Síndrome de intolerancia a múltiples medicamentos / Syndrome of intolerance to multiple medicines

El síndrome de intolerancia a múltiples medicamentos (MDIS, por sus siglas en inglés) se caracteriza por la intolerancia a dos o más medicamentos no relacionados. Tiene una prevalencia baja y es común en pacientes con polifarmacia. A pesar de que las reacciones adversas a los medicamentos son muy frecuentes, es raro que los pacientes debuten con este síndrome, el cual tiene implicaciones clínicas de leves a graves que afectan su vida; de acuerdo con esto varían el abordaje y su manejo. La sintomatología presentada varía desde síntomas gastrointestinales como reflujo gastroesofágico, dolores musculares y cefalea, hasta síntomas cutáneos; estos son los más frecuentes, tales como urticaria y erupciones maculopapulares o presentaciones menos comunes como el síndrome de Stevens-Johnson. El MDIS es causado por una amplia variedad de fármacos; por ello el conocimiento del síndrome, así como un adecuado interrogatorio de los antecedentes del paciente, es necesario para realizar un diagnóstico oportuno e instaurar un manejo adecuado y preventivo, evitando reacciones adversas que pongan en riesgo su vida. Con los hallazgos del cuadro clínico en la paciente, y basados en los antecedentes alérgicos presentados anteriormente a diferentes medicamentos no relacionados entre ellos, más la presentación de un rash maculopapular generalizado posterior a la administración de trimetoprim/sulfametoxazol se realiza el diagnóstico de MDIS. Se decide cambiar de medicamento por fosfomicina, con una consecuente evolución favorable. (AU)

Genotyping HLA alleles to predict the development of Severe cutaneous adverse drug reactions (SCARs): state-of-the-art.

Introduction: Pharmacogenomics has great potential in reducing drug-induced severe cutaneous adverse drug reactions (SCARs). Pharmacogenomic studies have revealed an association between HLA genes and SCARs including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).Areas covered: Pharmacogenomics-guided therapy could prevent severe drug hypersensitivity reactions. The US Food and Drug Administration (FDA), Clinical Pharmacogenetics Implementation Consortium (CPIC), and Dutch Pharmacogenetics Working Group (DPWG) provided guidelines in the translation of clinically relevant and evidence-based SCARs pharmacogenomics research into clinical practice. In this review, we intended to summarize the significant HLA alleles associated with SCARs induced by different drugs in different populations. We also summarize the SCARs associated with genetic and non-genetic factors and the cost-effectiveness of screening tests.Expert opinion: The effectiveness of HLA screening on a wider scale in clinical practice requires significant resources, including state-of-the-art laboratory; multidisciplinary team approach and health care provider education and engagement; clinical decision support alert system via electronic medical record (EMR); laboratory standards and quality assurance; evidence of cost-effectiveness; and cost of pharmacogenomics tests and reimbursement.

Unravelling cases of clozapine-related Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) in patients reported otherwise: A systematic review.

BACKGROUND: The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction. AIMS: Aim was to review reports of clozapine-related reactions fulfilling the registry of severe cutaneous adverse reaction (RegiSCAR) criteria for DRESS syndrome reported as such or otherwise, to provide a descriptive overview of demographic patterns, clinical manifestations, and DRESS course and investigate associations between demographic, DRESS parameters, and clinical outcomes. METHODS: This review was conducted following preferred reporting items for systematic reviews and meta-analyses guidelines and registered with PROSPERO (registration number CRD42020156385). We searched PubMed/Embase/PsychInfo/Cochrane for reports of clozapine-related reactions meeting RegiSCAR criteria. Associations between RegiSCAR scores and time-to-recovery with demographic/clinical variables were assessed. Demographic/clinical characteristics of patients with versus without reported DRESS were compared using non-parametrical tests. RESULTS: We identified 26 reports of 27 patients meeting RegiSCAR criteria. Males (n = 19, 70.4%) and patients with schizophrenia (n = 18, 66.7%) were mainly affected. Twelve patients (44.4%) received clozapine-monotherapy. DRESS symptoms manifested within a month after clozapine initiation (n = 24, 88.9%). Lungs and liver were the most common organs involved (n = 12, 44.4%; n = 11, 40.7%), with a mean time to recovery of 33.75 days. Clozapine rechallenge led to DRESS recurrence in four patients. Death rate was 7.4%. No associations were detected between RegiSCAR criteria or days to recovery with any demographic/clinical variables. No differences between patients with versus without reported DRESS were detected. CONCLUSIONS: Clozapine-related DRESS may be rare, but also underreported. Clinicians need to be aware of it even in patients under clozapine-monotherapy or without skin rash.

Antibacterial antibiotic-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a literature review.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) is a delayed infrequent potentially life-threatening idiosyncratic drug reaction. Aromatic anticonvulsants and allopurinol are the most frequent causative agents. However, various reports of antibiotic-induced DRESS are available. In this review, we try to summarize reports of antibacterial antibiotic-induced DRESS focusing on characteristics of DRESS induced by each antibiotic group. METHODS: The data were collected by searching PubMed/MEDLINE and ScienceDirect. The keywords used as search terms were "DRESS syndrome," "drug-induced hypersensitivity syndrome (DIHS)," "antibiotics," "antimicrobial," and names of various antimicrobial groups. Finally, 254 relevant cases with a definite or probable diagnosis of DRESS based on RegiSCAR criteria were found until 30 May 2020 and reviewed. RESULTS AND CONCLUSION: Totally, 254 cases of antibacterial antibiotic-induced DRESS are reported. Most of them are related to antituberculosis drugs, vancomycin, and sulfonamides, respectively. Rash and fever were most frequent clinical findings. Eosinophilia and liver injury were the most reported hematologic and visceral organ involvement, respectively. Most of the patients are managed with systemic corticosteroids. The death occurred in 16 patients which most of them experienced liver or lung involvement. The reactivation of various viruses especially HHV-6 is reported in 33 cases. The mean latency period was 29 days. It is necessary to perform thorough epidemiological, genetic, and immunological studies, also systematic case review and causality assessment, as well as well-designed clinical trials for better management of antibiotic-induced DRESS.

Clozapine-related drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a systematic review.

INTRODUCTION: The Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a severe, multiorganic, and potentially life-threatening drug-induced hypersensitivity reaction, linked to several common drugs, including antiepileptics, antibiotics, and several psychotropic drugs, including clozapine. Due to the importance of clozapine in the management of treatment-resistant schizophrenia, a systematic review and characterization of clozapine-related DRESS syndrome is long overdue. AREAS COVERED: This systematic review was conducted following PRISMA guidelines. PubMed, Embase, PsychINFO, and the Cochrane Library databases were independently reviewed up to 1 November 2019 for articles reporting clozapine-related DRESS syndrome cases. The RegiSCAR score system was applied to systematically characterize the clinical presentations of selected studies. EXPERT OPINION: Clozapine-related DRESS syndrome was reported in six patients from four articles. Five patients received polypharmacy. Skin rash and liver involvement with elevated liver enzymes were very common. No fatal cases were found. Treatment mainly included clozapine discontinuation and immunosuppression. The mismatch between incidences of DRESS with other responsible drugs, the common misdiagnosis of this syndrome, and the fact that an extensive literature search only identified six cases suggests that clozapine-related DRESS may be overlooked. It is, therefore, necessary to optimize diagnostic strategies to identify immune-related side effects of clozapine.

A rare and severe cutaneous adverse effect of telaprevir: drug rash with eosinophilia and systemic symptoms.

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.

Vancomycin-associated drug-induced hypersensitivity syndrome.

BACKGROUND: Although hypersensitivity reactions are well characterized for certain medications, vancomycin-associated drug-induced hypersensitivity syndrome (DIHS), or drug reaction with eosinophilia and systemic symptoms (DRESS), has yet to be defined. OBJECTIVE: To better define the clinical phenotype of vancomycin-associated DIHS. METHODS: A retrospective case series was conducted over an 8-year period at a single, academic institution. A total of 29 cases of DIHS/DRESS were identified, of which 4 were attributed to vancomycin. A literature review was performed; it identified 28 additional cases of vancomycin-induced DIHS. Vancomycin-associated acute interstitial nephritis was also reviewed to detect additional, previously uncharacterized cases of systemic hypersensitivity. The review yielded 11 additional cases. RESULTS: In this literature review and retrospective series, the incidence of renal dysfunction among vancomycin-induced cases (75% and 68% of cases in the series and literature, respectively) was notably higher than the overall reported incidence in DIHS (10%-40%). The degree of renal impairment was also significantly increased in the retrospective series (a median 4.98-fold change in baseline creatinine level vs a 2.25-fold increase in non-vancomycin-associated cases [P = .011]). LIMITATIONS: The principal limitation of this study is the small sample size. Other notable limitations include the retrospective nature of the study and absence of confirmatory renal biopsies. CONCLUSION: Although the current understanding of DIHS/DRESS is imperfect, our findings suggest that vancomycin-induced cases present with a unique phenotype characterized by a higher burden of renal involvement.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in two young children: the importance of an early diagnosis.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a serious life-treating condition characterized by skin eruption, fever, haematologic abnormalities, and multi-organ involvement that can be fatal if unrecognized, especially in patients with liver failure. Diagnosis may be difficult because it is rarely described in children and can mimic many different conditions. CASE PRESENTATION: We report two cases of DRESS syndrome due to prolonged antibiotic treatment in young children in whom recovery occurred following different therapeutic approaches. A previously healthy 5-year-old boy had been receiving intravenous vancomycin for right wrist and left elbow osteomyelitis and developed DRESS syndrome on day 30. The patient achieved a complete resolution of all symptoms with pulse methylprednisolone followed by oral prednisone. A 4-year-old girl with cystic fibrosis, pancreatic insufficiency, chronic pulmonary colonization by Gram-positive bacteria admitted for pulmonary exacerbation was treated with intravenous piperacillin-tazobactam and tobramycin. After 14 days of treatment, she developed DRESS syndrome: antibiotic treatment was therefore stopped, and without any further therapy, a progressive resolution of the patient's clinical features was observed within 7 days, while the normalization of laboratory abnormalities was achieved at 14 days. CONCLUSIONS: Our cases highlight that paediatricians should be aware of the clinical presentations of and therapeutic approaches for DRESS syndrome, especially in children receiving long-term antibiotic treatment. The removal of the offending drug is crucial and may be the only life-saving measure. In more aggressive cases, corticosteroid or other immunosuppressive drugs should be considered to achieve the best outcome.

DRESS syndrome with thrombotic microangiopathy revealing a Noonan syndrome: Case report.

RATIONALE: The life-threatening drug rash with eosinophilia and systemic symptoms (DRESS) syndrome occurs most commonly after exposure to drugs, clinical features mimic those found with other serious systemic disorders. It is rarely associated with thrombotic microangiopathy. PATIENT CONCERNS: We describe the unique case of a 44-year-old man who simultaneously experienced DRESS syndrome with thrombotic microangiopathy (TMA) after a 5 days treatment with fluindione. DIAGNOSES: Clinical evaluation leads to the discovery of an underlying lymphangiomatosis, due to a Noonan syndrome. INTERVETIONS: The anticoagulant was withdrawn, and corticosteroids (1 mg/kg/day) and acenocoumarol were started. OUTCOMES: Clinical improvement ensued. At follow-up the patient is well. LESSONS: The association of DRESS with TMA is a rare condition; we believe that the presence of the underlying Noonan syndrome could have been the trigger. Moreover, we speculate about the potential interrelations between these entities.

Cardiac involvement in DRESS syndrome.

OBJECTIVE: Cardiac involvement in drug rash with eosinophilia and systemic symptoms (DRESS) syndrome varies considerably between 4% and 21%. Here we present our case and review literatures for its diagnosis and management. An algorithm for diagnosis of cardiac involvement in DRESS syndrome is proposed in this article. DATA SOURCES: Data regarding DRESS-associated myocarditis and eosinophilic myocarditis were gather primarily from MEDLINE database. RESULTS: DRESS syndrome is a hypersensitivity reaction which is due to massive T cell stimulation resulting in cytotoxicity and eosinophil activation and recruitment. It is characterized by fever, morbilliform rash, and various systemic symptoms, in particular hepatitis. Hypersensitivity myocarditis (acute eosinophilic myocarditis) which is typically related to a drug reaction can lead to acute necrotizing eosinophilic myocarditis, cardiac thrombosis and fibrotic stage. Cardiac symptoms range from no symptoms to cardiogenic shock. Diagnosis is based on history, clinical findings, cardiac biomarkers and cardiac imaging techniques. Endomyocardial biopsy is done in a minority of patients for definite diagnosis. If suspected, drug discontinuation and suppression of immune reactions are the first therapies. Corticosteroids are the cornerstone of systemic treatments and should be initiated at the time of diagnosis of DRESS syndrome. Additional therapy and ventricular assist devices could be considered in refractory cases. CONCLUSIONS: According to its high morbidity and mortality, patients with DRESS syndrome should be carefully monitored or screened for cardiac involvement. Multidisciplinary care is important for a successful treatment outcome.

Eosinophilic drug reactions detected by a prospective pharmacovigilance programme in a tertiary hospital.

AIM: We conducted a prospective evaluation of all eosinophilic drug reactions (EDRs) through the Prospective Pharmacovigilance Program from Laboratory Signals at Hospital to find out the incidence and distribution of these entities in our hospital, their causative drugs, and predictors. METHODS: All peripheral eosinophilia >700 × 106  cells l-1 detected at admission or during hospitalisation, were prospectively monitored over 42 months. The spectrum of the localised or systemic manifestation of EDR, the incidence, the distribution of causative drugs, and the predictors were analysed. RESULTS: The incidence of EDR was 16.67 (95% Poisson confidence interval [CI]: 9.90-25.98) per 10 000 admissions. Of 274 cases of EDR, 154 (56.2%) cases in 148 patients were asymptomatic hypereosinophilia. In the remaining 120 (43.8%) cases, there was other involvement. Skin and soft tissue reactions were detected in 36 (13.1%) cases; visceral EDRs in 19(7.0%) cases; and drug-induced eosinophilic cutaneous and visceral manifestations were detected in the remaining 65 (23.7%) cases, 64 of which were potential drug reaction with eosinophilia and systemic symptoms (DRESS). After adjusting for age, sex, and hospitalisation wards, predictors of symptomatic eosinophilia were earlier onset of eosinophilia (hazard ratio [HR], 10.49; 95%CI: 3.13-35.16) higher eosinophil count (HR, 8.51; 95%CI: 3.28-22.08), and a delayed onset of corticosteroids (HR, 1.34; 95%CI: 1.01-1.73). A higher eosinophil count in patients with DRESS was significantly associated with greater impairment of liver function, prolonged hospitalisation, higher cumulative doses of corticosteroids, and if hypogammaglobinaemia was detected, a reactivation of human-herpesvirus 6 was subsequently detected. CONCLUSIONS: Half (53.3%, 64/120 cases) of symptomatic EDRs were potential DRESS. The main predictor of severity of EDR was an early severe eosinophilia.

Bronchoscopic Investigation of Atypical Drug-induced Hypersensitivity Syndrome Showing Viral Lung Involvement.

We herein report a case of atypical drug-induced hypersensitivity syndrome (DIHS) involving serological reactivation of cytomegalovirus induced by carbamazepine with pulmonary and skin manifestations. These lesions were not present on admission, but developed on virus reactivation as indicated by the presence of inclusion bodies and multinucleated giant cells in alveolar cells with CD8(+) T lymphocyte infiltration on a transbronchial lung biopsy. Although the precise mechanism of DIHS remains unknown, this case suggests the crucial role of viral reactivation in pulmonary lesions in DIHS.

Sulthiame-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially life-threatening acute drug-induced hypersensitivity reaction. Antiepileptic drugs (AEDs) predominantly aromatic AEDs are commonly reported in DRESS. To date there are no reports of sulthiame AED causing DRESS syndrome. METHOD: We report a 10-year-old girl of Indian descent with AED resistant epilepsy on maintenance sodium valproate and clonazepam. Sulthiame AED was initiated to try to improve her seizure control. Five weeks after commencing sulthiame, she developed fever with a diffuse erythematous morbilliform maculopapular rash, elevated transaminases and atypical lymphocytes. At day 3 of illness, she deteriorated with worsening elevation of liver transaminases, thrombocytopenia, progression of rash, hepatosplenomegaly, pneumonitis and markedly elevated inflammatory markers. Immunomodulatory treatment of pulse methylprednisolone was given from day 7 which was associated with improvement inflammatory markers and complete resolution of rash from day 30 of illness. RESULTS: The diagnosis of sulthiame-induced DRESS syndrome was made based on clinical, laboratory and skin histology findings. She was HLA-B heterozygous for HLA-B∗15:123 and 15:240 and HLA-A homozygous for HLA-A∗11:01:09. Both these HLA-A and HLA-B typing has not been reported before in cutaneous drug reactions. CONCLUSION: This is the first reported case of sulthiame-induced DRESS syndrome. Our case expands the list of possible susceptible HLA alleles associated with cutaneous drug reactions. It also raises the awareness of possible DRESS syndrome among patients commenced on sulthiame who will require immediate discontinuation of sulthiame and consideration of prompt treatment of corticosteroids.