Novel Biological Therapies for Severe Asthma Endotypes

Severe asthma comprises several heterogeneous phenotypes, underpinned by complex pathomechanisms known as endotypes. The latter are driven by intercellular networks mediated by molecular components which can be targeted by specific monoclonal antibodies. With regard to the biological treatments of either allergic or non-allergic eosinophilic type 2 asthma, currently available antibodies are directed against immunoglobulins E (IgE), interleukin-5 (IL-5) and its receptor, the receptors of interleukins-4 (IL-4) and 13 (IL-13), as well as thymic stromal lymphopoietin (TSLP) and other alarmins. Among these therapeutic strategies, the best choice should be made according to the phenotypic/endotypic features of each patient with severe asthma, who can thus respond with significant clinical and functional improvements. Conversely, very poor options so far characterize the experimental pipelines referring to the perspective biological management of non-type 2 severe asthma, which thereby needs to be the focus of future thorough research

Indacaterol/glycopyrronium/mometasone fixed dose combination for uncontrolled asthma

Introduction: Asthma symptoms can be relieved through a maintenance treatment combining long-acting β2-agonist and inhaled corticosteroids (LABA/ICS). However, for patients with inadequately controlled asthma, the LABA/ICS combination might not be sufficient, and clinical guidelines recommend the administration of inhaled long-acting muscarinic antagonists (LAMA) as an add-on therapy to better control asthma and improve lung function. For nearly two decades, the only LAMA to be approved on the market has been tiotropium. Areas covered: We reviewed recent clinical studies evaluating the safety and efficacy of LABA/LAMA/ICS fixed dose combinations by searching the PubMed database. Molecular mechanisms and clinical data support the use of a once-daily, single-inhaler fixed dose combination of the LABA/LAMA/ICS indacaterol/glycopyrronium/mometasone (IND/GLY/MF), the first therapy combining three agents in a fixed dose approved in Europe for the treatment of uncontrolled asthma. Expert opinion: IND/GLY/MF was superior to both IND/MF and salmeterol/fluticasone, a well-established LABA/ICS combination improving the lung function in uncontrolled asthma. Moreover, IND/GLY/MF, delivered through the Breezhaler inhaler in a single inhalation, is the first inhaled therapy prescribed alongside a digital companion, a sensor and the Propeller app, allowing for improved treatment adherence, reduced rescue inhaler usage and hospitalizations, increased patient satisfaction and asthma control

S. aureus and IgE-mediated diseases: pilot or copilot? A narrative review

Introduction: S. aureus is a major opportunistic pathogen that has been implicated in the pathogenesis of several chronic inflammatory diseases including bronchial asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), chronic spontaneous urticaria (CSU), and atopic dermatitis. S. aureus can induce the production of both polyclonal and specific IgE that can elicit an inflammatory cascade. Areas covered: The link between the sensitization to S. aureus enterotoxins and the severity of several chronic inflammatory diseases is reviewed in detail, as well as its therapeutic implications. Expert opinion: An anti-IgE strategy to inhibit S. aureus enterotoxins would be a valid approach to treat several endotypes of severe asthma, CRSwNP and CSU in which IgE against S. aureus enterotoxins should represent, not only a marker of severity of the diseases but also a target of a treatment

To verify four 5-year-old mathematical models to predict the outcome of ICU patients

The aim of this study is to verify calibration and discrimination after 5 years in the case mix of patients admitted to the Intensive Care Unit (ICU) during the year 2000. In this way we want to perform a quality control of our ICU in order to justify the increased amount of money spent for intensive care.A prospective study has been made on the 357 patients admitted to the ICU during the year 2000. The Apache II score was calculated within the first 24 hours and, depending on the length of stay in the ICU, on the 5(th), 10(th) and 15(th) day after ICU admission. On the basis of the 4 mathematical models death risk has been calculated for each of the 4 times. The Hosmer-Lemeshow test was performed for calibration and ROC curves for discrimination, always for each of the 4 mathematical models.The 1(st) model, at 24 hours from ICU admission, showed a bad calibration (p=0.000088), while the ROC curve was 0.744+/-0.32. Also the 2(nd) model, at the 5(th) day from admission, showed a bad calibration (p=0.000588), with ROC curve of 0.827+/-0.04. The 3(rd) model (10(th) day), was well calibrated (p=0.112247) and discriminating (ROC=0.888 +/-0.04). Finally the models at 15 days showed again a bad calibration (p=0.001422) but a very good discrimination (area=0.906+/-0.06).Developing mathematical models to predict mortality within ICUs can be useful to assess quality of care, even if these models should not be the only ICU quality controls, but must be accompanied by other indicators, looking at quality of life of the patients after ICU discharge

Basophil activation test for Staphylococcus aureus enterotoxins in severe asthmatic patients

Background: Several studies have shown an association between severe asthma and serum immunoglobulins E (IgE) against Staphylococcus aureus enterotoxins (SEs). SEs—the prototypes being types A (SEA), B (SEB) and toxic shock syndrome toxin 1 (TSST-1)—can induce both polyclonal and specific IgE responses. Objective: The aim of the study was to evaluate the ability of SEs to induce basophil activation in severe asthmatic patients using the basophil activation test (BAT). Methods: 57 severe asthmatic patients were enrolled. BAT in response to SEA, SEB and TSST-1 was performed in all patients, while serum IgE to SEA, SEB and SEC was available in 49 patients. BAT was considered positive when CD203c+ basophils to SEs were ≥5%, and the stimulation index (SI, ratio between % of CD203c+ basophils to SEs and to negative control) was >2. Two threshold values (>0.1 kU/L and >0.35 kU/L, respectively) were used to assess serum SEsIgE. Results: 36.8% of severe asthmatic patients had a BAT positive for at least one SE (BAT SEs+). Serum SEsIgE >0.35 kU/L (SEs IgE+) was associated with BAT SEs positivity. Among patients with negative skin prick test, 35% were BAT SEs+, 30% SEs IgE+, 55% BAT or IgE− SEs+. A negative correlation between SI of BAT to SEs and both clinical (ACT score) and functional parameters was observed, together with a positive correlation of BAT with asthma exacerbations. Conclusions: The positivity of BAT for SEs in a subgroup of severe asthmatic patients further supports the pathogenic role of Staphylococcus aureus in severe asthma

Effectiveness of benralizumab in severe eosinophilic asthma: Distinct sub-phenotypes of response identified by cluster analysis.

Background: Benralizumab is effective in severe eosinophilic asthma (SEA), but suboptimal responses are observed in some patients. Although several factors have been associated with benralizumab response, no cluster analysis has yet been undertaken to identify different responsiveness sub-phenotypes. Objective: To identify SEA sub-phenotypes with differential responsiveness to benralizumab. Methods: One hundred and five patients diagnosed with SEA who had completed 6 months of benralizumab treatment were included in a hierarchical cluster analysis based on a set of clinical variables that can be easily collected in routine practice (age, age at disease onset, disease length, allergen sensitization status, blood eosinophil count, IgE levels, FEV1% predicted, nasal polyposis, bronchiectasis). Results: Four clusters were identified: Clusters 2 and 3 included patients with high levels of both IgE and eosinophils (type-2 biomarkers high), whereas Clusters 1 and 4 included patients with only one type-2 biomarker at a high level: IgE in Cluster 1 and eosinophils in Cluster 4. Clusters 2 and 3 (both type-2 biomarkers high) showed the highest response rate to benralizumab in terms of elimination of exacerbations (79% and 80% respectively) compared to Clusters 1 and 4 (52% and 60% respectively). When super-response (the absence of exacerbation without oral corticosteroid use) was assessed, Cluster 2, including patients with more preserved lung function than the other clusters, but comparable exacerbation rate, oral corticosteroid use and symptom severity, was the most responsive cluster (87.5% of patients). Conclusions: Our cluster analysis identified benralizumab differential response sub-phenotypes in SEA, with the potential of improving disease treatment and precision management

Primary mucosal melanoma presenting with a unilateral nasal obstruction of the left inferior turbinate

We report the case of a primitive nasal melanoma in an 82-year-old patient, showing how this rare malignancy, with non-specific signs and symptoms, can represent a challenging diagnosis for the physician. A 82-year-old Caucasian patient presented for unilateral nasal obstruction and occasional epistaxis. Computerized tomography (CT) and magnetic resonance imaging (MRI) of the facial massif revealed turbinate hypertrophy and a polypoid phlogistic tissue isointense in T1 with an intermediate signal in T2 and Short-TI Inversion Recovery (STIR)-T2, occupying the middle meatus and the anterior upper and lower left meatus with partial obliteration of the ostium and the infundibulum of the maxillary sinus. The Positron emission tomography (PET) exam was negative for metastases. Conservatory surgery in the left anterior video rhinoscopy was performed, allowing a radical 4-cm tumor excision. Histology reported epithelioid cell melanoma, PanK−, CD45−, and PanMelanoma+. Adjuvant radiotherapy was suggested, even considering a complete resection as the result of surgery. No local or systemic relapse was noticed at the 2-month follow-up visit. Although mucosal melanoma is a rare and aggressive malignancy characterized by a poor prognosis, early diagnosis allows a more conservative approach, with little surgical difficulty and no aesthetic effect. Our case raises awareness of the importance of early intervention even in those cases where the clinic symptoms and diagnostic images show uncertain severity

Glycaemic variability, infections and mortality in a medical-surgical intensive care unit.

In critically ill patients, glycaemic variability (GV) was reported as a better predictor of mortality than mean blood glucose level (BGL). We compared the ability of different GV indices and mean BGLs to predict mortality and intensive care unit-acquired infections in a population of ICU patients.Retrospective study on adult ICU patients with ≥ three BGL measurements. GV was assessed by SD, coefficient of variation (CV) and mean amplitude of glycaemic excursion (MAGE), and by one timeweighted index, the glycaemic lability index (GLI), and compared with mean BGL. We studied 2782 patients admitted to the 12-bed medical-surgical ICU of a teaching hospital from January 2004 until December 2010.Logistic regression analyses were performed to assess the association between GV and ICU mortality and ICU-acquired infections. The areas under receiver operating characteristic curves were calculated to compare the discriminatory ability of GV and mean BGL for infections and mortality.Mortality was 16.6%, and 30% of patients had at least one infection. Patients with infections or diabetes or who were treated with insulin had a higher mean BGL and GV than other patients. GLI, SD, CV and MAGE were significantly associated with infections and mortality; mean BGL was not. Quartiles of increasing GLI were independently associated with higher mortality and an increased infection rate. Patients in the upper quartile of mean BGL and GLI had the strongest association with infections (odds ratio, 5.044 [95% CI, 1.695-15.007]; P = 0.004).High GV is associated with higher risk of ICUCrit acquired infection and mortality