Drug reaction with Eosinophilia and Systemic Symptoms (DRESS) / Drug-induced Hypersensitivity Syndrome (DIHS): a review of current concepts

The Drug Reaction with Eosinophilia and Systemic Symptoms syndrome, also known as Drug Induced Hypersensitivity Syndrome presents clinically as an extensive mucocutaneous rash, accompanied by fever, lymphadenopathy, hepatitis, hematologic abnormalities with eosinophilia and atypical lymphocytes, and may involve other organs with eosinophilic infiltration, causing damage to several systems, especially to the kidneys, heart, lungs, and pancreas. Recognition of this syndrome is of paramount importance, since the mortality rate is about 10% to 20%, and a specific therapy may be necessary. The pathogenesis is related to specific drugs, especially the aromatic anticonvulsants, altered immune response, sequential reactivation of herpes virus and association with HLA alleles. Early recognition of the syndrome and withdrawal of the offending drug are the most important and essential steps in the treatment of affected patients. Corticosteroids are the basis of the treatment of the syndrome, which may be associated with intravenous immunoglobulin and, in selected cases, Ganciclovir. The article reviews the current concepts involving this important manifestation of adverse drug reaction.

Variations in peak expiratory flow measurements associated to air pollution and allergic sensitization in children in Sao Paulo, Brazil

Background In the last 20 years, there has been an increase in the incidence of allergic respiratory diseases worldwide and exposure to air pollution has been discussed as one of the factors associated with this increase. The objective of this study was to investigate the effects of air pollution on peak expiratory flow (PEF) and FEV1 in children with and without allergic sensitization. Methods Ninety-six children were followed from April to July, 2004 with spirometry measurements. They were tested for allergic sensitization (IgE, skin prick test, eosinophilia) and asked about allergic symptoms. Air pollution, temperature, and relative humidity data were available. Results Decrements in PEF were observed with previous 24-hr average exposure to air pollution, as well as with 310-day average exposure and were associated mainly with PM10, NO2, and O3 in all three categories of allergic sensitization. Even though allergic sensitized children tended to present larger decrements in the PEF measurements they were not statistically different from the non-allergic sensitized. Decrements in FEV1 were observed mainly with previous 24-hr average exposure and 3-day moving average. Conclusions Decrements in PEF associated with air pollution were observed in children independent from their allergic sensitization status. Their daily exposure to air pollution can be responsible for a chronic inflammatory process that might impair their lung growth and later their lung function in adulthood. Am. J. Ind. Med. 55:10871098, 2012. (c) 2012 Wiley Periodicals, Inc.

Eosinophils may predict occult lymph node metastasis in early oral cancer

Objective The aim of this study was to investigate whether tumor-associated tissue eosinophilia (TATE) in early oral squamous cell carcinoma (OSCC) would aid in predicting occult lymph node metastasis. Patients and methods Seventy-one patients undergoing elective neck dissection for T1 and T2 OSCC were evaluated for clinical features, prognosis, and TATE. The degree of TATE in OSCC was statistically analyzed in relation to the clinicopathological features, tumor invasion, occult lymph node metastasis, and survival using chi (2) test and Kaplan-Meier method. Results Statistical analysis revealed that intense TATE was a significant feature (p = 0.004) to predict occult lymph node metastasis in patients with early OSCC. All regional recurrences of the OSCC occurred in patients showing intense TATE. Conclusions These results suggest that intense TATE can be clinically used as a predictive factor for occult lymph node metastasis. Clinical relevance The presence of intense TATE is an adjunctive histopathological marker to reinforce the indication of elective neck dissection of the patients with early OSCC.

Clinical characteristics and possible phenotypes of an adult severe asthma population

Background: Currently, there are no studies of well-characterized severe asthmatics in Brazil. We aimed to study a population of severe treated asthmatics still uncontrolled to characterize them and define possible phenotypes. Methods: Descriptive cross-sectional outpatient study of severe asthmatics, evaluating functional and inflammatory markers, health-related quality of life, anxiety and depression symptoms, clinical control status, and characteristics related to atopy, age of asthma onset, induced sputum eosinophil levels, and airflow limitation. We also grouped the subgroups characteristics to identify phenotypes. The study is registered on ClinicalTrial.gov NCT 01089322. Results: From 128 eligible patients with severe/uncontrolled asthma, 74 fulfilled the inclusion criteria. The cohort was comprised of 85% women, frequently with a body mass index higher than 31 kg m(-2), atopy (60%), early-onset disease (50%), sputum eosinophilia (80%), comorbidities, and reduced quality of life. Nonatopics had significant higher asthma onset (19 y.a.) and twice level of induced sputum eosinophil. Late-onset patients had significantly less atopy (57%) and higher levels of induced sputum eosinophils. Non-eosinophilics had lower levels of inflammatory markers. Patients with airflow limitation had more intensive care unit admissions (56%) and 1.5 times more airway resistance. Subgroups characteristics identified a priori four well-characterized phenotypes, with 55% presenting sputum eosinophilia. Conclusion: Our data emphasize the high burden of disease, the persistence of inflammation and the existence of clinical possible phenotypes population sharing common features with published cohorts. Despite the necessity of further investigation into pathogenic mechanisms, this study with clinically difficult patient group may help to improve future asthma care. (C) 2011 Elsevier Ltd. All rights reserved.

Intrauterine Undernourishment Alters TH1/TH2 Cytokine Balance and Attenuates Lung Allergic Inflammation in Wistar Rats

IL-4 produced by Th2 cells can block cytokine production by Th1 cells, and Th1 IFN-gamma is known to counterregulate Th2 immune response, inhibiting allergic eosinophilia. As intrauterine undernutrition can attenuate lung inflammation, we investigated the influence of intrauterine undernourishment on the Th1/Th2 cytokine balance and allergic lung inflammation. Intrauterine undernourished offspring were obtained from dams fed 50% of the nourished diet of their counterparts and were immunized at 9 weeks of age. We evaluated the cell counts and cytokine protein expression in the bronchoalveolar lavage, mucus production and collagen deposition, and cytokine gene expression and transcription factors in lung tissue 21 days after ovalbumin immunization. Intrauterine undernourishment significantly reduced inflammatory cell airway infiltration, mucus secretion and collagen deposition, in rats immunized and challenged. Intrauterine undernourished rats also exhibited an altered cytokine expression profile, including higher TNF-alpha and IL-1 beta expression and lower IL-6 expression than well-nourished rats following immunization and challenge. Furthermore, the intrauterine undernourished group showed reduced ratios of the IL-4/IFN-gamma and the transcription factors GATA-3/T-Bet after immunization and challenge. We suggest that the attenuated allergic lung inflammation observed in intrauterine undernourished rats is related to an altered Th1/Th2 cytokine balance resulting from a reduced GATA-3/T-bet ratio. Copyright (C) 2012 S. Karger AG, Basel

Recombinant DNA immunotherapy ameliorate established airway allergy in a IL-10 dependent pathway

Background Previous studies have established that mycobacterial infections ameliorate allergic inflammation. However, a non-infectious approach that controls allergic responses might represent a safer and more promising strategy. The 60-65 kDa heat shock protein (Hsp) family is endowed with anti-inflammatory properties, but it is still unclear whether and how single mycobacterial Hsp control allergic disorders. Objective Therefore, in this study we determined whether the administration of Mycobacterial leprae Hsp65 expressed by recombinant a DNA plasmid could attenuate a previously established allergic response. Methods We used an experimental model of airway allergic inflammation to test the effects of immunotherapy with DNA encoding Hsp65. Allergic mice, previously sensitized and challenged with ovalbumin, were treated with tree intramuscular doses of recombinant DNA encoding Hsp65. After treatment, mice received a second allergen challenge and the allergic response was measured. Results We found that immunotherapy attenuated eosinophilia, pulmonary inflammation, Th2 cytokine and mucus production. Moreover, we showed that the inhibition of allergic response is dependent on IL-10 production. Both Hsp65 and allergen-specific IL-10-producing cells contributed to this effect. Cells transferred from DNA-immunized mice to allergic mice migrated to allergic sites and down-modulated the Th2 response. Conclusions and Clinical Relevance Our findings clearly show that immunotherapy with DNA encoding Hsp65 can attenuate an established Th2 allergic inflammation through an IL-10-dependent mechanism; moreover, the migration of allergen-and Hsp65-specific cells to the allergic sites exerts a fundamental role. This work represents a novel contribution to the understanding of immune regulation by Hsp65 in allergic diseases.

PPAR-gamma agonists, mainly 15d-PGJ(2), reduce eosinophil recruitment following allergen challenge

We evaluate the immunomodulation of Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists 15d-PGJ(2) and rosiglitazone (RGZ) in a model of chronic eosinophilia. 15d-PGJ(2) and RGZ significantly reduce eosinophil migration into the peritoneal cavity and down-regulate the eosinopoiesis. The synthesis of IL-5 was decreased after the treatment with 15d-PGJ(2) and RGZ corroborating with the eosinophil migration inhibition. However, IgE was decreased only after the administration of 15d-PGJ(2) in part due to B-cell inhibition. We also observed a decrease in the synthesis of IL-33, IL-17 and IL-23, suggesting that besides the modulation of Th2 pattern, there is a modulation via IL-23 and IL-17 suggesting a role of these cytokines in the eosinophil recruitment. In fact IL-17(-1-) mice failed to develop an eosinophilic response. Altogether, the results showed that PPAR-gamma agonists mainly 15d-PGJ(2), have therapeutic efficacy in eosinophil-induced diseases with an alternative mechanism of control, via IL-23/IL-17 and IL-33. (C) 2011 Elsevier Inc. All rights reserved.

Human eosinophil adhesion and degranulation stimulated with eotaxin and RANTES in vitro: Lack of interaction with nitric oxide

Abstract Background Airway eosinophilia is considered a central event in the pathogenesis of asthma. The toxic components of eosinophils are thought to be important in inducing bronchial mucosal injury and dysfunction. Previous studies have suggested an interaction between nitric oxide (NO) and chemokines in modulating eosinophil functions, but this is still conflicting. In the present study, we have carried out functional assays (adhesion and degranulation) and flow cytometry analysis of adhesion molecules (VLA-4 and Mac-1 expression) to evaluate the interactions between NO and CC-chemokines (eotaxin and RANTES) in human eosinophils. Methods Eosinophils were purified using a percoll gradient followed by immunomagnetic cell separator. Cell adhesion and degranulation were evaluated by measuring eosinophil peroxidase (EPO) activity, whereas expression of Mac-1 and VLA-4 was detected using flow cytometry. Results At 4 h incubation, both eotaxin (100 ng/ml) and RANTES (1000 ng/ml) increased by 133% and 131% eosinophil adhesion, respectively. L-NAME alone (but not D-NAME) also increased the eosinophil adhesion, but the co-incubation of L-NAME with eotaxin or RANTES did not further affect the increased adhesion seen with chemokines alone. In addition, L-NAME alone (but not D-NAME) caused a significant cell degranulation, but it did not affect the CC-chemokine-induced cell degranulation. Incubation of eosinophils with eotaxin or RANTES, in absence or presence of L-NAME, did not affect the expression of VLA-4 and Mac-1 on eosinophil surface. Eotaxin and RANTES (100 ng/ml each) also failed to elevate the cyclic GMP levels above baseline in human eosinophils. Conclusion Eotaxin and RANTES increase the eosinophil adhesion to fibronectin-coated plates and promote cell degranulation by NO-independent mechanisms. The failure of CC-chemokines to affect VLA-4 and Mac-1 expression suggests that changes in integrin function (avidity or affinity) are rather involved in the enhanced adhesion.

Cardiac markers: profile in rats experimentally infected with Toxocara canis

The aim of this study was to evaluate the profile of the enzymes creatine kinase (CK), creatine kinase MB (CK-MB) and lactate dehydrogenase (LDH) in Wistar rats infected with 250 (GI, n = 24) or 1000 (GII, n = 24) Toxocara canis eggs. Animals were evaluated on days 7, 15, 30, 60, 120 and 180 post-infection (DPI). Only the GI rats showed an increase in CK and CK-MB, at 15 and 30 DPI, respectively. Anti-Toxocara spp. antibodies were detected by ELISA in infected animals. Despite of the presence of eosinophilic infiltrate in the heart of three infected animals, none larva was recovered from the organ neither by acid digestion nor by Baermann procedure. Eosinophilia was observed in both groups but there was no significant difference in the eosinophil counts between GI and GII (p = 0.2239). It is possible to consider that cardiac lesion is an eventual finding in murine model for toxocariasis.

Endotoxin exposure during sensitization to Blomia tropicalis allergens shifts TH2 immunity towards a TH17-mediated airway neutrophilic inflammation: role of TLR4 and TLR2

Experimental evidence and epidemiological studies indicate that exposure to endotoxin lipopolysaccharide (eLPS) or other TLR agonists prevent asthma. We have previously shown in the OVA-model of asthma that eLPS administration during alum-based allergen sensitization blocked the development of lung TH2 immune responses via MyD88 pathway and IL-12/IFN-γ axis. In the present work we determined the effect of eLPS exposure during sensitization to a natural airborne allergen extract derived from the house dust mite Blomia tropicalis (Bt). Mice were subcutaneously sensitized with Bt allergens co-adsorbed onto alum with or without eLPS and challenged twice intranasally with Bt. Cellular and molecular parameters of allergic lung inflammation were evaluated 24 h after the last Bt challenge. Exposure to eLPS but not to ultrapure LPS (upLPS) preparation during sensitization to Bt allergens decreased the influx of eosinophils and increased the influx of neutrophils to the airways. Inhibition of airway eosinophilia was not observed in IFN-γdeficient mice while airway neutrophilia was not observed in IL-17RA-deficient mice as well in mice lacking MyD88, CD14, TLR4 and, surprisingly, TLR2 molecules. Notably, exposure to a synthetic TLR2 agonist (PamCSK4) also induced airway neutrophilia that was dependent on TLR2 and TLR4 molecules. In the OVA model, exposure to eLPS or PamCSK4 suppressed OVA-induced airway inflammation. Our results suggest that B. tropicalis allergens engage TLR4 that potentiates TLR2 signaling. This dual TLR activation during sensitization results in airway neutrophilic inflammation associated with increased frequency of lung TH17 cells. Our work highlight the complex interplay between bacterial products, house dust mite allergens and TLR signaling in the induction of different phenotypes of airway inflammation.

Frequency of Toxocara infection in children attended by the health public service of Maringá, south Brazil.

The lack of specific laboratorial diagnosis methods and precise symptoms makes the toxocariasis a neglected disease in Public Health Services. This study aims to determine the frequency of Toxocara spp. infection in children attended by the Health Public Service of Hospital Municipal de Maringá, South Brazil. To evaluate the association of epidemiological and clinical data, and observational and cross-section study was carried out. From 14,690 attended children/year aged from seven month to 12 years old, 450 serum samples were randomly collected from September/2004 to September/2005. A questionnaire was used to evaluate epidemiological, clinical and hematological data. An ELISA using Toxocara canis larval excretory-secretory products as antigen detected 130 (28.8%) positive sera, mainly between children from seven month to five years old (p = 0.0016). Significant correlation was observed between positive serology for Toxocara, and frequent playing in sandbox at school or daycare center (p = 0.011) and the presence of a cat at home (p = 0.056). From the families, 50% were dog owners which exposed soil backyards. Eosinophilia (p = 0.776), and signs and symptoms analyzed (fever p = 0.992, pneumonia p = 0.289, cold-like symptoms p = 0.277, cough p =0.783, gastrointestinal problems p = 0.877, migraine p = 0.979, abdominal pain p = 0.965, joint pain p = 0.686 and skin rash p = 0.105) could not be related to the presence of anti-Toxocara antibodies. Therefore, two asthmatics children showed titles of1:10,240 and accentuated eosinophilia (p = 0.0001). The authors emphasize the needs of prevention activities.