Ethosuximide‐induced drug reaction with eosinophilia and systemic symptoms with mediastinal lymphadenopathy

Lymphadenopathy is a common sign for drug reaction and eosinophilia with systemic symptoms (DRESS) syndrome, but hilar and mediastinal lymphadenopathy may be underreported. We describe a 7‐year‐old boy who started taking ethosuximide for absence seizures and presented with diffuse rash, fever, elevated transaminases, facial swelling, and hilar and mediastinal lymphadenopathy. His mediastinal lymphadenopathy was concerning for lymphoma, which led to more invasive testing to rule out malignancy. This report highlights an unusual and likely underreported presenting sign of DRESS syndrome in children.     

Pustular‐type drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms due to carbamazepine with systemic muscle involvement

Drug‐induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe reaction usually associated with maculopapular eruptions and systemic involvement. Here we report the first case, to our knowledge, of DIHS/DRESS due to carbamazepine with acute generalized pustular bacterid‐like (AGPB‐like) eruptions and skeletal muscle involvement. Reviewing our case and the published work, we discuss pustular‐type DIHS/DRESS which, in most cases, involves acute generalized exanthematous pustulosis (AGEP)‐like skin eruptions in response to carbamazepine. Pustular eruptions may appear in relatively few cases of DIHS/DRESS, in particular, when the causative drug is carbamazepine and, even in cases of intractable pustular bacterid‐like eruptions, a reaction to a drug should be suspected. Skeletal muscle involvement may be associated with DIHS/DRESS as one of its systemic manifestations.     

Probable Griseofulvin‐Induced Drug Reaction with Eosinophilia and Systemic Symptoms in a Child

A 9‐year‐old boy presented with fever, rash, anterior cervical lymphadenopathy, high liver enzymes, atypical lymphocytosis, and eosinophilia (drug reaction with eosinophilia and systemic symptoms [DRESS]). His history was notable for having taken griseofulvin for 3 weeks prior to onset of these findings. He improved after treatment with oral prednisone. We present a rare case of probable DRESS secondary to griseofulvin.     

DRESS syndrome associated with carbamazepine and phenytoin

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome reflects a serious hypersensitivity reaction to drugs. Its clinical manifestations include diffuse maculopapular rash, exfoliative dermatitis, facial edema, lymphadenopathy, fever, multivisceral involvement and it is associated with a high mortality rate. We report a 62-year-old patient suffering from epilepsia presenting erythroderma following carbamazepine intake. Blood tests revealed eosinophilia, leukocytosis, elevated liver enzymes and high levels of Eosinophil Cationic Protein (ECP). We applied systemic steroids and anticonvulsant therapy was switched to phenytoin, which had been taken previously without adverse reactions. The skin eruptions persisted and the patient developed fever. Anticonvulsant medication was discontinued and skin eruptions finally resolved under steroid application. This case report demonstrates that cross reactivity between carbamazepine and phenytoin may not only lead to the development but also to the worsening of DRESS syndrome. ECP blood levels may represent a sufficient parameter to monitor the development of DRESS syndrome.     

A patch testing and cross‐sensitivity study of carbamazepine‐induced severe cutaneous adverse drug reactions

Background The usefulness of the drug patch testing for Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is still controversial. Recent studies have shown that HLA‐B*1502 is strongly associated with CBZ‐SJS/TEN in Chinese and Southeast Asian populations. Objective To evaluate the usefulness of patch tests for patients with carbamazepine (CBZ)‐induced SJS, TEN and drug reaction with eosinophilia and systemic symptoms (DRESS) and the cross‐reactivity in patch tests among the aromatic antiepileptic drugs. Methods We measure the frequency of positive patch test reactions and cross‐sensitivity to structure‐related aromatic anti‐epileptic drugs (AEDs) for patients after SJS/TEN or DRESS episodes caused by CBZ. CBZ and other structure‐related AEDs used for patch testing were prepared in 10% and 30% petrolatum. Secondary measures included the association of HLA‐B*1502 genotype and frequency of possible side effects from the patch tests. Results Positive patch test reactions to 30% CBZ in the CBZ‐SJS/TEN were 62.5% (10/16), and 70% (7/10) in the CBZ‐DRESS. None of the 10 healthy controls displayed a positive reaction to tested agents. Cross‐sensitivity to other aromatic AEDs was observed in both the CBZ‐SJS/TEN and the CBZ‐DRESS. Only the HLA‐B*1502 genotype was present and strongly associated with the CBZ‐SJS/TEN, but not with the CBZ‐DRESS. Conclusion Drug patch testing is a safe and useful method for the identification of CBZ as the culprit drug of SJS/TEN as well as DRESS. Testing of chemically or pharmacologically related AEDs may provide information on cross‐reactivity for these patients.     

Carbamazepine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: report of four cases and brief review

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but severe drug reaction, most commonly to aromatic anticonvulsants with a delayed onset, variable clinical presentation and protracted course. The exact incidence of DRESS syndrome is not known because of the variability in clinical presentation, lack of strict diagnostic criteria and universally accepted nomenclature.
We report four cases of DRESS syndrome associated with the use of carbamazepine. The clinical manifestation was similar: a maculopapular eruption progressing to exfoliative erythroderma, fever, and lymphadenopathy. Leukocytosis, atypical lymphocytes and liver injury (in 2 patients) were also observed. Assessment of causality using the Naranjo algorithm established a "probable" relationship with carbamazepine in three of the cases and a "possible" relationship in one case.
Detection of DRESS syndrome is dependent on the exclusion of a variety of diseases with similar manifestations and may be delayed in time. DRESS syndrome is a potentially life-threatening multisystem adverse drug reaction, and accidental reexposure or drug provocation tests must be avoided.     

Dress syndrome with sepsis, acute respiratory distress syndrome and pneumomediastinum

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome reflects a serious hypersensitivity reaction to drugs, and is characterized by skin rash, fever, lymph node enlargement, and internal organ involvement. So far, numerous drugs such as sulfonamides, phenobarbital, sulfasalazine, carbamazepine, and phenytoin have been reported to cause DRESS syndrome. We report a case of a 10-year-old girl who developed clinical manifestations of fever, rash, lymphadenopathy, hypereosinophilia, and visceral involvement (hepatitis and pneumonitis) after taking phenobarbital for seizures, with subsequent development of sepsis, acute respiratory distress syndrome (ARDS) and spontaneous air leak syndrome (pnemothorax and pneumomediastinum). She was put on steroids and various antibiotics and was ventilated, but ultimately succumbed to sepsis and pulmonary complications.     

Drug‐reaction eosinophilia and systemic symptoms and drug‐induced hypersensitivity syndrome

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug‐induced hypersensitivity syndrome (DIHS), is a rare, severe cutaneous adverse reaction characterised by fever, rash, lymphadenopathy, eosinophilia and/or other leukocyte abnormalities, and internal organ involvement and often has a relapsing–remitting course despite withdrawal of the drug. The drugs that are most implicated include aromatic anticonvulsants, allopurinol, sulphonamides, antiretrovirals (abacavir and nevirapine), and minocycline. The pathogenesis of DRESS/DIHS is far from clear but probably involves a combination of impaired pharmacokinetics and the accumulation of drug metabolites, the sequential reactivation of the herpesvirus family and genetic susceptibility conferred by the association with certain human leukocyte antigen (HLA) class I alleles. The strong association between abacavir and HLA‐B*5701 has enabled pharmacogenetics screening to be employed successfully to minimise the occurrence of hypersensitivity. A prolonged course of oral corticosteroids is required to treat DRESS/DIHS, given the relapsing–remitting nature of the condition with i.v. immunoglobulin and valgangciclovir reserved for refractory or life‐threatening cases.     

Case Report of Drug Rash with Eosinophilia and Systemic Symptoms Demonstrating Human Herpesvirus‐6 Reactivation

Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe drug‐induced hypersensitivity syndrome that presents with diffuse cutaneous eruptions, fever, and multiorgan involvement. Here we present a pediatric case of DRESS complicated by human herpesvirus (HHV)‐6 reactivation. After 1 week of sulfasalazine, our patient developed a diffuse morbilliform eruption. Sulfasalazine was discontinued. The patient presented to the emergency department soon thereafter with worsening eruption, fever, rigors, facial edema, and lymphadenopathy. Methylprednisolone was initiated. Peripheral smear did not demonstrate eosinophilia but showed toxic granulation with atypical lymphocytes. Transaminase levels and white blood cell count quickly became elevated, with increased eosinophils, suggesting DRESS. During the methylprednisolone taper, our patient experienced symptom exacerbation, acute hepatitis, and HHV‐6 seroconversion, indicating HHV‐6 reactivation as the cause. As demonstrated by our patient, a decelerated methylprednisone taper is important because of potential symptom flaring during taper. Additionally, in the care of individuals with DRESS, HHV‐6 is often tested for upon admission and not repeated. Delay in the rise of titers necessitates repeat testing.     

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe cutaneous drug reaction characterized by fever, lymphadenopathy, hematologic abnormalities, multisystem involvement, and viral reactivation. Although most patients with DRESS syndrome are able to fully recover, a subset of patients go on to have a prolonged course with recurrence, and/or autoimmune complications. Severe systemic involvement is associated with significant morbidity and mortality. Viral reactivation, especially of human herpes virus 6, Epstein-Barr virus, and cytomegalovirus, is a common feature of DRESS, with a high viral load and antibody titers being associated with poor outcomes. Aside from prompt discontinuation of the offending drug, treatment for patients with significant disease consists of systemic therapy with corticosteroids.     

A review of DRESS-associated myocarditis

DRESS (drug rash with eosinophilia and systemic symptoms), also known as drug-induced hypersensitivity syndrome, is a severe, systemic drug reaction most commonly associated with aromatic anticonvulsants and sulfonamides. Patients typically present with fever, facial edema, cervical lymphadenopathy and a morbilliform eruption, which may progress to erythroderma. Hematologic abnormalities are a hallmark of the condition, including eosinophilia and atypical lymphocytosis. Visceral organ involvement typically manifests as hepatic dysfunction but may include lymphadenopathy, nephritis, interstitial pneumonitis, and myocarditis. Five to ten percent of patients with DRESS die from systemic complications, making timely recognition and treatment essential to prevent life-threatening manifestations. Myocarditis is a fatal and under-recognized manifestation of DRESS, which may occur long after the initial diagnosis. We review the literature of previously reported cases of DRESS and myocardial involvement, highlighting the presenting symptoms associated with cardiac involvement, treatments used, and the outcome for each patient. In addition, we offer an algorithm for early diagnosis, treatment, and subsequent monitoring of these patients.     

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

Background. 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. Methods. 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). Results. 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. Conclusions. 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.     

Drug reaction with eosinophilia and systemic symptoms: A drug-induced hypersensitivity syndrome with variable clinical features

Drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS) involves a unique and severe adverse drug reaction. Patients present with fever, rash, lymphadenopathy, hematological abnormalities, systemic illness, and may suffer from prolonged courses. Although the precise pathogenesis of DRESS/DIHS is not fully understood, it is widely considered to be an immunological reaction to a drug or drug metabolites. In this review article, we discuss the historical aspects of nosology, variable clinical and histopathological features, advantages and disadvantages of using an international Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) and Japanese DIHS criteria, pathogenesis, treatment, and long-term sequelae of DRESS/DIHS. Early recognition of this syndrome, withdrawal of suspected culprit drugs, and adequate supportive care are mainstays of improving patient prognosis and reducing morbidities and mortality. Moreover, some DRESS/DIHS patients may develop long-term sequelae, especially autoimmune diseases and end organ failure. Physicians should be aware of these possibilities in patients after DRESS/DIHS and cautiously follow-up symptoms and laboratory tests for early detection of these sequelae.     

Alopecia universalis after drug reaction with eosinophilia and systemic symptoms (Dress)

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse reaction characterized by a morbilliform cutaneous eruption, fever, lymphadenopathy, and multiorgan involvement. Alopecia universalis is a variant of alopecia areata characterized by complete loss of hair on the entire body. Herein, we report a case of alopecia universalis that presented after DRESS.     

Levetiracetam Induced Drug Reaction with Eosinophilia and Systemic Symptom Syndrome

Drug reaction with eosinophilia and systemic symptom syndrome (DRESS) is a hypersensitivity drug reaction, most frequently associated with antiepileptic drugs, characterized by skin rash, fever, pharyngitis, lymphadenopathy, and visceral organ involvement, typically presenting within 8 weeks of initiation of therapy. Management involves prompt withdrawal of the offending drug and use of systemic corticosteroids. We here present a rare case of DRESS secondary to levetiracetam. Only few case reports of DRESS secondary to levetiracetam have been published so far.     

Allopurinol‐Induced DRESS Syndrome in an Adolescent Patient

Abstract: A 16‐year‐old male patient, with a history of essential hypertension enrolled in an experimental drug protocol using allopurinol, presented to our emergency department with a 10‐day history of fever. Initial laboratory evaluation revealed leukocytosis, eosinophilia, and transaminitis. After extensive work‐up and exclusion of infectious and oncologic etiologies, the diagnosis of allopurinol‐induced drug reaction and eosinophilia with systemic symptoms syndrome was carried out. The patient responded to administration of IV methylprednisolone, with complete resolution of symptoms and improvement of laboratory abnormalities. This case represents the first report of allopurinol‐induced drug reaction and eosinophilia with systemic symptoms syndrome in a pediatric patient.     

Presence of the HLA‐A*3101 allele in a familial case of drug reaction with eosinophilia and systemic symptoms,secondary to carbamazepine

Anticonvulsants such as carbamazepine and phenytoin are associated with adverse skin reactions ranging from maculopapular exanthems to more severe reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome and toxic epidermal necrolysis. In addition to their antiepileptic role, anticonvulsants are also used to treat pain syndromes including trigeminal neuralgia. Until recently, the associated skin reactions were thought to be unpredictable; however, the current literature suggests a genetic predisposition involving the human leucocyte antigen (HLA) in cutaneous reactions associated with carbamazepine usage. We present two familial cases of DRESS secondary to carbamazepine, in which an underlying genetic predisposition and allelic association were identified.     

Drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms due to lamotrigine differs from that due to other drugs

Drug‐induced hypersensitivity syndrome (DIHS), also referred to as drug reaction with eosinophilia and systemic symptoms (DRESS), is a multi‐organ systemic drug reaction characterized by hematological abnormalities and reactivation of human herpesvirus‐6 (HHV‐6). DIHS/DRESS is typically associated with a limited number of drugs, such as the anticonvulsants. Our group has treated 12 patients for DIHS/DRESS due to lamotrigine (LTG), but their presentation differed from that of patients with DIHS/DRESS caused by other drugs. The aim of the present study was to identify significant differences between DIHS/DRESS caused by LTG versus other drugs. We retrospectively reviewed data of 12 patients with DIHS/DRESS caused by LTG and 32 patients with DIHS/DRESS due to other drugs. The increase in alanine aminotransferase level was significantly milder in the LTG group than the DIHS/DRESS group due to other drugs. The percentage of atypical lymphocytes in the blood during DIHS/DRESS was lower in the LTG group. Serum levels of lactate dehydrogenase and thymus and activation‐regulated chemokine were also lower in the LTG group. There were fewer DIHS/DRESS patients with HHV‐6 reactivation in the LTG group than in the group treated with other drugs. Lymphocyte transformation after DIHS/DRESS onset was faster in the LTG group. The two groups did not differ with respect to the interval from first drug intake to rash, white blood cell count, blood eosinophilia or DRESS score. There were no significant histopathological differences between the two groups. The features of LTG‐associated DIHS/DRESS and DIHS/DRESS due to other drugs differ.     

A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions

Background Drug patch tests (PTs) can reproduce delayed hypersensitivity to drugs and entail a moderate re‐exposure of patients to offending drugs. Objectives To determine the value of PTs for identifying the responsible drug in severe cutaneous adverse drug reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Methods In a multicentre study, PTs were conducted on patients referred for DRESS, AGEP or SJS/TEN within 1 year of their SCAR. All drugs administered in the 2 months prior to and the week following the onset of the SCAR were tested. Results Among the 134 patients included (48 male, 86 female; mean age 51·7 years), positive drug PTs were obtained for 24 different drugs. These included positive tests for 64% (46/72) of patients with DRESS, 58% (26/45) of those with AGEP and 24% (4/17) of those with SJS/TEN, with only one relapse of AGEP. The value of PTs depended on the type of drug and the type of SCAR (e.g. carbamazepine was positive in 11/13 DRESS cases but none of the five SJS/TEN cases). PTs were frequently positive for beta lactams (22 cases), pristinamycin (11 cases) and in DRESS with pump proton inhibitors (five cases), but were usually negative for allopurinol and salazopyrin. Of 18 patients with DRESS, eight had virus reactivation and positive PTs. In DRESS, multiple drug reactivity was frequent (18% of cases), with patients remaining sensitized many years later. Conclusions PTs are useful and safe for identifying agents inducing SCAR.     

Exfoliative Dermatitis Due to Immunologically Confirmed Carbamazepine Hypersensitivity

Abstract: A 6–year-old Caucasian girl experienced a generalized erythematous skin rash during carbamazepine therapy. Over the next four days the eruption worsened into erythroderma with fever and generalized lymphadenopathy. Routine laboratory studies revealed increased serum levels of liver enzymes and eosinophilia. Immunologic reactivity to the anticonvulsant carbamazepine and its analogs was investigated both in vivo and in vitro by patch tests and lymphocyte proliferation assays, respectively.