The New Therapeutic Frontiers in the Treatment of Eosinophilic Esophagitis: Biological Drugs.

Eosinophilic esophagitis (EoE) is a multifaceted disease characterized by a wide heterogeneity of clinical manifestations, endoscopic and histopathologic patterns, and responsiveness to therapy. From the perspective of an effective approach to the patient, the different inflammatory mechanisms involved in the pathogenesis of EoE and biologics, in particular monoclonal antibodies (mAbs), targeting these pathways are needed. Currently, the most relevant is dupilumab, which interferes with both interleukin (IL)-4 and IL-13 pathways by binding IL-4 receptor α, and is the only mAb approved by the European Medicine Agency and US Food and Drug Administration for the treatment of EoE. Other mAbs investigated include mepolizumab, reslizumab, and benralizumab (interfering with IL-5 axis), cendakimab and dectrekumab (anti-IL-13s), tezepelumab (anti-TSLP), lirentelimab (anti-SIGLEG-8), and many others. Despite the undeniable economic impact of biologic therapies, in the near future, there will be room for further reflection about the opportunity to prescribe biologic agents, not only as a last-line therapy in selected cases such as patients with comorbidities involving common pathways. Although recent findings are very encouraging, the road to permanent success in the treatment of EoE is still long, and further studies are needed to determine the long-term effects of mAbs and to discover new potential targets.

The effects of climate change on respiratory allergy and asthma induced by pollen and mold allergens.

The impact of climate change on the environment, biosphere, and biodiversity has become more evident in the recent years. Human activities have increased atmospheric concentrations of carbon dioxide (CO2 ) and other greenhouse gases. Change in climate and the correlated global warming affects the quantity, intensity, and frequency of precipitation type as well as the frequency of extreme events such as heat waves, droughts, thunderstorms, floods, and hurricanes. Respiratory health can be particularly affected by climate change, which contributes to the development of allergic respiratory diseases and asthma. Pollen and mold allergens are able to trigger the release of pro-inflammatory and immunomodulatory mediators that accelerate the onset the IgE-mediated sensitization and of allergy. Allergy to pollen and pollen season at its beginning, in duration and intensity are altered by climate change. Studies showed that plants exhibit enhanced photosynthesis and reproductive effects and produce more pollen as a response to high atmospheric levels of carbon dioxide (CO2 ). Mold proliferation is increased by floods and rainy storms are responsible for severe asthma. Pollen and mold allergy is generally used to evaluate the interrelation between air pollution and allergic respiratory diseases, such as rhinitis and asthma. Thunderstorms during pollen seasons can cause exacerbation of respiratory allergy and asthma in patients with hay fever. A similar phenomenon is observed for molds. Measures to reduce greenhouse gas emissions can have positive health benefits.

Allergen immunotherapy for birch-apple syndrome: what do we know?

Apple allergy is common in patients allergic to birch pollen, and this is defined as 'birch-apple syndrome'. Allergens responsible for cross-reactivity belong to the pathogenesis-related-10 family, and high homology in the amino acid sequences of the major allergens Bet v 1 from birch and Mal d 1 from apple has been demonstrated. Here we review the literature on the treatment of birch-apple syndrome by allergen immunotherapy. The only allergen immunotherapy method available thus far is based on the administration of birch-pollen extracts, through the subcutaneous or sublingual route, to induce tolerance to Bet v1 and to the homologous allergen Mal d 1. However, the studies performed thus far show modest efficacy, and thus other methods of immunotherapy should be investigated.

The current overuse and misuse of meta-analyses on sublingual immunotherapy: the case of grass pollen allergy.

PURPOSE OF REVIEW: Meta-analysis provides the highest level of evidence-based efficacy of a medical treatment or intervention. Allergen immunotherapy in its two forms of subcutaneous immunotherapy and sublingual immunotherapy (SLIT) is an effective treatment of respiratory allergy as shown by meta-analyses, but in recent years there has been an overflow of meta-analyses on SLIT, with contrasting results that may generate confusion among physicians. RECENT FINDINGS: It can be observed that flaws are often present in meta-analyses including: incorrect selection of trials, inappropriate use of evaluation parameters for the analysis, and unsuitable analyses. For instance, it is clear that a meta-analysis of several small studies does not predict the results of a single large study that remains the gold standard to assess the efficacy and safety of a treatment. To assess the interest of the matter, we calculated the number of citations of meta-analyses on SLIT efficacy in the 10 years after the first publication in 2005 and detected a continuous decrease in citations. SUMMARY: Today, the appropriateness of a meta-analysis should be carefully evaluated, taking into account that a meta-analysis uses a statistical approach to combine the results from multiple small studies to increase power, to improve estimates of the size of the effect, and/or to resolve uncertainty when reports disagree. Editors and reviewers of medical journals should consider that to judge a meta-analysis requires a high level of expertise that is obvious in reviewers belonging to the Cochrane organization.

New combinations in the treatment of COPD: rationale for aclidinium-formoterol.

The current guidelines on chronic obstructive pulmonary disease (COPD) recommend the prominent use of bronchodilators, including long-acting ß2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), while inhaled corticosteroids are recommended only in patients with severe disease or frequent exacerbations. LABA-LAMA combinations are indicated when single bronchodilators are insufficient to control COPD. A number of LABA-LAMA combinations are available, based on twice-daily or once-daily administration according to the 12- or 24-hour duration of action, respectively. The aclidinium-formoterol combination is based on the new LAMA aclidinium bromide, which has a high selectivity for M3 muscarinic receptors and a fast onset of action, and the well-known LABA formoterol. Both drugs require twice-daily administration. The fixed-dose combination of aclidinium 400 µg/formoterol 12 µg has shown in randomized controlled trials fast and sustained bronchodilation that was greater than either monotherapy and provided clinically significant improvements in dyspnea and health status compared with placebo, also reducing the use of rescue medications. The overall incidence of adverse events was low and comparable to placebo. These data define the aclidinium-formoterol fixed-dose combination as a new treatment option for patients with COPD. The need for twice-daily administration could be an apparent disadvantage compared to the available once-daily LABA-LAMA combinations, but the immediately perceived benefit in reducing dyspnea due to the fast onset of action, as well as reported correct patient use and satisfaction with the Genuair inhaler might prove useful in favoring adherence.

Sublingual immunotherapy for allergic rhinitis: where are we now?

Sublingual immunotherapy (SLIT) was introduced in the 1980s as a safer option to subcutaneous immunotherapy and in the latest decade achieved significant advances. Its efficacy in allergic rhinitis is supported by a number of meta-analyses. The development of SLIT preparations in tablets to fulfill the requirements of regulatory agencies for quality of allergen extracts made available optimal products for grass-pollen-induced allergic rhinitis. Preparations of other allergens based on the same production methods are currently in progress. A notable outcome of SLIT, that is shared with subcutaneous immunotherapy, is the evident cost-effectiveness, showing significant cost savings as early as 3 months from starting the treatment, that become as high as 80% compared with drug treatment in the ensuing years.

Glycopyrronium bromide for the treatment of chronic obstructive pulmonary disease.

Glycopyrronium bromide is a new long-acting muscarinic antagonist to be used once-daily, which is approved as a bronchodilator for the symptomatic maintenance treatment of adult patients with chronic obstructive pulmonary disease (COPD). In the Glycopyrronium bromide in chronic Obstructive pulmonary disease airWays trials, treatment with inhaled glycopyrronium bromide at 50 µg once daily achieved a significantly better lung function than placebo, as measured by the trough forced expiratory volume in 1 s in patients with moderate-to-severe COPD. The lung function improvement was maintained for up to 52 weeks. Other improved indexes were dyspnea scores, health status, exacerbation rates and time of exercise endurance. Studies comparing the efficacy of glycopyrronium versus tiotropium bromide found substantial equivalence of the two drugs. Glycopyrronium was generally well tolerated. These data add inhaled glycopyrronium bromide to the treatment of patients with moderate to severe COPD as an effective once-daily LAMA.

The effect of fruits and vegetables on urinary stone risk factors.

BACKGROUND: The overall effect of fruit and vegetable intake on urinary stone risk profile is not yet known. METHODS: We studied the effect of a two-week period of fruit and vegetable elimination on urinary stone risk profile in 12 normal adults, and of supplementing the diet with a fair quantity of low-oxalate fruits and vegetables in 26 idiopathic calcium stone formers characterized by hypocitraturia and a very low fruit and vegetable intake in their usual diet. RESULTS: In the normal subjects, the elimination of fruits and vegetables from the diet decreased the urinary excretion of potassium (-62%), magnesium (-26%), citrate (-44%) and oxalate (-31%), and increased that of calcium (+49%) and ammonium (+12%) (P < 0.05 for all). The relative saturation for calcium oxalate and calcium phosphate increased from 6.33 to 8.24 (P = 0.028), and from 0.68 to 1.58 (P = 0.050), respectively. In the hypocitraturic stone formers, the introduction of these foods in the diet increased urinary volume (+64%), pH (from 5.84 to 6.19), excretion of potassium (+68%), magnesium (+23%), and citrate (+68%), while it decreased the excretion of ammonium (-18%) (P < 0.05 for all). The relative saturation for calcium oxalate and uric acid fell from 10.17 to 4.96 (P < 0.001), and from 2.78 to 1.12 (P = 0.003), respectively. CONCLUSION: The total elimination of fruits and vegetables in normal subjects brings about adverse changes in the urinary stone risk profile that are only partially counterbalanced by a reduction in oxalate. In contrast, the addition of these foods to the diet of hypocitraturic stone formers not used to eating them not only significantly increases citrate excretion without affecting oxalate excretion, but also decreases calcium oxalate and uric acid relative saturation.

[Analysis of the problem of "difficult hospital discharges" in the University Hospital of Parma]. / Analisi del problema "dimissioni difficili" nell'Azienda Ospedaliera-Universitaria di Parma.

We analyzed, in a middle-sized hospital, the problems related to the so-called "difficult discharges", conceived as situations involving an economic, human and organizational burden exceeding patients' and their families' capacities and requiring a specific involvement of territorial services. During a whole year (July 1, 2001-June 30, 2002) the cases found were 591. We demonstrated that the problem concerns mainly elderly patients, almost equally distributed between males and females, a quarter of the sample being represented by patients who had recently undergone surgery and whose discharge difficulties were mostly related to mixed social and sanitary problems. This kind of patients is faced with long-term hospitalization implicating a large number of intra-hospital transfers due to the presence of severe and disabling pathologies, mainly neoplasms and strokes, often associated with other serious diseases, various complications and difficult situations from the health point of view. About half of the patients had the possibility to go back home, while the rest required lodging in territorial structures such as nursing homes and retirement homes. The average time-lapse between the possible discharge indicated by the hospital physician and the actual discharge was 10 days, with global annual 6106 days of "improper" hospitalization. Our conclusion is that the phenomenon of difficult discharges is nowadays a very topical problem and that it should be faced with a new model of continuous and integrated assistance organization.