Role of C-reactive protein as a biomarker for prediction of the severity of pulmonary exacerbations in patients with cystic fibrosis.

BACKGROUND: Pulmonary exacerbation is one of the main risk factors for death in patients with cystic fibrosis. Several biomarkers have proven useful in the diagnosis and treatment of pulmonary exacerbations, although none has been associated with severity. The objective of the present study was to investigate whether C-reactive protein (CRP) level was associated with the severity of pulmonary exacerbation requiring admission to hospital in patients with cystic fibrosis. METHODS: We designed a severity index for exacerbations based on 4 clinical parameters and determined whether there was an association between CRP levels and severity of the exacerbation. We also investigated the association between CRP and baseline functional and clinical variables. RESULTS: Twenty-seven patients with cystic fibrosis required 62 admissions to hospital. CRP levels were not significantly associated with the severity index, although they were associated with specific patient characteristics: colonization by Pseudomonas aeruginosa, allergic bronchopulmonary aspergillosis, treatment with oral corticosteroids, and number of severe exacerbations treated with intravenous antibiotics during the previous year. CONCLUSIONS: CRP level is not associated with the severity of pulmonary exacerbations, but it is associated with specific clinical characteristics. This simple scoring system (severity index) could prove very useful for evaluating the severity of exacerbations.

Multidisciplinary management of type 2 inflammation diseases using a screening tool.

Dysregulation of type 2 (T2) immune response leads to an aberrant inflammatory reaction that constitutes the pathophysiological basis of diseases involving various organs. For this reason, several disorders can coexist in a single patient; however, as different specialists often treat these pathologies, T2 dysregulation, particularly when mild, is not always the first diagnostic suspicion. A breakdown in interdisciplinary communication or the lack of adequate tools to detect these entities can delay diagnosis, and this, together with a lack of coordination, can lead to suboptimal care. In this context, a multidisciplinary group of specialists in pneumology, immunology, allergology, dermatology and otorhinolaryngology compiled a list of the cardinal symptoms reported by patients presenting with T2 inflammation-related diseases: asthma, chronic rhinosinusitis, allergic rhinitis, allergic conjunctivitis, IgE-mediated food allergy, atopic dermatitis, eosinophilic oesophagitis, and NSAID-exacerbated respiratory disease (NERD). Using this information, we propose a simple, patient-friendly questionnaire that can be administered at any level of care to initially screen patients for suspected coexisting T2 diseases and referral to the appropriate specialist.

Asthma control and concordance of opinions between patients and pulmonologists.

UNLABELLED: Patient-physician opinion concordance could play a key role in asthma control. There have been no studies evaluating this association in large samples of patients. OBJECTIVES: To determine opinion concordance between asthma patients and their pulmonologists on the impact of the disease and to correlate concordance to asthma control. METHODS: This was a cross-sectional multicentre study including 1160 patients and 300 pulmonologists. Patient-physician concordance rates were assessed by two semi-structured qualitative questionnaires: (1) impact of the disease and (2) treatment satisfaction. Subsequently, participating pulmonologists determined the concordance between their perceptions and their patient's. Sociodemographic and clinical data were recorded for all patients. RESULTS: In 53.6% of cases, asthma was controlled. The rate of patient-pulmonologist concordance on disease impact on patient daily life was 57%, with physicians underestimating the impact (compared to patients) in 26% of cases. Concordance on satisfaction with treatment was 56%, with physicians underestimating satisfaction in 26% of cases. Patient-physician discordance rates were significantly lower among patients with controlled asthma (29 and 32.1%) than those with poor control (73.7 and 73.1%). CONCLUSIONS: Patient-pulmonologist concordance on perceptions of disease impact is low, particularly in uncontrolled asthma. This poor concordance should be addressed in education programmes, particularly for patients with uncontrolled symptoms.

[Unmet Needs in Severe Allergic Asthma]. / Necesidades no cubiertas en asma alérgica grave.

Severe asthma affects 3%-10% of the world's population, according to estimates by the Global Initiative for ASTHMA (GINA). Allergic asthma is one of the most common phenotypes of severe asthma and it is characterized by allergen-induced type 2 inflammation in which immunoglobulin E (IgE) is a key mediator, making it an important therapeutic target. The introduction of targeted biological therapies or treatments has entered the management for severe asthma in the era of precision medicine, and the goal of treatment is clinical remission of the disease. There is a significant percentage of patients with severe allergic asthma who do not respond to treatments and whose symptoms are not controlled. In this paper, a group of experts in the management of severe allergic asthma reviewed and evaluated the most relevant evidence regarding the pathophysiology and phenotypes of severe allergic asthma, the role of IgE in allergic inflammation, allergen identification, techniques, biomarkers and diagnostic challenges, available treatments and strategies for disease management, with a special focus on biological treatments. From this review, recommendations were developed and validated through a Delphi consensus process with the aim of offering improvements in the management of severe allergic asthma to the professionals involved and identifying the unmet needs in the management of this pathology.

Obstructive sleep apnea: The key for a better asthma control?

INTRODUCTION: Obstructive sleep apnea (OSA) is an important risk factor for poor asthma control. The objective of this study is to analyze the symptomatic control in asthmatic patients with OSA after using continuous positive airway pressure (CPAP). METHODS: Patients were collected in a monographic asthma consult and a polygraphy was performed due to clinical suspicion or poor disease control. Asthma associated pathologies, as well as clinical and patient-perceived asthma control parameters were evaluated before and after the initiation of CPAP. RESULTS: A hundred patients were included, 59% were women and 41% men. From them, 54% had severe OSA, 33% moderate OSA and 13% mild OSA, and 10% could not tolerate CPAP. Eighty four percent had a moderate or severe degree of asthma with fractional exhaled nitric oxide (FENO) 32 ± 24.6 ppm and an asthma control test (ACT) before CPAP of 19 ± 4. Asthma control before CPAP was good in 41% of patients, partial in 29%, and bad in 30%. After three or more months of CPAP, clinical asthma control was good in 70% (p < 0.001), perceived control by ACT after CPAP was 21 ± 4 (p < 0.001). When asked for their opinion, 51.5% referred clinical improvement after CPAP, no change in 46.5%. CONCLUSIONS: The use of CPAP in asthmatic patients with OSA improves both clinical and perceived asthma control in a statistically significant way. Most patients had good adaptation to CPAP (90%) and 51.5% had clinical improvement.

Consensus on the management of united airways disease with type 2 inflammation: a multidisciplinary Delphi study.

BACKGROUND: Scientific evidence on patients with multimorbid type 2 asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) from a united airways disease (UAD) perspective remains scarce, despite the frequent coexistence of these entities. We aimed to generate expert consensus-based recommendations for the management of UAD patients. METHODS: Using a two-round Delphi method, Spanish expert allergists, pulmonologists and otolaryngologists expressed their agreement on 32 statements (52 items) on a 9-point Likert scale, classified as appropriate (median 7-9), uncertain (4-6) or inappropriate (1-3). Consensus was considered when at least two-thirds of the panel scored within the range containing the median. RESULTS: A panel of 30 experts reached consensus on the appropriateness of 43 out of the 52 (82.7%) items. The usefulness of certain biomarkers (tissue and peripheral blood eosinophil count, serum total IgE, and fraction of exhaled nitric oxide [FeNO]) in the identification and follow-up of type 2 inflammation, and assessment of the response to biologics, were agreed. Some of these biomarkers were also associated with disease severity and/or recurrence after endoscopic sinus surgery (ESS). Consensus was achieved on treatment strategies related to the prescription of anti-IL-4/IL-13 or anti-IgE agents, concomitant treatment with systemic corticosteroids, and combining or switching to biologics with a different mechanism of action, considering a number of UAD clinical scenarios. CONCLUSION: We provide expert-based recommendations to assist in clinical decision-making for the management of patients with multimorbid type 2 asthma and CRSwNP. Specific clinical trials and real-world studies focusing on the single-entity UAD are required to address controversial items.

Electron-Beam-Initiated Crosslinking of Methacrylated Alginate and Diacrylated Poly(ethylene glycol) Hydrogels.

An ideal wound dressing not only needs to absorb excess exudate but should also allow for a moist wound-healing environment as well as being mechanically strong. Such a dressing can be achieved by combining both a natural (alginate) and synthetic (poly(ethylene glycol) polymer. Interestingly, using an electron beam on (meth)acrylated polymers allows their covalent crosslinking without the use of toxic photo-initiators. The goal of this work was to crosslink alginate at different methacrylation degrees (26.1 and 53.5% of the repeating units) with diacrylated poly(ethylene glycol) (PEGDA) using electron-beam irradiation at different doses to create strong, transparent hydrogels. Infrared spectroscopy showed that both polymers were homogeneously distributed within the irradiated hydrogel. Rheology showed that the addition of PEGDA into alginate with a high degree of methacrylation and a polymer concentration of 6 wt/v% improved the storage modulus up to 15,867 ± 1102 Pa. Gel fractions > 90% and swelling ratios ranging from 10 to 250 times its own weight were obtained. It was observed that the higher the storage modulus, the more limited the swelling ratio due to a more crosslinked network. Finally, all species were highly transparent, with transmittance values > 80%. This may be beneficial for the visual inspection of healing progression. Furthermore, these polymers may eventually be used as carriers of photosensitizers, which is favorable in applications such as photodynamic therapy.

[Consensus document for severe asthma in adults. 2022 update]. / Documento de consenso de asma grave en adultos. Actualización 2022.

Severe asthma is a heterogeneous syndrome with several clinical variants and often represents a complex disease requiring a specialized and multidisciplinary approach, as well as the use of multiple drugs. The prevalence of severe asthma varies from one country to another, and it is estimated that 50% of these patients present a poor control of their disease. For the best management of the patient, it is necessary a correct diagnosis, an adequate follow-up and undoubtedly to offer the best available treatment, including biologic treatments with monoclonal antibodies. With this objective, this consensus process was born, which began in its first version in 2018, whose goal is to offer the patient the best possible management of their disease in order to minimize their symptomatology. For this 2020 consensus update, a literature review was conducted by the authors. Subsequently, through a two-round interactive Delphi process, a broad panel of asthma experts from SEPAR and the regional pulmonology societies proposed the recommendations and conclusions contained in this document.

Point-of-care therapeutic drug monitoring of adalimumab by integrating a FO-SPR biosensor in a self-powered microfluidic cartridge.

Disease treatment with advanced biological therapies such as adalimumab (ADM), although largely beneficial, is still costly and suffers from loss of response. To tackle these aspects, therapeutic drug monitoring (TDM) is proposed to improve treatment dosing and efficacy, but is often associated with long sampling-to-result workflows. Here, we present an in-house constructed ADM-sensor, allowing TDM of ADM at the doctor's office. This biosensor brings fiber optic surface plasmon resonance (FO-SPR), combined with self-powered microfluidics, to a point of care (POC) setting for the first time. After developing a rapid FO-SPR sandwich bioassay for ADM detection on a commercial FO-SPR device, this bioassay was implemented on the fully-integrated ADM-sensor. For the latter, we combined (I) a gold coated fiber optic (FO) probe for bioassay implementation and (II) an FO-SPR readout system with (III) the self-powered iSIMPLE microfluidic technology empowering plasma sample and reagent mixing on the-cartridge as well as connection to the FO-SPR readout system. With a calculated limit of detection (LOD) of 0.35 µg/mL in undiluted plasma, and a total time-to-result (TTR) within 12 min, this innovative biosensor demonstrated a comparable performance to existing POC biosensors for ADM quantification in patient plasma samples, while requiring only 1 µL of plasma. Whereas this study demonstrates great potential for FO-SPR biosensing at the POC using ADM as a model case, it also shows huge potential for bedside TDM of other drugs (e.g. other immunosuppressants, anti-epileptics and antibiotics), as the bioassay is highly amenable to adaptation.

Synthetic, Natural, and Semisynthetic Polymer Carriers for Controlled Nitric Oxide Release in Dermal Applications: A Review.

Nitric oxide (NO•) is a free radical gas, produced in the human body to regulate physiological processes, such as inflammatory and immune responses. It is required for skin health; therefore, a lack of NO• is known to cause or worsen skin conditions related to three biomedical applications- infection treatment, injury healing, and blood circulation. Therefore, research on its topical release has been increasing for the last two decades. The storage and delivery of nitric oxide in physiological conditions to compensate for its deficiency is achieved through pharmacological compounds called NO-donors. These are further incorporated into scaffolds to enhance therapeutic treatment. A wide range of polymeric scaffolds has been developed and tested for this purpose. Hence, this review aims to give a detailed overview of the natural, synthetic, and semisynthetic polymeric matrices that have been evaluated for antimicrobial, wound healing, and circulatory dermal applications. These matrices have already set a solid foundation in nitric oxide release and their future perspective is headed toward an enhanced controlled release by novel functionalized semisynthetic polymer carriers and co-delivery synergetic platforms. Finally, further clinical tests on patients with the targeted condition will hopefully enable the eventual commercialization of these systems.

Effectiveness of Text Message Reminders on Adherence to Inhaled Therapy in Patients With Asthma: Prospective Multicenter Randomized Clinical Trial.

BACKGROUND: Poor adherence to inhaled medication in asthma patients is of great concern. It is one of the main reasons for inadequate asthma control. OBJECTIVE: The goal of the research was to determine if motivational messages using short message service (SMS, or text) improved adherence to inhaled medication in patients with asthma. METHODS: A prospective multicenter randomized parallel-group clinical trial was conducted in 10 asthma clinics in Spain. Adherence was assessed with electronic monitors (Smartinhaler, Adherium Ltd) connected to inhalers. Patients in the SMS group received psychologist-developed motivational messages every 3 days for 6 months. RESULTS: There were 53 patients in the SMS group and 88 patients in the control group. After 6 months, mean electronic adherence was 70% (SD 17%) in the intervention group and 69% (SD 17%) in the control group (P=.82). Significant differences between the study groups in morning and evening adherence to inhaled therapy, asthma control, exhaled nitric oxide levels, or improvement of lung functions were not observed. CONCLUSIONS: Motivational messages were not useful to improve adherence to inhaled asthma medication compared with usual care.

Association of the CFTR gene with asthma and airway mucus hypersecretion.

INTRODUCTION: Asthma with airway mucus hypersecretion is an inadequately characterized variant of asthma. While several studies have reported that hypersecreting patients may carry genetic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, many of those studies have been questioned for their numerous limitations and contradictory results. OBJECTIVES: (1) To determine the presence of genetic variants of the CFTR gene in patients with asthma with and without airway mucus hypersecretion. (2) To identify the clinical, inflammatory and functional characteristics of the asthma phenotype with airway mucus hypersecretion. METHOD: Comparative multicentre cross-sectional descriptive study that included 100 patients with asthma (39 hypersecretors and 61 non-hypersecretors). Asthmatic hypersecretion was defined as the presence of cough productive of sputum on most days for at least 3 months in 2 successive years. The patients were tested for fractional exhaled nitric oxide, spirometry, induced sputum cell count, total immunoglobulin E (IgE), peripheral blood eosinophil count, C-reactive protein, blood fibrinogen and blood albumin and underwent a skin prick test. Asthma control and quality of life were assessed by the Asthma Control Test and Mini Asthma Quality of Life questionnaires, respectively. Blood DNA samples were collected from the patients and next-generation sequencing using a MiSeq sequencer and the Illumina platform was used for the CFTR gene analysis. RESULTS: Genetic differences were observed in the c.1680-870T>A polymorphism of the CFTR gene, significantly more evident in hypersecretors than in non-hypersecretors: 78.94% vs. 59.32% in the majority allele and 21.05% vs. 40.67% in the minority allele (p = 0.036). Clinically, asthma hypersecretors compared to non-hypersecretors were older (57.4 years vs. 49.4 years; p = 0.004); had greater asthma severity (58.9% vs. 23.7%; p = 0.005); experienced greater airway obstruction (FEV1/FVC% 64.3 vs. 69.5; p = 0.041); had poorer asthma control (60% vs. 29%; p = 0.021); had lower IgE levels (126.4 IU/mL vs. 407.6 IU/mL; p = 0.003); and were less likely to have a positive prick test (37.5% vs. 68.85%; p = 0.011). CONCLUSION: The results suggest that patients with asthma and with mucus hypersecretion (1) may have a different phenotype and disease mechanism produced by an intronic polymorphism in the CFTR gene (NM_000492.3:c.1680-870T>A), and (2) may have a poorer clinical outcome characterized by severe disease and poorer asthma control with a non-allergic inflammatory phenotype.

Bronchial reactivity indices are determinants of health-related quality of life in patients with stable asthma.

BACKGROUND: A very weak relationship has been reported between the health-related quality of life (HRQL) of patients with asthma and their degree of airway hyper-responsiveness (AHR), evaluated in terms of sensitivity. However, this relationship still has not been sufficiently explored for bronchial reactivity indices. OBJECTIVES: To analyse the relationship between bronchial reactivity and sensitivity with the HRQL of patients with stable asthma, identifying the functional parameters that determine HRQL. METHODS: In 103 consecutive patients with stable asthma, HRQL was evaluated using the Asthma Quality of Life Questionnaire (AQLQ). Patients underwent spirometry and non-specific bronchial provocation with methacoline. Sensitivity (PD(20)) and reactivity (dose-response slope (DRS), continuous index of responsiveness (CIR) and bronchial reactivity index (BRI)) of the dose-response curve were analysed. RESULTS: BRI presented significant differences with different degrees of asthma severity. Although patients with AHR showed poorer quality of life than patients without AHR, the AQLQ total score was not related to PD(20) but rather to DRS (r=-0.784), CIR (r=-0.712) and BRI (r=-0.776). The indices of bronchial reactivity reached a negative correlation with all the domains of the AQLQ. In a multiple linear regression model, BRI, DRS, FIV(1) (forced inspiratory volume in 1 s) and VCIN (inspiratory vital capacity) were identified as independent predictors of the AQLQ total score (r(2)=0.742, p<0.001). CONCLUSION: In patients with stable asthma, bronchial reactivity is associated with HRQL. This could justify incorporating bronchial reactivity indices in bronchial provocation analyses.

A Proposed Approach to Chronic Airway Disease (CAD) Using Therapeutic Goals and Treatable Traits: A Look to the Future.

Chronic airflow obstruction affects a wide range of airway diseases, the most frequent of which are asthma, COPD, and bronchiectasis; they are clearly identifiable in their extremes, but quite frequently overlap in some of their pathophysiological and clinical characteristics. This has generated the description of new mixed or overlapping disease phenotypes with no clear biological grounds. In this special article, a group of experts provides their perspective and proposes approaching the treatment of chronic airway disease (CAD) through the identification of a series of therapeutic goals (TG) linked to treatable traits (TT) - understood as clinical, physiological, or biological characteristics that are quantifiable using biomarkers. This therapeutic approach needs validating in a clinical trial with the strategy of identification of TG and treatment according to TT for each patient independently of their prior diagnosis.

Pneumonic and non-pneumonic exacerbations in bronchiectasis: Clinical and microbiological differences.

OBJECTIVES: Despite the clinical relevance of exacerbations in bronchiectasis (BE), little is known about the microbiology and outcomes of pneumonic (CAP) vs. non-pneumonic (NOCAP) exacerbations. METHODS: This study compares clinical and microbiological characteristics of CAP vs. NOCAP in adults with BE. We performed a multicenter prospective observational study of consecutive cases of NOCAP and CAP from four Spanish hospitals (2011-2015). RESULTS: We recruited 144 patients, 47 of them CAP (33%) cases. CAP patients were older, with a larger representation of males, more comorbidities, higher arterial hypertension and COPD but less chronic bronchial infection and previous history of exacerbations. Clinical presentation was similar, excepting creatinine, C-reactive protein (C-RP), glucose and leukocytes which were higher in CAP. C-RP of 8.38 mg/dL showed a significant predictive discrimination for CAP. Streptococcus pneumoniae and Pseudomonas aeruginosa were the first causes of CAP and NOCAP, respectively. The rate of microbiological concordance with previous chronic bronchial infection was variable. Main clinical outcomes (mortality, length of stay, etc.) were similar in the two groups. Chronic bronchial infection and history of frequent exacerbations (≥ 2/year) were associated with a reduced risk of CAP. CONCLUSIONS: CAP and NOCAP in BE had similar clinical presentation with the exception of fever, leukocytosis, and C-RP. Microbiology also differed. A cut-off value of C-RP ≥ 8.38 mg/dL can predict CAP in bronchiectasis.