EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders.

Biologic agents (also termed biologicals or biologics) are therapeutics that are synthesized by living organisms and directed against a specific determinant, for example, a cytokine or receptor. In inflammatory and autoimmune diseases, biologicals have revolutionized the treatment of several immune-mediated disorders. Biologicals have also been tested in allergic disorders. These include agents targeting IgE; T helper 2 (Th2)-type and Th2-promoting cytokines, including interleukin-4 (IL-4), IL-5, IL-9, IL-13, IL-31, and thymic stromal lymphopoietin (TSLP); pro-inflammatory cytokines, such as IL-1ß, IL-12, IL-17A, IL-17F, IL-23, and tumor necrosis factor (TNF); chemokine receptor CCR4; and lymphocyte surface and adhesion molecules, including CD2, CD11a, CD20, CD25, CD52, and OX40 ligand. In this task force paper of the Interest Group on Biologicals of the European Academy of Allergy and Clinical Immunology, we review biologicals that are currently available or tested for the use in various allergic and urticarial pathologies, by providing an overview on their state of development, area of use, adverse events, and future research directions.

[Allergies and adverse events associated with fluoroquinolones]. / Allergies et effets indésirabtes dus aux fluoroquinolones.

The prescription ot fluoroquinolones has been constantly increasing over the past decade. consequently, an increasing number of hyper-sensitivity reactions and adverse events have been reported. The aim of the review is to discuss the incidence of hypersensitivity reactions either IgE (immediate) or T cells mediated (delayed). We will make an overview ofthe diagnostic tools available to detect such hypersensitivity reactions. Finally, the specific adverse events associated with fluoroquinolones, including tendinopathy, chondrotoxicity, peripheral neuropathy or retinal detachment will be discussed.

The role of iodine in hypersensitivity reactions to radio contrast media.

INTRODUCTION: Hypersensitivity reactions to iodinated radio contrast media (RCM) are either immediate-type (IT) or delayed reactions (DT). In IT, the pathomechanism is unclear. In DT, delayed positive patch (PT) and intradermal tests (IDT) and RCM-specific T cells suggest a T cell-mediated mechanism. In both, the role of iodine has not been clarified; however, patients are often labelled as 'iodine allergic'. Occasionally, positive skin tests to iodine-containing drugs are observed. OBJECTIVE: We investigated the presence of hypersensitivity to iodine in patients with a history of hypersensitivity reactions to RCM. METHODS: Nineteen patients with a history of IT (n=9) or DT (n=10) to RCM were investigated. Skin prick tests, IDT and PT with several RCM and iodine formulations were carried out. All underwent oral provocation with Lugol's solution (LS). Two patients each with iodine mumps, contact dermatitis to iodized antiseptics and chronic idiopathic urticaria served as control or proof of concept. RESULTS: In the IT group, skin tests were positive in three out of nine patients to one RCM. One patient with negative skin tests reacted twice to oral iodine with urticaria. In the DT group, sensitization to one or several RCM was identified in 10 out of 10 patients. In seven out of 10 patients, additional sensitizations to the iodine formulations were found. Two patients developed a mild exanthema after oral provocation with LS. CONCLUSION: We have previously demonstrated in patients with iodine mumps that an oral challenge with LS is a valid means to elicit hypersensitivity reactions to iodine. In 19 patients, we showed that iodine is rarely the eliciting agent in hypersensitivity reactions to RCM. Only one patient with a late urticaria to an RCM with a late urticaria to LS and two patients with DT and broad sensitization to all RCM tested reacted to LS with an exanthema. In most cases, more likely the RCM molecules and not iodine are the eliciting compounds.

Regression of basal cell carcinoma by intralesional interferon-alpha treatment is mediated by CD95 (Apo-1/Fas)-CD95 ligand-induced suicide.

Basal cell carcinoma (BCC) is the most common skin cancer in humans, and although metastasis rarely occurs, the tumor cells are nevertheless able to invade and destroy the surrounding tissue. Intralesional injection of IFN-alpha has been found to be highly effective in inducing BCC regression by an unknown mechanism. We show that in untreated patients, BCC cells express CD95 ligand, but not the receptor, which may allow tumor expansion by averting the attack of activated CD95 receptor-positive lymphoid effector cells. The CD95 ligand of BCC cells is functional as CD95-positive cells incubated on BCC cryosections become apoptotic and are lysed. In IFN-alpha-treated patients BCC cells express not only CD95 ligand but also CD95 receptor, whereas the peritumoral infiltrate that mainly consists of CD4+ T cells predominantly contains CD95 receptor and only few CD95 ligand-positive cells. Thus, in treated patients BCC most likely regresses by committing suicide through apoptosis induction via CD95 receptor-CD95 ligand interaction.

Anaphylactic shock following castor bean contact: a case report.

BACKGROUND: The castor bean plant, Ricinus communis, is known to have allergenic and toxic properties. Castor bean allergy has been described mainly as an occupational inhalation allergy in laboratory workers, in persons working in oil processing mills or in agricultural industry. So far, only one case of anaphylactic reaction due to castor bean sensitization confirmed by specific IgE has been described in literature. CASE PRESENTATION: A 30-year-old woman presented to the emergency room with severe angioedema followed by urticaria, hypotension and tachycardia. She recovered after treatment with antihistamines, corticosteroids, nebulized adrenaline and intravenous fluids. Food induced anaphylaxis was excluded by allergological investigations. After repeated thorough history, the patient mentioned having bitten into a castor bean just before the reaction. Cutaneous test (prick-to-prick) and specific IgE for castor bean were highly positive. CONCLUSIONS: We report the second case of a severe anaphylactic reaction to castor beans, confirmed by IgE testing, reported in the literature. It underlines the importance of a meticulous history in allergology and highlights the fact, that castor beans may cause potentially fatal anaphylaxis.

Primary stenting versus primary balloon angioplasty for treating acute myocardial infarction.

BACKGROUND: Balloon angioplasty following myocardial infarction (MI) reduces death, non-fatal MI and stroke compared to thrombolytic reperfusion. However up to 50% of patients experience restenosis and 3% to 5% recurrent myocardial infarction. Therefore, primary stenting may offer additional benefits compared to balloon angioplasty in patients with acute myocardial infarction. OBJECTIVES: To examine whether primary stenting compared to primary balloon angioplasty reduces clinical outcomes in patients with acute myocardial infarction. SEARCH STRATEGY: We searched MEDLINE, EMBASE, Pascal, Index medicus and The Cochrane Controlled Trials Register (The Cochrane Library) from 1979 to March 2002. SELECTION CRITERIA: Randomised controlled trials of primary stenting or balloon angioplasty prior to the invasive procedure; intervention in native coronary arteries within 24 hours after onset of symptoms of myocardial infarction; report of death or reinfarction; and follow-up of at least 1 month. Trials were excluded when randomisation occurred after an invasive procedure and if they exclusively included patients with cardiogenic shock. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected and extracted data from identified trials. Outcomes included mortality, reinfarction, coronary artery bypass grafting, target vessel revascularization, need for vascular repair or blood transfusion. Peto odds ratios were calculated. To explore the stability of the overall treatment effect various sensitivity analyses were performed. MAIN RESULTS: We included nine trials of 4433 participants. Odds ratios for mortality after stenting compared to balloon angioplasty at 30 days, 6 and 12 months were 1.16 (95% CI 0.78 to 1.73), 1.27 (95% CI 0.89 to 1.83), and 1.06 (95% CI 0.77 to 1.45). At 30 days, 6 and 12 months odds ratios for reinfarction after stenting compared to balloon angioplasty were 0.52 (95% CI 0.31 to 0.87), 0.67 (95% CI 0.45 to 1.00), and 0.67 (95% CI 0.45-0.98) and odds ratio for target vessel revascularization after stenting compared to balloon angioplasty were 0.45 (95%CI 0.34 to 0.60), 0.42 (95% CI 0.35 to 0.51), and 0.47 (95% CI 0.38 to 0.57). The odds ratio for post-interventional bleeding complications after stenting compared to balloon angioplasty was 1.34 (95% CI 0.95 to 1.88; test of heterogeneity p > 0.1). AUTHORS' CONCLUSIONS: There is no evidence to suggest that primary stenting reduces mortality when compared to balloon angioplasty. Stenting seems to be associated with a reduced risk of reinfarction and target vessel revascularization, but potential confounding due to unbalanced post-interventional antithrombotic/anticoagulant therapies can not be ruled out on basis of this review.

[Skin manifestations of lupus erythematosus]. / Hautmanifestationen bei Lupus Erythematodes.

There are multiple forms of cutaneous manifestations of lupus erythematosus. In general strictly cutaneous forms are distinguished from systemic lupus erythematosus with cutaneous involvement. Systemic lupus erythematosus can be regarded either as primarily with skin signs or secundarily after initial involvement of the skin. Typical forms of cutaneous lupus erythematosus are the subacute cutaneous and the discoid form.

Cost effectiveness of highly active antiretroviral therapy in HIV-infected patients. Swiss HIV Cohort Study.

BACKGROUND: Highly active antiretroviral therapy (HAART) has become the most important strategy for treating HIV infection in developed countries; however, access to HAART might vary under different funding policies. The Swiss health care system provides unrestricted access to HAART for all patients who need these newer combination therapies. This study investigated the impact of this funding policy on the society and health care system. METHODS: A cost-effectiveness analysis with natural history data and productivity estimates was based on the Swiss HIV Cohort Study. A random sample of patient charts was used to estimate health care costs. In addition to a base-case scenario, a pessimistic and an optimistic scenario of natural disease history was developed. Costs were expressed in 1997 Swiss francs (100 CHF correspond to about US$67) and effects as projected years of life gained. RESULTS: In the analysis limited to health care costs, on the basis of projected survival in each scenario, the cost-effectiveness ratio was 33,000 CHF (base case), 14,000 CHF (optimistic), and 45,000 CHF (pessimistic) per year of life gained. When changes in productivity were included, cost savings occurred in the base-case and optimistic scenarios. The cost-effectiveness ratio was 11,000 CHF per year of life gained in the pessimistic scenario. CONCLUSIONS: HAART increases expected survival and health care costs. However, when productivity gains are included, society will probably save costs or pay a low price for substantial health benefits. The study provides strong arguments, from a societal perspective, to continue the current policy of providing unrestricted access to HAART in Switzerland. The presented results also suggest that this policy could be of interest for other developed countries. Decision makers in developed countries where access to HAART is limited should re-evaluate their policy for the benefit of the society at large.

Downregulation of Bcl-2, but not of Bax or Bcl-x, is associated with T lymphocyte apoptosis in HIV infection and restored by antiretroviral therapy or by interleukin 2.

The role of Bcl-2, Bax, and Bcl-x in the apoptosis of T lymphocytes in HIV-infected individuals was investigated. A strong correlation between Bcl-2 downregulation and spontaneous apoptosis has been reported by various groups in short-term cultures of CD8+ but not of CD4+ T lymphocytes. We describe a similar correlation in CD4+ T cells and provide an explanation why Bcl-2 downregulation in these cells has not been detected so far. In apoptotic cells not only Bcl-2, but also the CD4 surface receptors, are downregulated, preventing the detection of these cells in flow cytometric analysis. In contrast to Bcl-2, no correlation is detectable between Bax or Bcl-x expression and apoptosis. T lymphocytes of HIV-infected, but not of control, individuals display ex vivo a heterogeneous Bcl-2 expression pattern with a low and a high Bcl-2-expressing lymphocyte fraction. The proportion of low Bcl-2-expressing T cells correlates with a higher viral load in these individuals. Antiretroviral therapy significantly reduces the proportion of low Bcl-2-expressing lymphocytes, which is associated with a decrease in apoptosis. Bcl-2 downregulation and spontaneous apoptosis of T lymphocytes from HIV-infected individuals can be partially prevented by the exogeneous addition of IL-2, but not of IL-12, IL-4, or antibodies that prevent the CD95/CD95 ligand pathway of apoptosis.

Self-experienced physical workload and risk of breast cancer.

OBJECTIVES: The association between the risk of breast cancer and the physical load of work was studied because physical activity may reduce breast cancer risk via hormonal mechanisms. METHODS: Occupational physical activity was estimated from a self-determined rating [scale 1 (low)-5 (high)] of occupational physical load for 1800 randomly selected women born in 1930-1969. The medians of the ratings were used as occupation-specific indices of occupational physical activity. All 65 occupations with at least 5 ratings, covering 75% of the economically active female population in Finland, were included in further analyses. The occupation-specific numbers of observed and expected cases of breast cancer during 1971-1995 among women born in 1906-1945 (17,986 cases) were grouped according to the index for occupational physical activity. Expected rates were calculated with the social-class-specific population and the entire Finnish female population as reference populations. The relative risks (RR) of breast cancer for categories 3-5, in comparison with categories 1-2 were calculated using Poisson regression models. The occupation-specific mean number of children and mean age at first childbirth were adjusted for. RESULTS: The RR was lower for occupations in category 5 than for those in categories 1-4, especially in the youngest (25-39 years) age group (RR 0.51, 95% confidence interval 0.44-0.58). Adjustment for social class and reproductive factors raised the RR (95% confidence interval 0.56-0.74) for category 5 in different age strata, all the RR values still being statistically significant. CONCLUSIONS: The results support the hypothesis that occupational physical activity, if high enough, markedly reduces breast cancer risk.

Hypersensitivity reactions to anticoagulant drugs: diagnosis and management options.

Anticoagulants, including heparins, coumarins, hirudins, and some of the previously used plasma volume expanders, belong to the most widely used drugs. Hypersensitivity reactions from these agents are uncommon. However, they may have a considerable impact on patient safety and treatment decisions. Therefore, early diagnosis of potentially life-threatening adverse events and identification of alternatives is clinically important. This review contains an update on current knowledge about hypersensitivity reactions caused by the different anticoagulants. In addition, it discusses pathophysiologic mechanisms, diagnostic possibilities, and management options. The most common hypersensitivity reactions are erythematous plaques, occurring with a delay after subcutaneous application of heparins. Seldom they turn into maculopapular exanthema. Other hypersensitivity reactions are rare but may be life-threatening, e.g. skin necrosis because of heparin-induced thrombocytopenia. Skin and provocation tests with immediate and late readings are the most reliable diagnostic tools for heparin- or hirudin-induced urticaria/anaphylaxis or heparin-induced delayed plaques. If necrosis from heparins or coumarins is suspected, skin tests are contraindicated. In anaphylactic reactions caused by dextrans or hydroxyethyl starch skin tests are useless. Most in vitro tests have a low sensitivity and are not generally available. Therefore, in some anticoagulant-associated hypersensitivity reactions detailed allergologic investigation may help to identify safe treatment alternatives. However, several tests may be needed, and the procedures are usually time-consuming.

Salvage treatment against human immunodeficiency virus.

Despite dramatic declines in human immunodeficiency virus (HIV)-associated morbidity and mortality as a result of highly active antiretroviral combination therapies, including protease inhibitors, treatment failure occurs at such high rates as 20-50%. As drug regimens are very demanding, even short decreases of drug concentrations may trigger resistance. Viral loads can be decreased to very low concentrations, and there is no strict cut-off regarding the definition of treatment failure. Nevertheless, continuous detection of HIV of more than 50 copies per mL blood plasma is a predictor of increasing viral loads and of a suboptimal response to therapy. From a theoretical point of view, treatment changes should be made at low HIV RNA levels, but fewer options often dictate a more conservative approach. Drug susceptibility testing will be of increasing value, especially in patients experiencing drug failure for the first time. Success of salvage therapies is closely connected with the use of new compounds including new drug classes. As drugs susceptible to a multi-drug-resistant HIV are not yet available, regimens with more than three or even with five to nine drugs are used in clinical trials. Salvage therapies often fail in virological terms, ie in 50-80% of patients, depending primarily on the treatment history, but immunological and clinical stability can often be achieved.

Reversible dementia in idiopathic normal pressure hydrocephalus. A case report.

OBJECTIVE: To present a woman with idiopathic normal pressure hydrocephalus (NPH) showing marked improvement in mental function after shunt operation. DESIGN: Case report. SETTING: Primary health care. PATIENT: The clinical symptoms of gait disturbance, occasional urine incontinence and severely impaired mental function typical of NPH were all present. Although dementia predominated in the clinical picture, the diagnosis was confirmed by computer tomography (CT) and cerebrospinal fluid infusion test and cisternography. MAIN OUTCOME MEASURES: A marked improvement of mental functions was observed after shunt operation. RESULTS: Mini Mental State Examination score before shunt operation was 9 compared with 20 one year after operation. Also ventricle size was reduced as evaluated by CT scan. CONCLUSION: This reported case contrasts previous reports concluding that shunt responsive patients have only slight mental disturbances without significant improvement of mental status after shunt operation.

High human herpesvirus 8 seroprevalence in the homosexual population in Switzerland.

The seroprevalence of human herpesvirus 8 (HHV-8) in the Swiss population was investigated. By enzyme-linked immunosorbent assay, sera reactive to the recombinant HHV-8 antigen orf 65.2 were found in 24% of human immunodeficiency virus (HIV)-positive patients without and in 92% of HIV-positive patients with Kaposi's sarcoma. Surprisingly, 20% of homosexual HIV-negative men, versus only 7% of heterosexual HIV-negative individuals and 5% of blood donors, had antibodies to HHV-8.

Green fluorescent protein as a novel tool to measure apoptosis and necrosis.

BACKGROUND: Several apoptosis-detecting methods are currently available. Many of them are work intensive and require the additional use of antibodies, dyes, specific substrates, or enzymatic reactions. A simple, fast, and reliable method was developed to test for apoptosis or necrosis using mouse and human cell lines (e.g., Jurkat, A20.2J, and PB3c cells) stably transfected with a vector coding for green fluorescent protein (GFP) as indicator cells. METHODS: Apoptosis in GFP-transfected cell lines was induced either by soluble Fas-Ligand (sFasL), recombinant human TRAIL (rhTRAIL), or interleukin-3 (IL-3) deprivation. Necrosis was induced by polyclonal anti-A20 and complement treatment of GFP-transfected A20. Cells were analyzed by flow cytometry for GFP fluorescence. Propidium iodide and Annexin V staining were used to confirm the results obtained with the GFP-method. RESULTS: Live GFP-transfected cells show a strong fluorescence intensity, which is significantly diminished upon induction of apoptosis, whereas necrotic GFP-transfected cells almost completely lose their GFP-associated fluorescence. Apoptosis but not necrosis of GFP-transfected cells was blocked by the use of a caspase inhibitor. The results are highly comparable to conventional apoptosis-detecting methods. CONCLUSIONS: The advantage of our GFP-based assay compared with other methods is the analysis of apoptosis or necrosis without the necessity for additional staining or washing steps, making it an ideal tool for screening apoptotic or necrotic stimuli.