Drug-Induced Anaphylaxis Survey in Portuguese Allergy Departments

Background and Objective: Drug-induced anaphylaxis is an unpredictable and potentially fatal adverse drug reaction. The aim of this study was to identify the causes of drug-induced anaphylaxis in Portugal. Methods: During a 4-year period a nationwide notification system for anaphylaxis was implemented, with voluntary reporting by allergists. Data on 313 patients with drug anaphylaxis were received and reviewed. Statistical analysis included distribution tests and multiple logistic regression analysis to investigate significance, regression coefficients, and marginal effects. Results: The mean (SD) age of the patients was 43.8 (17.4) years, and 8.3% were younger than 18 years. The female to male ratio was 2:1. The main culprits were nonsteroidal anti-inflammatory drugs (NSAIDs) (47.9% of cases), antibiotics (35.5%), and anesthetic agents (6.1%). There was a predominance of mucocutaneous symptoms (92.2%), followed by respiratory symptoms (80.4%) and cardiovascular symptoms (49.0%). Patients with NSAID-induced anaphylaxis showed a tendency towards respiratory and mucocutaneous manifestations. We found no significant associations between age, sex, or atopy and type of drug. Anaphylaxis recurrence was observed in 25.6% of cases, and the risk was higher when NSAIDs were involved. Conclusions: NSAIDs were the most common cause of anaphylaxis in this study and were also associated with a higher rate of recurrence. We stress the need for better therapeutic management and prevention of recurring episodes of drug-induced anaphylaxis.

Intravenous Immunoglobulin for the Treatment of Quetiapin-Induced Bullous Pemphigoid in an HIV-Infected Patient

The authors present the case of a 48-year-old woman with HIV-­associated dementia treated with antiretroviral therapy and psychoactive drugs, to whom bullous pemphigoid(BP) was diagnosed. Given incomplete response to corticotherapy, and azathioprine-­induced bicytopenia,intravenous immunoglobulin(IVIG) was initiated. Despite transient disease control, recurrent flares suggested a persistent triggering factor. Specifically, quetiapin was implicated and discontinued with an immediate clinical response. Inadvertent re-­challenge with olanzapine(a related drug)led to a new eruption, confirming drug-­induced BP (DIBP). A total of six IVIG cycles were completed, without severe side effects to report, namely HIV disease progression. HIV-­related autoimmune bullous diseases are rare. Treatment of severe drug eruptions is primarily based on immunossupressive drugs, raising concerns regarding additional immunossupression. This case suggests IVIG as a valuable option for the treatment of BP in HIV patients. In addition, quetiapin should be added to the list of neuroleptics previously linked to DIBP.

Propylthiouracil Induced Pulmonary-Renal Syndrome: a Case Report.

Propylthiouracil (PTU) is known to induce antineutrophil cytoplasmatic antibody (ANCA) seropositivity; however, small vessel vasculitis (SVV) with pulmonary and renal involvement is rare. We present the case of an 81-year-old woman on PTU treatment due to toxic nodular goitre who developed alveolar hemorrhage and rapidly progressive glomerulonephritis. The authors highlight the importance of early recognising drug-induced pulmonary-renal syndrome (PRS) in order to avoid unnecessary tests, a delay in the diagnosis and evolution to end-stage kidney disease or life-threatening conditions.

Anafilaxia Induzida por Fármacos: Registo Nacional 2007-2010

Introdução: A anafilaxia a fármacos constitui uma situação potencialmente fatal e imprevisível, desconhecendo -se a real prevalência em diferentes grupos populacionais e os factores de risco relacionados. Objectivo: Contribuir para o melhor conhecimento epidemiológico da anafilaxia induzida por fármacos no nosso país. Métodos: Durante um período de 4 anos (Janeiro de 2007 a Dezembro de 2010) foi implementado um sistema de notificação nacional de anafilaxia, focalizado na notificação voluntária por clínicos com diferenciação em patologia imunoalérgica. Foram recebidas e analisadas notificações de anafilaxia a fármacos de 313 doentes. No estudo estatístico foram aplicados testes de distribuição e análise de regressão logística múltipla para obter significância e coeficientes de regressão e efeitos marginais. Resultados: A média de idade foi de 43,8 ±17,4 anos, sendo 8% de idade inferior a 18 anos. A relação género feminino/masculino foi de 2/1. A média de idade do primeiro episódio foi de 39 ±18,2 anos. Nove doentes apresentaram mais que uma causa de anafilaxia, correspondendo a um total de 322 notificações de grupos de fármacos envolvidos. As principais causas da anafilaxia a fármacos foram os anti -inflamatórios não esteróides (AINEs), os antibióticos e os agentes anestésicos, com respectivamente 48%, 36% e 6% dos casos. Outros fármacos implicados foram citostáticos, corticosteróides, inibidores da bomba de protões e meios de contraste iodados, entre outros. Houve predomínio de manifestações mucocutâneas (92%), seguido de respiratórias (81%) e de cardiovasculares (49%). Os doentes com anafilaxia a AINEs apresentaram aumento significativo da associação de manifestações mucocutâneas e respiratórias. Não foram observadas diferenças significativas em idade, género ou antecedentes de atopia entre os diferentes grupos de fármacos envolvidos. As reacções ocorreram em ambiente hospitalar em 45% dos casos. Em 53% nos 15 minutos após a administração do fármaco e 35% motivaram internamento. A recorrência da anafilaxia foi observada em 26% e o risco foi significativamente mais elevado nos casos de anafilaxia a AINEs. Apenas 48% dos doentes receberam tratamento com adrenalina e somente em 9% dos casos foi prescrito dispositivo para auto -administração de adrenalina. Conclusões: Neste estudo os AINEs foram os fármacos mais frequentes e os mais associados a recorrência de anafilaxia. Destaca -se o sub -tratamento com adrenalina e a necessidade de serem tomadas medidas no sentido do tratamento eficaz e da prevenção da recorrência de anafilaxia a fármacos.

Sirolimus-Induced Drug Fever in a Renal Transplant Patient: a Case Report

Herein we have described the case of a male renal transplant recipient who developed drug fever apparently related to sirolimus. He had been stable under an immunosuppressive regimen of tacrolimus and mycophenolate mofetil, but developed acute cellular rejection at 5 years after transplantation due to noncompliance. Renal biopsy showed marked interstitial fibrosis, and immunosuppression was switched from mycophenolate to sirolimus, maintaining low tacrolimus levels. One month later he was admitted to our hospital for investigation of intermittently high fever, fatigue, myalgias, and diarrhea. Physical examination was unremarkable and drug levels were not increased. Lactic dehydrogenase and C-reactive protein were increased. The blood cell count and chest radiographic findings were normal. After extensive cultures, he was started on broad-spectrum antibiotics. Inflammatory markers and fever worsened, but diarrhea resolved. All serologic and imaging tests excluded infection, immune-mediated diseases, and malignancy. After 12 days antibiotics were stopped as no clinical improvement was achieved. Drug fever was suspected; sirolimus was replaced by mycophenolate mofetil. Fever and other symptoms disappeared after 24 hours; inflammatory markers normalized in a few days. After 1 month the patient was in good health with stable renal function. Although infrequent, the recognition of drug fever as a potential side effect of sirolimus may avoid unnecessary invasive diagnostic procedures. Nevertheless, exclusion of other common causes of fever is essential.

Anti-Tumor Necrosis Factor Alpha-Induced Drug Eruptions: One Patient, More Than a Pattern

Background: Tumor necrosis factor alpha (TNFα) antagonists are effective in treating several immune-inflammatory diseases, including psoriasis and inflammatory bowel disease. The paradoxical and unpredictable induction of psoriasis and psoriasiform skin lesions is a recognized adverse event, although of unclear aetiology. However, histological analysis of these eruptions remains insufficient, yet suggesting that some might constitute a new pattern of adverse drug reaction, rather than true psoriasis. Case report: The authors report the case of a 43-year-old woman with severe recalcitrant Crohn disease who started treatment with infliximab. There was also a personal history of mild plaque psoriasis without clinical expression for the past eight years. She developed a heterogeneous cutaneous eruption of psoriasiform morphology with pustules and crusts after the third infliximab infusion. The histopathological diagnosis was of a Sweet-like dermatosis. The patient was successfully treated with cyclosporine in association with both topical corticosteroid and vitamin D3 analogue. Three weeks after switching to adalimumab a new psoriasiform eruption was observed, histologically compatible with a psoriasiform drug eruption. Despite this, and considering the beneficial effect on the inflammatory bowel disease, it was decided to maintain treatment with adalimumab and to treat through with topicals, with progressive control of skin disease. Discussion: Not much is known about the pathogenesis of psoriasiform eruptions induced by biological therapies, but genetic predisposition and Koebner phenomenon may contribute to it. Histopathology can add new facets to the comprehension of psoriasiform reactions. In fact, histopathologic patterns of such skin lesions appear to be varied, in a clear asymmetry with clinical findings. Conclusion: The sequential identification in the same patient of two clinical and histopathologic patterns of drug reaction to TNFα antagonists is rare. Additionally, to the authors’ knowledge, there is only one other description in literature of a TNFα antagonist-induced Sweet-like dermatosis, emphasizing the singularity of this case report.

Differences in Nevirapine Biotransformation as a Factor for its Sex-Dependent Dimorphic Profile of Adverse Drug Reactions

OBJECTIVES: Nevirapine is widely used for the treatment of HIV-1 infection; however, its chronic use has been associated with severe liver and skin toxicity. Women are at increased risk for these toxic events, but the reasons for the sex-related differences are unclear. Disparities in the biotransformation of nevirapine and the generation of toxic metabolites between men and women might be the underlying cause. The present work aimed to explore sex differences in nevirapine biotransformation as a potential factor in nevirapine-induced toxicity. METHODS: All included subjects were adults who had been receiving 400 mg of nevirapine once daily for at least 1 month. Blood samples were collected and the levels of nevirapine and its phase I metabolites were quantified by HPLC. Anthropometric and clinical data, and nevirapine metabolite profiles, were assessed for sex-related differences. RESULTS: A total of 52 patients were included (63% were men). Body weight was lower in women (P = 0.028) and female sex was associated with higher alkaline phosphatase (P = 0.036) and lactate dehydrogenase (P = 0.037) levels. The plasma concentrations of nevirapine (P = 0.030) and the metabolite 3-hydroxy-nevirapine (P = 0.035), as well as the proportions of the metabolites 12-hydroxy-nevirapine (P = 0.037) and 3-hydroxy-nevirapine (P = 0.001), were higher in women, when adjusted for body weight. CONCLUSIONS: There was a sex-dependent variation in nevirapine biotransformation, particularly in the generation of the 12-hydroxy-nevirapine and 3-hydroxy-nevirapine metabolites. These data are consistent with the sex-dependent formation of toxic reactive metabolites, which may contribute to the sex-dependent dimorphic profile of nevirapine toxicity.