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Abstract
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is characterized by an heterogeneous group of severe dermatologic manifestations and systemic involvement, due to several groups of medicaments. A series of 9 consecutive cases, observed from 2008 to 2013 in the Department of Dermatology, University of Pavia, is reported, all satisfying the clinical, hematological and systemic diagnostic criteria of DRESS. Clinically, 4 out of 9 patients had an urticarial and papular eruption, 2 an erythema-multiforme-like (EM-like) pattern, 2 erythroderma and 1 had an erythematous and macular reaction. Aim of the study was to describe the histopathologic features of DRESS and to trace a possible correlation between the four clinical recognized types of the syndrome and the histopathological patterns. Predominantly, a superficial perivascular lymphocytic infiltrate, extravasation of erythrocytes, and focal interface changes characterized DRESS cases. Less frequently, histopathology revealed the presence of necrotic keratinocytes; surprisingly, only in 2 cases the presence of rare dermal eosinophils was detected, even if all the patients had significant peripheral eosinophilia. A histopathological diagnosis of DRESS seems per se, according to our data, not feasible, since the main histopathological changes (interface changes, superficial perivascular dermatitis, focal spongiosis, lichenoid infiltrate, rare presence of necrotic keratinocytes) can be interpreted generically as a drug induced dermatitis. The above mentioned histopathological changes, however, when associated with clinical information on cutaneous and systemic involvement of the patient, allow the pathologist or the dermatopathologist to make a diagnosis of DRESS with a reliable margin of certainty.
... Skin histopathology of cutaneous lesions in DRESS syndrome highlights various associated inflammatory patterns in a single biopsy [6]. It reveals a perivascular lymphocytic infiltrate in the papillary dermis, with eosinophils, atypical lymphocytes, and spongiosis, interface dermatitis [7]. The histology of affected lymph nodes in DRESS syndrome may show either benign lymphoid hyperplasia or a pseudolymphoma pattern, which must be carefully distinguished from lymphoma [2,3,4,5]. ...
... The histology of affected lymph nodes in DRESS syndrome may show either benign lymphoid hyperplasia or a pseudolymphoma pattern, which must be carefully distinguished from lymphoma [2,3,4,5]. Clinico-pathological correlation is needed to make a diagnosis of DRESS with a reliable margin of certainty [7]. ...
A 50-year-old male Sudanese patient presented with a three-week history of jaundice, high-grade fever, and mucocutaneous eruption. For last months he was on compound therapy for leprosy, which had been confirmed recently. The patient’s face was prominent, along with the erythematous dusky morbilliform rash covering all the body. On examination, we detected hepatosplenomegaly and generalized lymphadenopathy. Laboratory investigations revealed hepatorenal impairment, and hematological analysis revealed leukocytosis mainly due to eosinophilia. The clinical and laboratory findings interpretation ranked DRESS or Drug-Induced Hypersensitivity Syndrome (DIHS) on top of possible causes before Dapsone Hypersensitivity Syndrome (DHS) and lepra reactions. We promptly discontinued MDT, admitted him to the dermatological ward. Two skin biopsies were sent to two different histopathologists, MF was suggested by one and Sezary syndrome by the other one. Besides the general conservative measures and vital functions monitoring, he received systemic and topical steroids. However, unfortunately, within the next three weeks, his condition deteriorated, and passed away from multi-systems failure.
... Recognition of the toxicity of carbamazepine, and its withdrawal, was delayed, which we attribute to the confusion generated by the great mimic power of SARS-CoV-2. The skin biopsy, performed in the period of symptom remission, revealed spongiotic lesions, one of the patterns observed in a study carried out in Italy, 22 although nonspecific. According to the RegiSCAR scoring system for classifying DRESS cases, our patient reached grade 6, i.e. a definite case. ...
The diagnosis of coronavirus disease (COVID-19) has been a great challenge since the infection affects not only the respiratory system, but also different organs, given the intense inflammatory and autoimmune reaction triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein we present a case of a 36-year-old male patient, with some comorbidities and previous use of carbamazepine, who developed a severe condition triggered by COVID-19, including extensive exfoliative erythroderma and severe impairment of liver function, which lasted approximately 80 days.
... Three punch biopsies demonstrated lichenoid dermatitis, which could have been interpreted as drug-induced dermatitis. However, the histopathological changes associated with DIHS are not well-established, and the patient's systemic involvement was more suggestive of DIHS [4]. The patient was discharged on prednisone (80 mg/day) and outpatient triamcinolone 0.01% ointment wraps. ...
Drug-induced hypersensitivity syndrome is a rare, severe, and delayed hypersensitivity reaction that may occur with exposure to a number of medications. Typical implicated medications include aromatic anticonvulsants, sulfonamides, minocycline, dapsone, and allopurinol. Bortezomib is a proteasome inhibitor and has rarely been associated with cutaneous hypersensitivity reactions. We report a case of recurrent drug-induced hypersensitivity syndrome secondary to bortezomib in a patient with multiple myeloma. The aim of this article is to highlight a unique mediation that may cause drug-induced hypersensitivity syndrome and to emphasize the challenge of managing these patients long-term to prevent relapse of the syndrome.
... Reported cases display a wide range of histologic findings, including interface dermatitis with basal cell vacuolar change, lichenoid infiltrate and necrotic keratinocytes resembling erythema multiforme (EM). 18 Autoimmune sequelae of DRESS can develop in 6e9% of patients, including type 1 diabetes mellitus, systemic lupus erythematosus, type III polyglandular autoimmune syndrome, and autoimmune thyroid disease in the later phase of DRESS. 19 In our cohort, case 2 with DRESS to nevirapine developed Hashimoto's thyroiditis 4 months post-resolution of DRESS. ...
DRESS is a potentially life-threatening severe cutaneous adverse reaction (SCAR). Historically, it was most frequently linked with phenytoin and was initially described as phenytoin hypersensitivity syndrome; however, it was later found to be caused by various other medications, with the commonest been aromatic anticonvulsants, allopurinol and sulfonamides. The severity of this entity is related to systemic involvement, which can result in multiorgan failure and death. The diagnosis of DRESS, especially in the early stages, remains challenging and elusive due to its heterogeneous clinical presentation and the complex course of the disease with different patterns depending on the causal drug. The most important step in the management of DRESS is early diagnosis and immediate cessation of the suspected offending drug along with oral steroids or immunosuppressants to control the disease. We describe the varying presentation and management of six adults with DRESS from a tertiary care hospital, observed over a two-year period with a brief review of the literature.
... The histopathological diagnosis included "drug reaction" in 12/17 patients (70.6%) and erythema multiforme in 5/17 (29.4%) which is a well-reported histological entity seen in DRESS. [11] The histological features of DRESS are interface dermatitis, eczematous, EM-like, and AGEP-like pustulosis. [12] Taken together, the pathologist was able to identify the histopathological features on the frozen section as consistent with that of a drug reaction/erythema multiforme. ...
Context:
Early diagnosis is the mainstay in the management of severe cutaneous adverse reactions (SCARs) to drugs.
Aims:
To study the role of frozen section in the rapid diagnosis of SCARs and the impact on outcome of the affected patients.
Settings and design:
A single-blind, hospital-based study was conducted from December 2014-July 2016.
Methods and material:
We biopsied 32 adults with SCARs diagnosed by clinical features and standard criteria. The histopathological features seen on frozen sections were compared to that of paraffin blocks. The impact of rapid diagnosis on the clinical outcome was studied in toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP).
Statistical analysis:
Z test was used to compare two proportions. Kappa statistic, sensitivity, specificity, positive predictive value, and negative predictive value of the frozen section diagnosis were calculated in TEN/SJS and DRESS using MedCalc software.
Results:
Frozen and paraffin sections were done in TEN/SJS spectrum (13), DRESS (17), and AGEP (2). The sensitivity, specificity and kappa values for frozen section diagnosis in SJS/TEN and DRESS were 91.7%, 95%, 0.867 and 94.4%, 100%, 0.937 respectively. The concordance between frozen and paraffin section diagnosis was 100% in TEN, SJS, DRESS and AGEP. All the 6 patients with TEN and 2 with AGEP survived. Taking the worst-case scenario, the mortality in SJS was 28.6%. The mortality among patients with DRESS was 11.8%.
Conclusions:
Frozen section helps in the rapid diagnosis and early treatment of SCARs and differentiates it from diseases that mimic it.
... In DRESS, it is sometimes possible to observe purpuric areas, resulting from erythrocyte extravasation ( Figure 12). 12 ...
A prompt recognition of life-threatening and severe acute rashes is of utmost importance to start an appropriate therapy as soon as possible. Consequently, clinicians often must rely only on clinical data to make a diagnosis because some diagnostic procedures may take a relatively long time to be performed (eg, histologic examination, microbiologic tests). In this scenario, dermatoscopy may be useful as an auxiliary tool to support the diagnosis by highlighting subclinical features. We have provided an up-to-date overview on the use of dermatoscopic assessment in life-threatening and severe acute dermatoses, including erythroderma (due to psoriasis, eczema, pityriasis rubra pilaris, mycosis fungoides, and drugs), pustular eruptions (pustular psoriasis and acute generalized exanthematous pustulosis), bullous eruptions (staphylococcal scalded skin syndrome, toxic epidermal necrolysis, and pemphigus vulgaris), hemorrhagic eruptions (necrotizing vasculitis and calciphylaxis), and erythematous eruptions (erythema multiforme major, Sweet syndrome, and DRESS syndrome).
... It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher. 10 For the exclusion of other diseases in the differential diagnosis that can mimic this presentation, we performed blood samples for antinuclear antibodies (ana), eBV, CmV, HHV 6, and cultures of the blood and urine. the results were negative. ...
Telaprevir is a specific inhibitor of the hepatitis C (HCV) serine protease 3. Cutaneous side effects have been reported with telaprevir. Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare yet severe adverse drug-induced reaction characterized by exfoliative dermatitis and maculopapular rash, lymphadenopathy, fever, eosinophilia, leukocytosis, and myriad internal organ involvement. We report a case of DRESS due to telaprevir. A 64-year-old Caucasian man with chronic hepatitis C developed a progressive diffuse, painful maculopapular exanthema with fever, facial edema, lymphadenopathy at week 11 of chronic hepatitis C therapy with telaprevir, Peg-Interferon alfa-2a, and ribavirin. He had no exposures to any other medications. He presented an eosinophilia (up to 6.29 X 109 cells/L), skin biopsy was consistent with a drug reaction. The HCV treatment was stopped and methylprednisolone 0.75 mg/kg/day was started. Cutaneous and systemic symptoms had a rapid resolution in few days. Telaprevir can activate severe skin reactions that can mimic an infectious disease, therefore early diagnosis and discontinuation of chronic hepatitis C treatment is mandatory.
... Eosinophils are not expected to be present in all cases, even in patients who have peripheral eosinophilia. Atypical lymphocytes with hyperchromatic nuclei have been described in different series [123]; however, a genetic clonal mutation has not been found [120]. Other common histologic findings are dermal edema, dilated blood vessels, and extravasated erythrocytes. ...
Drug reaction with eosinophilia and systemic symptoms (DReSS), also known as drug-induced hypersensitivity syndrome (DiHS), is an uncommon severe adverse reaction to medications. It is important to recognize it as it is potentially fatal and can cause significant morbidity. From the first reports of drug reactions related to certain anticonvulsants characterized by fever, liver enzyme elevation, and skin changes, our continuously growing understanding of this entity has allowed us to describe its physiopathology and clinical features even further. The relationship of genetic factors, viral activation, and specific drug exposure is now known to play a role in this disease. There is still not a widely accepted marker for DReSS/DiHS, but the spectrum of clinical and laboratory features has now been better outlined. The mainstay of treatment is the use of systemic corticosteroids, but other options such as intravenous immunoglobulin, cyclosporine, mycophenolate mofetil, rituximab, and cyclophosphamide have been described. We present a comprehensive review of the literature on DReSS/DiHS, focusing on its history, etiopathogenesis, diagnosis, therapeutic approach, and outcome.
The severe cutaneous adverse reactions (SCARs) are drug allergy syndromes characterised by a dermatosis and significant internal organ involvement which confers a risk of systemic morbidity and mortality. The major entities classified as SCARs are: acute generalised exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). The toxic dermatitis of AGEP is complicated by sheets of tiny pustules; DRESS is distinguished by an urticated exanthem, facial oedema, atypical targets and purpura; in SJS/TEN there is multisite mucositis and a blistering dermatosis resulting in widespread epidermal loss. Severe DRESS can be complicated by liver failure, whereas in SJS/TEN large insensible fluid losses, thermoregulatory dysfunction, metabolic stresses and sepsis can complicate skin loss. Management of all the SCAR syndromes depends on the immediate cessation of the culprit drug and the institution of supportive therapy and, when appropriate, active treatment.
Severe life‐threatening cutaneous drug reactions are rare phenomena, and may be clinically heterogeneous. They may be broadly categorized as Stevens–Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis and drug‐induced generalized exfoliative dermatitis. Each has distinct clinical features, and is associated with systemic disturbance. Overlap syndromes with clinical features of more than one diagnosis are described.
Background Drug reaction with eosinophilia and systemic symptoms (DRESS) describes a heterogeneous group of severe adverse reactions to medications. The cutaneous phenotype has a number of guises, accompanied by a variety of systemic features including fever, haematological abnormalities and visceral involvement, most commonly the liver. Clinical markers of prognosis have not been identified.
Objectives To assess the cutaneous signs and dermatopathological features of DRESS in order to identify potential prognostic markers.
Methods We reviewed the clinical features, dermatopathology and outcomes of 27 consecutive cases of DRESS presenting to a single unit.
Results Four distinct patterns of cutaneous involvement were identified: an urticated papular exanthem (13/27 patients), a morbilliform erythema (three of 27), an exfoliative erythroderma (three of 27) and an erythema multiforme-like (EM-like) reaction consisting of atypical targets (eight of 27). All patients mounted a fever, most developed lymphadenopathy (24/27) and peripheral eosinophilia (25/27) and the most common organ involved was the liver (27/27). Review of the dermatopathic features of patients with DRESS demonstrated a superficial spongiotic dermatitis in the majority of cases (16/27). A smaller number of cases showed basal cell vacuolar degeneration and necrotic keratinocytes (nine of 27). The patients with these biopsy findings more commonly had an EM-like cutaneous phenotype, and more severe hepatic involvement. Three patients died, two following failed liver transplants.
Conclusions Our series is the first in which a detailed dermatological assessment has been made of consecutive patients presenting with DRESS, and the largest U.K. series to date. Our results suggest a possible prognostic role of the cutaneous and dermatopathic findings in DRESS in predicting the severity of visceral involvement in this syndrome.
What’s already known about this topic?
What does this study add?
Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations.
We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions.
The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18).
The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).
BackgroundHLA-B*58:01 is associated with allopurinol-induced severe cutaneous adverse drug reactions (sCADR) particularly in Han Chinese, but the risk in European populations has seldom been studied. Objective
To study the association of HLA-B*58:01 with allopurinol-induced sCADR in a Portuguese population. Methods
We studied 25 patients (11 male/14 female, mean age 67·4 years) with sCARD from allopurinol: 19 DRESS (drug reaction eosinophilia and systemic symptoms) and six Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). HLA was genotyped by reverse sequence-specific oligonucleotide–polymerase chain reaction and results compared statistically with a control group of 23 allopurinol-tolerant individuals and the control population. ResultsHLA-B*58:01 was present in 16 patients with sCADR (64%) [12 DRESS (63%), four SJS/TEN (67%)], one allopurinol-tolerant individual (4%) and 63 normal controls (1·96%), with a statistically significant difference between sCADR and the two control groups. When compared with the normal population, HLA-B*58:01 was associated with a higher risk of sCADR, both DRESS [odds ratio (OR) 85·36, 95% confidence interval (CI) 32·52–224·04] and SJS/TEN (OR 99·59, 95% CI 17·91–553·72). There was no statistically different risk between these two types of CADR. Conclusions
Portuguese patients with sCADR from allopurinol, both DRESS and SJS/TEN, have a high frequency of HLA-B*58:01, with an OR similar to European patients with SJS/TEN. This study also extends this association to DRESS in Europeans. The recommendation to genotype systematically before therapy is controversial, particularly when HLA-B*58:01 prevalence in the normal population is low, as in Europe. However it could be an option for patients with other risks factors.
Objective:
To systematically review evidence on genetic risk factors for carbamazepine (CBZ)-induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA-B*15:02 and HLA-A*31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ-induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA-B*15:02 or HLA-A*31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results?
Methods:
A systematic literature search was performed for HLA-B*15:02 and HLA-A*31:01 and their association with CBZ-induced HSRs. Evidence was critically appraised and clinical practice recommendations were developed based on expert group consensus.
Results:
Patients carrying HLA-B*15:02 are at strongly increased risk for CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in populations where HLA-B*15:02 is common, but not CBZ-induced hypersensitivity syndrome (HSS) or maculopapular exanthema (MPE). HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported from Asian countries only, including China, Thailand, Malaysia, and India. HLA-B*15:02 is rare among Caucasians or Japanese; no HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported so far in these groups. HLA-A*31:01-positive patients are at increased risk for CBZ-induced HSS and MPE, and possibly SJS/TEN and acute generalized exanthematous pustulosis (AGEP). This association has been shown in Caucasian, Japanese, Korean, Chinese, and patients of mixed origin; however, HLA-A*31:01 is common in most ethnic groups. Not all patients carrying either risk variant develop an HSR, resulting in a relatively low positive predictive value of the genetic tests.
Significance:
This review provides the latest update on genetic markers for CBZ HSRs, clinical practice recommendations as a basis for informed decision making regarding the use of HLA-B*15:02 and HLA-A*31:01 genetic testing in patients with an indication for CBZ therapy, and identifies knowledge gaps to guide future research. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Since the first description by Saltzstein in 1959, the denomination of drug-induced pseudolymphoma was used to describe two cutaneous adverse drug reactions with a histological picture mimicking malignant lymphoma. On the basis of clinical 1resentation, this term includes two different patterms: (1) hypersensitivity syndrome which begins acutely in the first 2 months after the initiation of the drug and associates fever, a severe skin disease with characteristic infiltrated papules and facial edema or an exfoliative dermatitis, lymphadenopathy, hematologic abnormalities (hypereosinophilia, and atypical lymphocytes) and organ involvement such as hepatitis, carditis, interstitial nephritis, or interstial pneumonitis. The cutaneous histological pattern shows a lymphocytic infiltrate, sometimes mimicking a cutaneous lymphoma, and the mortality rate is about 10%. When organ involvement exists, corticosteroids are often prescribed with dramatic improvement. Relapses may occur. (2) drug-induced pseudolymphoma which has a more insidious beginning with nodules and infiltrated piaques appearing several weeks after the beginning of the drug without constitutional symptoms. A pseudolymphoma pattern is seen on cutaneous histological slides. Complete improvement is usual after drug withdrawal, but a delayed lymphoma is possible. To decrease the ambiguity of the denomination of hypersensitivity syndrome, we propose the term of DRESS (Drug Rash with Eosinophilla and Systemic Symptoms).
Noncovalent drug presentation leads to the activation of drug-specific T cells. In some patients with hypersensitivity, such a response occurs within hours even upon the first exposure to the drug. Thus, the reaction to the drug might not be due to a classical, primary response, but rather mediated by existing, preactivated T cells that are cross specific for the drug, and have an additional (peptide) specificity as well.
This article has no abstract; the first 100 words appear below.
Although the rate of acute severe adverse cutaneous reactions to medications is low, these reactions can affect anyone who takes medications and can result in death or disability¹. Even a small number of cases associated with a particular drug may alter the recommendations for its use²–⁴. Prompt differentiation of severe adverse cutaneous reactions from less serious skin disorders may be difficult. Rapid recognition of severe reactions is essential. Prompt withdrawal of the offending drug is often the most important action to minimize morbidity. Adverse cutaneous reactions to drugs are frequent, affecting 2 to 3 percent of hospitalized . . .
Supported in part by a grant from INSERM (90-0812).
Source Information
From the Department of Dermatology, Henri Mondor Hospital, University of Paris XII, Creteil, France (J.C.R.), and Beth Israel Hospital, Harvard Medical School, Boston (R.S.S.).
Address reprint requests to Dr. Stern at the Department of Dermatology, Beth Israel Hospital, 330 Brookline Ave., Boston, MA 02215.
Hypersensitivity to abacavir affects about 4% of patients who receive the drug for HIV-1 infection. We did a retrospective, case-control study to identify multiple markers in the vicinity of HLA-B associated with hypersensitivity reactions. HLA-B57 was present in 39 (46%) of 84 patients versus four (4%) of 113 controls (p<0 small middle dot0001). However, because of low numbers of women and other ethnic groups enrolled, these findings relate largely to white men. The lower sensitivity of HLA-B57 for predicting hypersensitivity to abacavir identified in this study compared with a previous report highlights that predictive values for markers will vary across populations. Clinical monitoring and management of hypersensitivity reactions among patients receiving abacavir must remain unchanged.