were 1) history of drug exposure (100%); 2) a morbilliform cutaneous eruption in 81.5% of the patients; and 3) systemic involvement with hepatitis (96.3%), hematologic abnormalities (81.5%), and fever (77.8%) being most common. Superficial perivascular dermatitis was the most common skin biopsy specimen findings, with tissue eosinophilia occurring in half the biopsy specimens. Severe complications included renal failure requiring dialysis in two patients and hyperthyroidism and myocarditis occurring in one patient. This is a retrospective study with a small number of patients during a 5-year period. We did not routinely document the presence of lymphadenopathy and hepatosplenomegaly in our patient's records. We do not measure viral serologies routinely as part of the workup for DIHS. DIHS is not uncommon. The presentation in an Asian population is similar to published studies. Treatment includes discontinuation of the offending drug, monitoring for organ involvement, and using systemic steroids.

Sulfasalazine-induced hypersensitivity syndrome in a 15-year-old boy associated with human herpesvirus-6 reactivation

Drug-induced hypersensitivity syndrome (DIHS) is characterized by high fever, facial edema, diffuse maculopapular eruption, and multiorgan involvement. Human herpesvirus (HHV)-6 reactivation is an accepted criterion for the diagnosis of DIHS and has prognostic importance. We report a 15-year-old boy with juvenile rheumatoid arthritis who developed DIHS due to sulfasalazine, associated with reactivation of HHV-6.

Drug-induced hypersensitivity syndrome associated with reactivation of human herpesvirus6 presenting with severe hepatic injury.

Little is known about the pathophysiology of liver complication seen in drug-induced hypersensitivity syndrome (DIHS). We describe herein a 32-year-old Japanese man with DIHS due to salazosulfapyridine (SASP) associated with reactivation of human herpesvirus6 (HHV-6) presenting with severe acute hepatic injury. The patient, with a 1-year history of ulcerative colitis (UC), presented with high fever and abnormally elevated liver enzymes. Six weeks prior to his symptoms, prednisolone (PSL) and SASP had been started because of UC aggravation. Besides fever and liver dysfunction, the appearance of atypical lymphocytes together with eosinophils and generalized erythematous maculopapular skin rash developed sequentially, and a diagnosis of DIHS was established. Despite cessation of SASP and increased dose of PSL, his initial abnormalities continued, and biphasic second alanine aminotransferase (ALT) flare with deep jaundice worsened. Based on the significant increase in the titer of HHV-6 IgG antibodies at the second peak of ALT level without HHV-6 IgM antibody elevation, strongly suggesting reactivation of the virus, HHV-6 was first considered to directly contribute to the deterioration of liver function. However, extensive histological analysis of the liver led to the realization that the cause of the DIHS liver injury was essentially drug-related hepatotoxicity induced by SASP, causing wide-ranging damage to both the hepatocytes and cholangiocytes.

Syndrome d’hypersensibilité à la fluindione (Préviscan®). Positivité des tests épicutanés

Fluindione (Previscan) is an oral anticoagulant belonging to the vitamin K antagonist class and is very widely used in France. While bleeding is a common complication, severe immunoallergic reactions are less frequent. The authors report a case of drug-induced hypersensitivity syndrome. A 75 year-old woman was hospitalized for diffuse erythematous papular rash associated with facial oedema. These symptoms appeared 3 weeks after the beginning of treatment with fluindione, allopurinol and perindopril. Laboratory tests showed hyperleukocytosis, mixed hepatitis and moderate renal failure, with the entire picture being evocative of drug-induced hypersensitivity reaction. The eruption was associated with eosinophilia, hepatic cytolysis with cholestasis, and acute renale failure. While allopurinol and perindopril were stopped definitively, fluindione was only suspended temporarily following overdosage. On reintroduction, rapid recurrence of clinical and biologic signs was observed with increased severity. The skin rash resolved completely on withdrawal of the drug. Patch tests performed later were positive for fluindione and negative for allopurinol and perindopril. These manifestations were consistent with the diagnosis of drug-induced hypersensitivity syndrome due to fluindione. Very few cases have been described with fluindione despite widespread prescription of the treatment is in France. While there may be no skin involvement, immunoallergic signs such as fever, hepatitis and acute tubular interstitial nephritis have been described with fluindione and these may be related to this syndrome (DRESS - Drug Reaction with Eosinophilia and Systemic Symptoms). Skin patch testing, which is easily performed, can be extremely helpful in determining a causal relationship with medication.

Human herpesvirus infection in drug-induced hypersensitivity syndrome, toxic epidermal necrolysis and Stevens-Johnson syndrome

ABSTRACT Background Reactivation of human herpesvirus (HHV) infection, especially HHV-6, has been observed in patients with drug-induced hypersensitivity syndrome (DIHS). In toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), the relevance of HHV infection to the symptoms is unclear. Methods Patients with a diagnosis of DIHS ( n = 7), TEN ( n = 5) and SJS ( n = 4) were included in the present study. These patients were evaluated for the presence of active HHV-6, HHV-7 and cytomegalovirus (CMV) infections by serological tests and polymerase chain reaction with blood. Results More than 3 weeks after the onset of DIHS, HHV-6 serological tests revealed a remarkable rise in IgG antibodies in six patients, including one treated without steroids. Human herpesvirus-6 DNA was detected in blood from three patients. In one patient with DIHS, reactivation of CMV was shown without reactivation of HHV-6, whereas in three patients anti-CMV IgG antibodies increased after the rise of anti-HHV-6 IgG antibodies. Anti-HHV-7 IgG antibodies did not show remarkable rises in any of these patients. As for patients with TEN and SJS, anti-HHV-6, anti-HHV-7 and anti-CMV IgG antibodies showed no significant increase, except for one patient in whom anti-HHV-6 and anti-HHV-7 IgG antibodies increased, but not more than 1: 160, after steroid therapy. Human herpesvirus-6 DNA was not detected in the blood of those patients. Conclusions Human herpesvirus-6 reactivation in patients with DIHS is not due to non-specific reactivation induced by steroid therapy, but to events specific to DIHS. We hypothesize that DIHS may occur as a result of reactivation of HHV, especially HHV-6, accompanied with an allergic reaction to drugs, followed by a substantial immune response to the virus that is probably responsible for visceral involvement.