The Impact of Thermal Water in Asthma and COPD: A Systematic Review According to the PRISMA Statement.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are global health challenges leading to substantial morbidity and mortality. While existing guidelines emphasize evidence-based treatments, the potential therapeutic role of thermal water (TW) inhalation remains under-investigated. METHODS: This systematic review followed PRISMA-P guidelines and sought to evaluate the impact of TW in asthma and COPD. A thorough literature search, performed up to May 2023, encompassed in vitro, in vivo, randomized controlled trial (RCT), non-RCT, and observational studies. RESULTS: The review included 12 studies reporting different findings. In vitro studies suggested TW could enhance antioxidant capacity and cell proliferation. In a murine model of non-atopic asthma, TW inhalation reduced airway hyperresponsiveness and inflammation. RCTs in COPD patients indicated mixed effects, including improved quality of life, reduced airway oxidant stress, and enhanced exercise tolerance. Asthma patients exposed to water aerosols exhibited improved lung function and reduced airway inflammation. Non-RCTs showed improved lung function and antioxidant activity after TW therapy. Additionally, observational studies reported enhanced lung function and reduced airway inflammation. CONCLUSION: The current evidence suggests potential benefits of TW therapy in asthma and COPD. However, limited high-quality RCTs and concerns regarding occupational TW exposure necessitate further investigation. While TW therapy offers a non-invasive treatment, its therapeutic potential still needs definitive demonstration. Future research should therefore prioritize well-designed RCTs to thoroughly establish the efficacy and safety of TW as a potential therapeutic intervention for asthma and COPD.

Pulmonary nodules and primary Sjögren syndrome: a case report.

Primary Sjögren syndrome (pSS) is a systemic autoimmune disorder that principally affects the exocrine glands but can also affect systemic or extra-glandular sites. Approximately 65-80% of patients with Sjogren's demonstrate pulmonary involvement at the CT scan and pulmonary nodules (PNs) can be encountered as a common finding. We present the case of a 49-year-old woman admitted to the emergency department for chest pain and fever. The patient was diagnosed with pSS fourteen years prior and had never taken therapy or followed regular check-ups. At the HRTC were found PNs that were studied trough a CT-PET and a needle biopsy via CT guidance, which showed diffuse large B cell lymphoma. This case report underlies the importance of check-ups and the need for a multidisciplinary approach in the care of Sjögren's syndrome patients.

Disentangling the interactions between nasopharyngeal and gut microbiome and their involvement in the modulation of COVID-19 infection.

The human organism is inhabited by trillions of microorganisms, known as microbiota, which are considered to exploit a pivotal role in the regulation of host health and immunity. Recent investigations have suggested a relationship between the composition of the human microbiota and COVID-19 infection, highlighting a possible role of bacterial communities in the modulation of the disease severity. In this study, we performed a shotgun metagenomics analysis to explore and compare the nasopharyngeal microbiota of 38 hospitalized Italian patients with and without COVID-19 infection during the third and fourth pandemic waves. In detail, the metagenomic analysis combined with specific correlation analyses suggested a positive association of several microbial species, such as S. parasanguinis and P. melaninogenica, with the severity of COVID-19 infection. Furthermore, the comparison of the microbiota composition between the nasopharyngeal and their respective fecal samples highlighted an association between these different compartments represented by a sharing of several bacterial species. Additionally, lipidomic and deep-shotgun functional analyses of the fecal samples suggested a metabolic impact of the microbiome on the host's immune response, indicating the presence of key metabolic compounds in COVID-19 patients, such as lipid oxidation end products, potentially related to the inflammatory state. Conversely, the patients without COVID-19 displayed enzymatic patterns associated with the biosynthesis and degradation of specific compounds like lysine (synthesis) and phenylalanine (degradation) that could positively impact disease severity and contribute to modulating COVID-19 infection. IMPORTANCE The human microbiota is reported to play a major role in the regulation of host health and immunity, suggesting a possible impact on the severity of COVID-19 disease. This preliminary study investigated the possible correlation between nasopharyngeal microbiota and COVID-19 infection. In detail, the analysis of the nasopharyngeal microbiota of hospitalized Italian patients with and without COVID-19 infection suggested a positive association of several microbial species with the severity of the disease and highlighted a sharing of several bacteria species with the respective fecal samples. Moreover, the metabolic analyses suggested a possible impact of the microbiome on the host's immune response and the disease severity.

Detection of Small Airway Dysfunction in Asthmatic Patients by Spirometry and Impulse Oscillometry System.

BACKGROUND: There is no gold standard in diagnosing SAD. Indicators of SAD are considered: (a) a value <65% of predicted values of two of three measures, FEF25-75, FEF50 e FEF75 (FEF+); (b) a value of FEV3/FEV6 < LLN (FEV3/FEV6+); (c) an IOS value of R5-R20 >0.07 kPa·s·L-1 (R5-R20+). AIM AND OBJECTIVES: The aim of the study was to ascertain, in asthmatic patients, whether spirometry and IOS indicators agree in detecting SAD. We also assessed the relationship between spirometry and IOS indicators and clinical features of asthma. METHODS: We prospectively recruited adult asthmatic patients. Anthropometric and clinical characteristics were recorded. All patients performed spirometry and IOS tests. RESULTS: We enrolled 301 asthmatic patients (179 females; mean age 50 ± 16 years) with normal to moderately severe degree of airway obstruction; 91% were non-smokers, 74% were atopic, 28% had an exacerbation in the previous year, and 18% had a poor asthma control by ACT. SAD was diagnosed in 62% of patients through FEF+, in 40% through FEV3/FEV6+ and in 41% through R5-R20+. κ values were 0.49 between FEF+ and FEV3/FEV6+, 0.20 between FEF+ and R5-R20+, 0.07 between FEV3/FEV6+ and R5-R20+. R5-R20+ but not FEF+ and FEV3/FEV6+ was significantly associated with ACT score (p < 0.05). CONCLUSIONS: Our study shows that in mild to moderately severe asthmatic patients, spirometry and IOS indicators are complementary in diagnosing SAD. Additionally, IOS indicator, but not spirometry ones, was related to asthma control.

Experimental drugs in clinical trials for COPD: artificial intelligence via machine learning approach to predict the successful advance from early-stage development to approval.

INTRODUCTION: Therapeutic advances in drug therapy of chronic obstructive pulmonary disease (COPD) really effective in suppressing the pathological processes underlying the disease deterioration are still needed. Artificial Intelligence (AI) via Machine Learning (ML) may represent an effective tool to predict clinical development of investigational agents. AREAL COVERED: Experimental drugs in Phase I and II development for COPD from early 2014 to late 2022 were identified in the ClinicalTrials.gov database. Different ML models, trained from prior knowledge on clinical trial success, were used to predict the probability that experimental drugs will successfully advance toward approval in COPD, according to Bayesian inference as follows: ≤25% low probability, >25% and ≤50% moderate probability, >50% and ≤75% high probability, and >75% very high probability. EXPERT OPINION: The Artificial Neural Network and Random Forest ML models indicated that, among the current experimental drugs in clinical trials for COPD, only the bifunctional muscarinic antagonist - ß2-adrenoceptor agonists (MABA) navafenterol and batefenterol, the inhaled corticosteroid (ICS)/MABA fluticasone furoate/batefenterol, and the bifunctional phosphodiesterase (PDE) 3/4 inhibitor ensifentrine resulted to have a moderate to very high probability of being approved in the next future, however not before 2025.

Nebulizers effectiveness on pulmonary delivery of alpha-1 antitrypsin.

The nebulization of alpha-1 antitrypsin (AAT) for its administration to the lung could be an interesting alternative to parenteral infusion for patients suffering from AAT genetic deficiency (AATD). In the case of protein therapeutics, the effect of the nebulization mode and rate on protein conformation and activity must be carefully considered. In this paper two types of nebulizers, i.e., a jet and a mesh vibrating system, were used to nebulize a commercial preparation of AAT for infusion and compared. The aerosolization performance, in terms of mass distribution, respirable fraction, and drug delivery efficiency, as well as the activity and aggregation state of AAT upon in vitro nebulization were investigated. The two nebulizers demonstrated equivalent aerosolization performances, but the mesh nebulizer provided a higher efficiency in the delivery of the dose. The activity of the protein was acceptably preserved by both nebulizers and no aggregation or changes in its conformation were identified. This suggests that nebulization of AAT represents a suitable administration strategy ready to be translated to the clinical practice for delivering the protein directly to the lungs in AATD patients, either as a support therapy to parenteral administration or for subjects with a precocious diagnosis, to prevent the onset of pulmonary symptoms.

Palliative care and end of life management in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease with an unknown etiology that causes deterioration of the structure of the lung parenchyma, resulting in a severe and progressive decline in respiratory function and early mortality. IPF is essentially an incurable disease, with a mean overall survival of 5 years in approximately 20% of patients without treatment. The combination of a poor prognosis, uncertainty about the disease's progression, and the severity of symptoms has a significant impact on the quality of life of patients and their families. New antifibrotic drugs have been shown to slow disease progression, but their impact on health-related quality of life (HRQoL) has to be proven yet. To date, studies have shown that palliative care can improve symptom management, HRQoL, and end-of-life care (EoL) in patients with IPF, reducing critical events, hospitalization, and health costs. As a result, it is essential for proper health planning and patient management to establish palliative care early and in conjunction with other therapies, beginning with the initial diagnosis of the disease.

The BNT162b2 mRNA COVID-19 Vaccine Increases the Contractile Sensitivity to Histamine and Parasympathetic Activation in a Human Ex Vivo Model of Severe Eosinophilic Asthma.

The BNT162b2 COVID-19 vaccine is composed of lipid-nanoparticles (LNP) containing the mRNA that encodes for SARS-CoV-2 spike glycoprotein. Bronchospasm has been reported as an early reaction after COVID-19 mRNA vaccines in asthmatic patients. The aim of this study was to investigate the acute impact of BNT162b2 in a human ex vivo model of severe eosinophilic asthma. Passively sensitized human isolated bronchi were challenged with the platelet-activating factor to reproduce ex vivo the hyperresponsiveness of airways of patients suffering from severe eosinophilic asthma. BNT162b2 was tested on the contractile sensitivity to histamine and parasympathetic activation via electrical field stimulation (EFS); some experiments were performed after mRNA denaturation. BNT162b2 increased the resting tone (+11.82 ± 2.27%) and response to histamine in partially contracted tissue (+42.97 ± 9.64%) vs. the control (p < 0.001); it also shifted the concentration-response curve to histamine leftward (0.76 ± 0.09 logarithm) and enhanced the response to EFS (+28.46 ± 4.40%) vs. the control. Denaturation did not significantly modify (p > 0.05) the effect of BNT162b2. BNT162b2 increases the contractile sensitivity to histamine and parasympathetic activation in hyperresponsive airways, a detrimental effect not related to the active component but to some excipient. A possible candidate for the bronchospasm elicited by BNT162b2 could be the polyethylene glycol/macrogol used to produce LNP.

Ventilatory associated barotrauma in COVID-19 patients: A multicenter observational case control study (COVI-MIX-study).

BACKGROUND: The risk of barotrauma associated with different types of ventilatory support is unclear in COVID-19 patients. The primary aim of this study was to evaluate the effect of the different respiratory support strategies on barotrauma occurrence; we also sought to determine the frequency of barotrauma and the clinical characteristics of the patients who experienced this complication. METHODS: This multicentre retrospective case-control study from 1 March 2020 to 28 February 2021 included COVID-19 patients who experienced barotrauma during hospital stay. They were matched with controls in a 1:1 ratio for the same admission period in the same ward of treatment. Univariable and multivariable logistic regression (OR) were performed to explore which factors were associated with barotrauma and in-hospital death. RESULTS: We included 200 cases and 200 controls. Invasive mechanical ventilation was used in 39.3% of patients in the barotrauma group, and in 20.1% of controls (p<0.001). Receiving non-invasive ventilation (C-PAP/PSV) instead of conventional oxygen therapy (COT) increased the risk of barotrauma (OR 5.04, 95% CI 2.30 - 11.08, p<0.001), similarly for invasive mechanical ventilation (OR 6.24, 95% CI 2.86-13.60, p<0.001). High Flow Nasal Oxygen (HFNO), compared with COT, did not significantly increase the risk of barotrauma. Barotrauma frequency occurred in 1.00% [95% CI 0.88-1.16] of patients; these were older (p=0.022) and more frequently immunosuppressed (p=0.013). Barotrauma was shown to be an independent risk for death (OR 5.32, 95% CI 2.82-10.03, p<0.001). CONCLUSIONS: C-PAP/PSV compared with COT or HFNO increased the risk of barotrauma; otherwise HFNO did not. Barotrauma was recorded in 1.00% of patients, affecting mainly patients with more severe COVID-19 disease. Barotrauma was independently associated with mortality. TRIAL REGISTRATION: this case-control study was prospectively registered in clinicaltrial.gov as NCT04897152 (on 21 May 2021).

The interplay between diabetes mellitus and chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) and diabetes mellitus (DM) are common and chronic disorders. COPD is characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities and it is considered currently the fourth leading cause of death worldwide. DM is a systemic disease characterized by a chronic hyperglycemia associated with inflammation and oxidative stress. The relationship between the two conditions is not completely understood and conflicting results are reported in the literature. Many studies have investigated the mechanisms through with the respiratory disease is associated with an increased risk of metabolic condition or whether the incidence risk of COPD in individuals affected by DM is higher. The link between the two chronic conditions has relevant implications in the management of patients affected by the both of them. Respiratory patients should be screened for diabetes mellitus as a frequent comorbidity of lung disease since therapeutic options should be assessed about risk-to-benefit ratios associated with the indication for the steroid use. Furthermore, the role of hyperglycemia on pulmonary function (e.g. infection or inflammatory processes) should be evaluated in DM. Finally, in presence of both diseases potential treatment interactions should be considered. In this overview we explored the common aspects of both clinical chronic illnesses and investigated the interplay between the two conditions.

An Impairment in Resting and Exertional Breathing Pattern May Occur in Long-COVID Patients with Normal Spirometry and Unexplained Dyspnoea.

Background: Long-term sequelae, called Long-COVID (LC), may occur after SARS-CoV-2 infection, with unexplained dyspnoea as the most common symptom. The breathing pattern (BP) analysis, by means of the ratio of the inspiratory time (TI) during the tidal volume (VT) to the total breath duration (TI/TTOT) and by the VT/TI ratio, could further elucidate the underlying mechanisms of the unexplained dyspnoea in LC patients. Therefore, we analysed TI/TTOT and VT/TI at rest and during maximal exercise in LC patients with unexplained dyspnoea, compared to a control group. Methods: In this cross-sectional study, we enrolled LC patients with normal spirometry, who were required to perform a cardio-pulmonary exercise test (CPET) for unexplained dyspnoea, lasting at least 3 months after SARS-CoV-2 infection. As a control group, we recruited healthy age and sex-matched subjects (HS). All subjects performed spirometry and CPET, according to standardized procedures. Results: We found that 42 LC patients (23 females) had lower maximal exercise capacity, both in terms of maximal O2 uptake (VO2peak) and workload, compared to 40 HS (22 females) (p < 0.05). LC patients also showed significantly higher values of TI/TTOT at rest and at peak, and lower values in VT/TI at peak (p < 0.05). In LC patients, values of TI/TTOT at peak were significantly related to ∆PETCO2, i.e., the end-tidal pressure of CO2 at peak minus the one at rest (p < 0.05). When LC patients were categorized by the TI/TTOT 0.38 cut-off value, patients with TI/TTOT > 0.38 showed lower values in VO2peak and maximal workload, and greater values in the ventilation/CO2 linear relationship slope than patients with TI/TTOT ≤ 0.38 (p < 0.05). Conclusions: Our findings show that LC patients with unexplained dyspnoea have resting and exertional BP more prone to diaphragmatic fatigue, and less effective than controls. Pulmonary rehabilitation might be useful to revert this unpleasant condition.

The Impact of Corticosteroids on Human Airway Smooth Muscle Contractility and Airway Hyperresponsiveness: A Systematic Review.

Classically, the effects elicited by corticosteroids (CS) are mediated by the binding and activation of cytosolic glucocorticoid receptors (GR). However, several of the non-genomic effects of CS seem to be mediated by putative non-classic membrane receptors characterized by pharmacological properties that are different from those of classic cytosolic GR. Since pre-clinical findings suggest that inhaled CS (ICS) may also regulate the bronchial contractile tone via putative CS membrane-associate receptors, the aim of this review was to systematically report and discuss the impact of CS on human airway smooth muscle (ASM) contractility and airway hyperresponsiveness (AHR). Current evidence indicates that CS have significant genomic/non-genomic beneficial effects on human ASM contractility and AHR, regardless of their anti-inflammatory effects. CS are effective in reducing either the expression, synthesis or activity of α-actin, CD38, inositol phosphate, myosin light chain kinase, and ras homolog family member A in response to several pro-contractile stimuli; overall these effects are mediated by the genomic action of CS. Moreover, CS elicited a strong bronchorelaxant effect via the rapid activation of the Gsα-cyclic-adenosine-monophosphate-protein-kinase-A pathway in hyperresponsive airways. The possibility of modulating the dose of the ICS in a triple ICS/long-acting ß2-adrenoceptor agonist/long-acting muscarinic antagonist fixed-dose combination supports the use of a Triple MAintenance and Reliever Therapy (TriMART) in those asthmatic patients at Step 3-5 who may benefit from a sustained bronchodilation and have been suffering from an increased parasympathetic tone.

Impulse Oscillometry, Small Airways Disease, and Extra-Fine Formulations in Asthma and Chronic Obstructive Pulmonary Disease: Windows for New Opportunities.

In recent years, the perspective of management of respiratory disease has been gradually changing in light of the increasing evidence of small airways as the major site of airflow obstruction contributing to the development of both COPD and asthma already in early stages of disease. First and foremost, the evidence is redefining disease severity, identifying small airways disease phenotypes and early signs of disease, and revising prevalence and overall epidemiological data as well. Much effort has been put toward the instrumental assessment of small airways' involvement and early detection. Several clinical trials have evaluated the advantage of extra-fine formulations which can best target the small airways in uncontrolled asthma and severe COPD. Here, we briefly present a practical overview of the role of the small airways in disease, the most appropriate diagnostic methods for quantifying their impairment, and provide some insight into the costs of respiratory management in Italy, especially in sub-optimally controlled disease.

Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma.

Inhaled corticosteroids (ICS) remain the mainstay of asthma treatment, along with bronchodilators serving as control agents in combination with ICS or reliever therapy. Although current pharmacological treatments improve symptom control, health status, and the frequency and severity of exacerbations, they do not really change the natural course of asthma, including disease remission. Considering the highly heterogeneous nature of asthma, there is a strong need for innovative medications that selectively target components of the inflammatory cascade. The aim of this review was to systematically assess current investigational agents in Phase I and II randomised controlled trials (RCTs) over the last five years. Sixteen classes of novel therapeutic options were identified from 19 RCTs. Drugs belonging to different classes, such as the anti-interleukin (IL)-4Rα inhibitors, anti-IL-5 monoclonal antibodies (mAbs), anti-IL-17A mAbs, anti-thymic stromal lymphopoietin (TSLP) mAbs, epithelial sodium channel (ENaC) inhibitors, bifunctional M3 receptor muscarinic antagonists/ß2-adrenoceptor agonists (MABAs), and anti-Fel d 1 mAbs, were found to be effective in the treatment of asthma, with lung function being the main assessed outcome across the RCTs. Several novel investigational molecules, particularly biologics, seem promising as future disease-modifying agents; nevertheless, further larger studies are required to confirm positive results from Phase I and II RCTs.

Impact of Sex on Proper Use of Inhaler Devices in Asthma and COPD: A Systematic Review and Meta-Analysis.

Despite females being more often affected by asthma than males and the prevalence of COPD rising in females, conflicting evidence exists as to whether sex may modulate the correct inhaler technique. The aim of this study was to assess the impact of sex on the proper use of inhaler devices in asthma and COPD. A pairwise meta-analysis was performed on studies enrolling adult males and females with asthma or COPD and reporting data of patients making at least one error by inhaler device type (DPI, MDI, and SMI). The data of 6,571 patients with asthma or COPD were extracted from 12 studies. A moderate quality of evidence (GRADE +++) indicated that sex may influence the correct use of inhaler device in both asthma and COPD. The critical error rate was higher in females with asthma (OR 1.31, 95%CI 1.14−1.50) and COPD (OR 1.80, 95%CI 1.22−2.67) using DPI vs. males (p < 0.01). In addition, the use of SMI in COPD was associated with a greater rate of critical errors in females vs. males (OR 5.36, 95%CI 1.48−19.32; p < 0.05). No significant difference resulted for MDI. In conclusion, choosing the right inhaler device in agreement with sex may optimize the pharmacological treatment of asthma and COPD.

Distribution of the Clinical Manifestations of Alpha 1 Antitrypsin Deficiency in Respiratory Outpatients from an Area of Northern Italy.

BACKGROUND: Alpha 1 antitrypsin deficiency (AATD) is an autosomal codominant genetic condition that affects Caucasians of the European population due to the presence of a deficient allele of the SERPINA1 gene. A frequency of about 1/5,000 individuals has been estimated in Italy. OBJECTIVES: The aim of the study was to evaluate the distribution of the clinical manifestations of severe and intermediate genetic AATD in the geographic area around Parma in Northern Italy. METHOD: 238 subjects were submitted to molecular analysis of the SERPINA1 gene, and data on anthropometric variables, smoking habits, number of packs per year, AAT serum concentration, and clinical manifestations were recorded and presented as mean ± SD or median values (1st quartile; 3rd quartile). RESULTS: The results show a distribution of genetic AATD of 4.1% of the screened population in the area encompassing the city of Parma. PI*MS and PI*MZ were the most common genotypes at 40.9% and 28.2% of the population with genetic AATD, and asthma and emphysema were the most represented clinical manifestations. CONCLUSION: Our study allowed to increase the knowledge of the distribution of genetic AATD in Northern Italy providing information regarding frequencies of genotypes and clinical manifestations of the disorder.

Small Airways: Not Just Air Ducts - Pathophysiological Aspects and Clinical Implications.

The airways smaller than 2 mm diameter are named small airways. They are essential for the transport and exchange of oxygen and carbon dioxide and at the same time play a relevant role in pulmonary mechanics, contributing to the subdivision of lung volumes. Measurement of small airway function is, therefore, crucial in patients with respiratory disease. This overview focuses on the physiological aspects of the small airways, considered as air ducts as well as determinants of pulmonary mechanics, the most common tools for evaluating their function and treatment implications.

Stem Cell-Based Regenerative Therapy and Derived Products in COPD: A Systematic Review and Meta-Analysis.

COPD is an incurable disorder, characterized by a progressive alveolar tissue destruction and defective mechanisms of repair and defense leading to emphysema. Currently, treatment for COPD is exclusively symptomatic; therefore, stem cell-based therapies represent a promising therapeutic approach to regenerate damaged structures of the respiratory system and restore lung function. The aim of this study was to provide a quantitative synthesis of the efficacy profile of stem cell-based regenerative therapies and derived products in COPD patients. A systematic review and meta-analysis was performed according to PRISMA-P. Data from 371 COPD patients were extracted from 11 studies. Active treatments elicited a strong tendency towards significance in FEV1 improvement (+71 mL 95% CI -2−145; p = 0.056) and significantly increased 6MWT (52 m 95% CI 18−87; p < 0.05) vs. baseline or control. Active treatments did not reduce the risk of hospitalization due to acute exacerbations (RR 0.77 95% CI 0.40−1.49; p > 0.05). This study suggests that stem cell-based regenerative therapies and derived products may be effective to treat COPD patients, but the current evidence comes from small clinical trials. Large and well-designed randomized controlled trials are needed to really quantify the beneficial impact of stem cell-based regenerative therapy and derived products in COPD.

Follicular helper T cell signature of replicative exhaustion, apoptosis, and senescence in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent, and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD-1 levels. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID.

Potential Drawbacks of ICS/LABA/LAMA Triple Fixed-Dose Combination Therapy in the Treatment of Asthma: A Quantitative Synthesis of Safety Profile.

Introduction: Inhaled corticosteroid/long-acting ß2-adrenoceptor agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) fixed-dose combination (FDC) is currently recommended as controller option at asthma Step 4 and as preferred treatment at asthma Step 5, but no research investigated the potential drawbacks of this therapeutic option in a large asthmatic population. Thus, the aim of this study was to quantify the potential drawbacks of triple FDC therapy in asthma. Methods: A pairwise meta-analysis was performed according to PRISMA-P guidelines to assess the risk of overall serious adverse events (SAEs), cardiovascular SAEs, and pneumonia reported as SAE in asthmatic patients treated with ICS/LABA/LAMA FDC vs ICS/LABA FDC. A pooled analysis was performed to calculate the frequency of SAEs. Results: Data from 7204 asthmatic patients were extracted from the CAPTAIN, IRIDIUM, TRIMARAN, and TRIGGER studies. Triple FDC vs ICS/LABA FDC did not increase the risk of total SAEs (RR 0.99 95% CI 0.83-1.18) and cardiac SAEs (RR 0.74 95% CI 0.39-1.40), whereas the sensitivity analysis performed to resolve heterogeneity resulted in increased risk of vascular SAEs (RR 3.23 95% CI 1.05-9.90, P<0.05). The level of ICS dose did not modulate the risk of pneumonia, in any case pneumonia was the most frequent SAE (0.57%). These results were not affected by significant risk of bias. Conclusion: Triple FDC is a safe pharmacological therapy in severe asthmatic patients; it is characterized by a favourable safety profile and few potential drawbacks, namely, the increased risk of vascular SAEs, that certainly are worthy of future investigations.