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Article: The polyhedric reality of the interaction between COVID-19, asthma and inhaled corticosteroids.

Gonzalez-Barcala, Francisco-Javier / Nieto-Fontarigo, Juan-Jose / Mendez-Brea, Paula / Salgado, Francisco-Javier

2022 Volume 8, Issue 2

Abstract: The impact of ICS on the prognosis for #COVID19 in #asthma patients requires a thorough evaluation of a range of factors that interact in this process, in order to draw solid conclusions, since at the present time the debate ... ...

Abstract	The impact of ICS on the prognosis for #COVID19 in #asthma patients requires a thorough evaluation of a range of factors that interact in this process, in order to draw solid conclusions, since at the present time the debate continues
Language	English
Publishing date	2022-05-30
Publishing country	England
Document type	Editorial
ZDB-ID	2827830-6
ISSN	2312-0541
ISSN	2312-0541
DOI	10.1183/23120541.00179-2022
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Article ; Online: The polyhedric reality of the interaction between COVID-19, asthma and inhaled corticosteroids

Francisco-Javier Gonzalez-Barcala / Juan-Jose Nieto-Fontarigo / Paula Mendez-Brea / Francisco-Javier Salgado

ERJ Open Research, Vol 8, Iss

2022 Volume 2

Keywords	Medicine ; R
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	European Respiratory Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Prognostic Usefulness of Basic Analytical Data in Chronic Obstructive Pulmonary Disease Exacerbation.

Martínez-Gestoso, Sandra / García-Sanz, María-Teresa / Carreira, José-Martín / Nieto-Fontarigo, Juan-José / Calvo-Álvarez, Uxío / Doval-Oubiña, Liliana / Camba-Matos, Sandra / Peleteiro-Pedraza, Lorena / Roibás-Veiga, Iria / González-Barcala, Francisco-Javier

Open respiratory archives

2023 Volume 5, Issue 4, Page(s) 100271

Abstract: Introduction: COPD causes high morbidity and mortality and high health costs. Thus, identifying and analyzing the distinctive and treatable traits seems useful to optimize the management of AEPOC patients. While various biomarkers have been researched, ... ...

Abstract	Introduction: COPD causes high morbidity and mortality and high health costs. Thus, identifying and analyzing the distinctive and treatable traits seems useful to optimize the management of AEPOC patients. While various biomarkers have been researched, no solid data for systematic use have been made available. Aim: Assessing the short-term prognostic usefulness of clinical and analytical parameters available in routine clinical practice in COPD exacerbations. Material and methods: Multicenter prospective observational study conducted between 2016 and 2018. Patients admitted for COPD exacerbation who agreed to participate and signed an informed consent form were included. Prolonged stay, in-hospital mortality or early readmission was considered an unfavorable progression. 30-Day mortality was also analyzed. Results: 615 patients were included. Mean age was 73.9 years (SD 10.6); 86.2% were male. Progression of 357 patients (58%) was considered unfavorable. Mortality at 1 month from discharge was 6.7%. The multivariate analysis shows a relationship between the CRP/Albumin ratio and unfavorable progression (OR 1.008, 95% CI 1.00; 1.01), as well as increased risk of death at 1 month from discharge with elevated urea (OR 1.01, 95% CI 1.005; 1.02) and troponin T (OR 2.21, 95% CI 1.06; 4.62). Conclusion: Elevated CRP/Albumin, urea and TnT are prognostic indicators of poor short-term outcome in patients admitted for COPD exacerbation. Cardiovascular comorbidity and systemic inflammation could explain these findings.
Language	English
Publishing date	2023-09-20
Publishing country	Spain
Document type	Journal Article
ISSN	2659-6636
ISSN (online)	2659-6636
DOI	10.1016/j.opresp.2023.100271
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Article: C57Bl/6N mice have an attenuated lung inflammatory response to dsRNA compared to C57Bl/6J and BALB/c mice.

Malm Tillgren, Sofia / Nieto-Fontarigo, Juan José / Cerps, Samuel / Ramu, Sangeetha / Menzel, Mandy / Mahmutovic Persson, Irma / Meissner, Anja / Akbarshahi, Hamid / Uller, Lena

Journal of inflammation (London, England)

2023 Volume 20, Issue 1, Page(s) 6

Abstract: Background: Lower respiratory infections caused by ssRNA viruses are a major health burden globally. Translational mouse models are a valuable tool for medical research, including research on respiratory viral infections. In in vivo mouse models, ... ...

Abstract	Background: Lower respiratory infections caused by ssRNA viruses are a major health burden globally. Translational mouse models are a valuable tool for medical research, including research on respiratory viral infections. In in vivo mouse models, synthetic dsRNA can be used as a surrogate for ssRNA virus replication. However, studies investigating how genetic background of mice impacts the murine lung inflammatory response to dsRNA is lacking. Hence, we have compared lung immunological responses of BALB/c, C57Bl/6N and C57Bl/6J mice to synthetic dsRNA. Methods: dsRNA was administered intranasally to BALB/c, C57Bl/6N and C57Bl/6J mice once/day for three consecutive days. Lactate dehydrogenase (LDH) activity, inflammatory cells, and total protein concentration were analyzed in bronchoalveolar lavage fluid (BALF). Pattern recognition receptors levels (TLR3, MDA5 and RIG-I) were measured in lung homogenates using RT-qPCR and western blot. Gene expression of IFN-β, TNF-α, IL-1β and CXCL1 was assessed in lung homogenates by RT-qPCR. ELISA was used to analyze protein concentrations of CXCL1 and IL-1β in BALF and lung homogenates. Results: BALB/c and C57Bl/6J mice showed infiltration of neutrophils to the lung, and an increase in total protein concentration and LDH activity in response to dsRNA administration. Only modest increases in these parameters were observed for C57Bl/6N mice. Similarly, dsRNA administration evoked an upregulation of MDA5 and RIG-I gene and protein expression in BALB/c and C57Bl/6J, but not C57Bl/6N, mice. Further, dsRNA provoked an increase in gene expression of TNF-α in BALB/c and C57Bl/6J mice, IL-1β only in C57Bl/6N mice and CXCL1 exclusively in BALB/c mice. BALF levels of CXCL1 and IL-1β were increased in BALB/c and C57Bl/6J mice in response to dsRNA, whereas the response of C57Bl/6N was blunt. Overall, inter-strain comparisons of the lung reactivity to dsRNA revealed that BALB/c, followed by C57Bl/6J, had the most pronounced respiratory inflammatory responses, while the responses of C57Bl/6N mice were attenuated. Conclusions: We report clear differences of the lung innate inflammatory response to dsRNA between BALB/c, C57Bl/6J and C57Bl/6N mice. Of particular note, the highlighted differences in the inflammatory response of C57Bl/6J and C57Bl/6N substrains underscore the value of strain selection in mouse models of respiratory viral infections.
Language	English
Publishing date	2023-02-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2164385-4
ISSN	1476-9255
ISSN	1476-9255
DOI	10.1186/s12950-023-00331-4
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Article ; Online: Airway hyperresponsiveness reflects corticosteroid-sensitive mast cell involvement across asthma phenotypes.

Hvidtfeldt, Morten / Sverrild, Asger / Pulga, Alexis / Frøssing, Laurits / Silberbrandt, Alexander / Hostrup, Morten / Thomassen, Martin / Sanden, Caroline / Clausson, Carl Magnus / Siddhuraj, Premkumar / Bornesund, Daisy / Nieto-Fontarigo, Juan Jose / Uller, Lena / Erjefält, Jonas / Porsbjerg, Celeste

The Journal of allergy and clinical immunology

2023 Volume 152, Issue 1, Page(s) 107–116.e4

Abstract: Background: Airway hyperresponsiveness is a hallmark of asthma across asthma phenotypes. Airway hyperresponsiveness to mannitol specifically relates to mast cell infiltration of the airways, suggesting inhaled corticosteroids to be effective in reducing ...

Abstract	Background: Airway hyperresponsiveness is a hallmark of asthma across asthma phenotypes. Airway hyperresponsiveness to mannitol specifically relates to mast cell infiltration of the airways, suggesting inhaled corticosteroids to be effective in reducing the response to mannitol, despite low levels of type 2 inflammation. Objective: We sought to investigate the relationship between airway hyperresponsiveness and infiltrating mast cells, and the response to inhaled corticosteroid treatment. Methods: In 50 corticosteroid-free patients with airway hyperresponsiveness to mannitol, mucosal cryobiopsies were obtained before and after 6 weeks of daily treatment with 1600 μg of budesonide. Patients were stratified according to baseline fractional exhaled nitric oxide (Feno) with a cutoff of 25 parts per billion. Results: Airway hyperresponsiveness was comparable at baseline and improved equally with treatment in both patients with Feno-high and Feno-low asthma: doubling dose, 3.98 (95% CI, 2.49-6.38; P < .001) and 3.85 (95% CI, 2.51-5.91; P < .001), respectively. However, phenotypes and distribution of mast cells differed between the 2 groups. In patients with Feno-high asthma, airway hyperresponsiveness correlated with the density of chymase-high mast cells infiltrating the epithelial layer (ρ, -0.42; P = .04), and in those with Feno-low asthma, it correlated with the density in the airway smooth muscle (ρ, -0.51; P = .02). The improvement in airway hyperresponsiveness after inhaled corticosteroid treatment correlated with a reduction in mast cells, as well as in airway thymic stromal lymphopoietin and IL-33. Conclusions: Airway hyperresponsiveness to mannitol is related to mast cell infiltration across asthma phenotypes, correlating with epithelial mast cells in patients with Feno-high asthma and with airway smooth muscle mast cells in patients with Feno-low asthma. Treatment with inhaled corticosteroids was effective in reducing airway hyperresponsiveness in both groups.
MeSH term(s)	Humans ; Mast Cells/metabolism ; Nitric Oxide/metabolism ; Asthma/drug therapy ; Asthma/metabolism ; Adrenal Cortex Hormones/therapeutic use ; Respiratory Hypersensitivity/drug therapy ; Mannitol ; Phenotype
Chemical Substances	Nitric Oxide (31C4KY9ESH) ; Adrenal Cortex Hormones ; Mannitol (3OWL53L36A)
Language	English
Publishing date	2023-03-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2023.03.001
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Article ; Online: Allergen Immunotherapy Enhances Airway Epithelial Antiviral Immunity in Patients with Allergic Asthma (VITAL Study): A Double-Blind Randomized Controlled Trial.

Woehlk, Christian / Ramu, Sangeetha / Sverrild, Asger / Nieto-Fontarigo, Juan José / Vázquez-Mera, Sara / Cerps, Samuel / Pulga, Alexis / Andreasson, Louise Munkholm / Eriksen, Lise Lotte / Dyhre-Petersen, Nanna / Menzel, Mandy / Klein, Ditte K / Hansen, Susanne / Uller, Lena / Porsbjerg, Celeste

American journal of respiratory and critical care medicine

2023 Volume 207, Issue 9, Page(s) 1161–1170

Abstract: Rationale: ...

Abstract	Rationale:
MeSH term(s)	Adult ; Animals ; Humans ; Pyroglyphidae ; Antiviral Agents/therapeutic use ; Desensitization, Immunologic/methods ; Asthma/drug therapy ; Antigens, Dermatophagoides ; Treatment Outcome ; Tumor Necrosis Factor-alpha ; Poly C/therapeutic use ; Allergens ; Rhinitis, Allergic/drug therapy
Chemical Substances	Antiviral Agents ; Antigens, Dermatophagoides ; Tumor Necrosis Factor-alpha ; Poly C (30811-80-4) ; Allergens
Language	English
Publishing date	2023-04-01
Publishing country	United States
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.202209-1708OC
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Article ; Online: House dust mite sensitization and exposure affects bronchial epithelial anti-microbial response to viral stimuli in patients with asthma.

Cerps, Samuel / Sverrild, Asger / Ramu, Sangeetha / Nieto-Fontarigo, Juan José / Akbarshahi, Hamid / Menzel, Mandy / Andersson, Cecilia / Tillgren, Sofia / Hvidtfeldt, Morten / Porsbjerg, Celeste / Uller, Lena

Allergy

2022 Volume 77, Issue 8, Page(s) 2498–2508

Abstract: Introduction: Allergen exposure worsens viral-triggered asthma exacerbations and could predispose the host to secondary bacterial infections. We have previously demonstrated that exposure to house dust mite (HDM) reduced TLR-3-induced IFN-β in human ... ...

Abstract	Introduction: Allergen exposure worsens viral-triggered asthma exacerbations and could predispose the host to secondary bacterial infections. We have previously demonstrated that exposure to house dust mite (HDM) reduced TLR-3-induced IFN-β in human bronchial epithelial cells (HBECs) from healthy donors. We hypothesize that HDM sensitization in different ways may be involved in both viral and bacterial resistance of HBECs in asthma. In this study, the role of HDM sensitization and effects of HDM exposure on viral stimulus-challenged HBECs from asthmatic donors have been explored with regard to expression and release of molecules involved in anti-viral and anti-bacterial responses, respectively. Methods: HBECs from HDM-sensitized (HDM+) and unsensitized (HDM-) patients with asthma were used. HBECs were exposed to HDM or heat inactivated (hi)-HDM (20 μg/ml) for 24 h prior to stimulation with the viral infection mimic, Poly(I:C), for 3 or 24 h. Samples were analyzed with ELISA and RT-qPCR for β-defensin-2, IFN-β, TSLP, and neutrophil-recruiting mediators: IL-8 and TNF-⍺. NFκB signaling proteins p105, p65, and IκB-⍺ were analyzed by Western blot. Results: Poly(I:C)-induced IFN-β expression was reduced in HBECs from HDM + compared to HDM- patients (p = 0.05). In vitro exposure of HBECs to HDM furthermore reduced anti-microbial responses to Poly(I:C) including β-defensin-2, IL-8, and TNF-⍺, along with reduced NFκB activity. This was observed in HBECs from asthma patients sensitized to HDM, as well as in non-sensitized patients. By contrast, Poly (I:C)-induced release of TSLP, a driver of T2 inflammation, was not reduced with exposure to HDM. Conclusion: Using HBECs challenged with viral infection mimic, Poly(I:C), we demonstrated that allergic sensitization to HDM was associated with impaired anti-viral immunity and that HDM exposure reduced anti-viral and anti-bacterial defense molecules, but not TSLP, across non-allergic as well as allergic asthma. These data suggest a role of HDM in the pathogenesis of asthma exacerbations evoked by viral infections including sequential viral-bacterial and viral-viral infections.
MeSH term(s)	Animals ; Asthma ; Dermatophagoides pteronyssinus ; Humans ; Interleukin-8 ; Poly I-C/pharmacology ; Pyroglyphidae ; Virus Diseases ; beta-Defensins
Chemical Substances	Interleukin-8 ; beta-Defensins ; Poly I-C (O84C90HH2L)
Language	English
Publishing date	2022-02-11
Publishing country	Denmark
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	391933-x
ISSN	1398-9995 ; 0105-4538
ISSN (online)	1398-9995
ISSN	0105-4538
DOI	10.1111/all.15243
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Article ; Online: Phenotype and severity of asthma determines bronchial epithelial immune responses to a viral mimic.

Porsbjerg, Celeste / Nieto-Fontarigo, Juan Jose / Cerps, Samuel / Ramu, Sangheeta / Menzel, Mandy / Hvidtfeldt, Morten / Silberbrandt, Alexander / Frøssing, Laurits / Klein, Ditte / Sverrild, Asger / Uller, Lena

The European respiratory journal

2022 Volume 60, Issue 1

Abstract: Background: Asthma is characterised by an aggravated immune response to respiratory viral infections. This phenomenon is a clinically well-recognised driver of acute exacerbations, but how different phenotypes of asthma respond immunologically to ... ...

Abstract	Background: Asthma is characterised by an aggravated immune response to respiratory viral infections. This phenomenon is a clinically well-recognised driver of acute exacerbations, but how different phenotypes of asthma respond immunologically to viruses is unclear. Objectives: To describe the association between different phenotypes and severity of asthma and bronchial epithelial immune responses to viral stimulation. Methods: In the Immunoreact study, healthy subjects (n=10) and 50 patients with asthma were included; 30 (60%) were atopic, and 34 (68%) were eosinophilic; 14 (28%) had severe asthma. All participants underwent bronchoscopy with collection of bronchial brushings. Bronchial epithelial cells (BECs) were expanded and stimulated with the viral replication mimic poly (I:C) (Toll-like receptor (TLR)3 agonist) Results: Patients with atopic asthma had increased induction of interleukin (IL)-4, interferon (IFN)-β, IL-6, tumour necrosis factor-α, and IL-1β after poly (I:C) stimulation compared to non-atopic patients, whereas in patients with eosinophilic asthma only IL-6 and IL-8 induction was higher than in non-eosinophilic asthma. Patients with severe asthma displayed a decreased antiviral IFN-β, and increased expression of IL-8, most pronounced in atopic and eosinophilic asthmatics. Furthermore, induction of IL-33 in response to poly (I:C) was increased in severe atopic and in severe eosinophilic asthma, but thymic stromal lymphopoietin only in severe eosinophilic asthma. Conclusions: The bronchial epithelial immune response to a viral mimic stimulation differs between asthma phenotypes and severities, which may be important to consider when targeting novel asthma treatments.
MeSH term(s)	Antiviral Agents/therapeutic use ; Asthma/drug therapy ; Humans ; Immunity ; Interferon-beta/metabolism ; Interferon-beta/therapeutic use ; Interleukin-6 ; Interleukin-8 ; Phenotype ; Poly I-C/pharmacology
Chemical Substances	Antiviral Agents ; Interleukin-6 ; Interleukin-8 ; Interferon-beta (77238-31-4) ; Poly I-C (O84C90HH2L)
Language	English
Publishing date	2022-07-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639359-7
ISSN	1399-3003 ; 0903-1936
ISSN (online)	1399-3003
ISSN	0903-1936
DOI	10.1183/13993003.02333-2021
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Article ; Online: Serum exosome inflamma-miRs are surrogate biomarkers for asthma phenotype and severity.

Vázquez-Mera, Sara / Martelo-Vidal, Laura / Miguéns-Suárez, Pablo / Saavedra-Nieves, Paula / Arias, Pilar / González-Fernández, Coral / Mosteiro-Añón, Mar / Corbacho-Abelaira, María Dolores / Blanco-Aparicio, Marina / Méndez-Brea, Paula / Salgado, Francisco Javier / Nieto-Fontarigo, Juan José / González-Barcala, Francisco Javier

Allergy

2022 Volume 78, Issue 1, Page(s) 141–155

Abstract: Background: Asthma is a heterogeneous disease with several phenotypes, endotypes and severity degrees, in which different T-cell subpopulations are involved. These cells express specific miRNAs (i.e. inflamma-miRs) that can be released to serum in ... ...

Abstract	Background: Asthma is a heterogeneous disease with several phenotypes, endotypes and severity degrees, in which different T-cell subpopulations are involved. These cells express specific miRNAs (i.e. inflamma-miRs) that can be released to serum in exosomes after activation and be used as biomarkers of underlying inflammation. Thus, we aim to evaluate specific T-cell miRNA signatures in serum exosomes from different subgroups of asthmatic patients. Methods: Samples from healthy donors (N = 30) and patients (N = 119) with different asthma endotypes (T2 Results: We detected five miRNAs with high confidence in serum exosomes: miR-16-5p, miR-21-5p, miR-126-3p, miR146a-5p and miR-215-5p. All of them, except miR-16-5p were upregulated in MSA patients compared to MA. A logistic regression model including each of these miRNAs was created to discriminate both conditions, rendering a ROC curve AUC of 0.896 (0.830-0.961). miR-21-5p and miR-126-3p, both involved in Th1/Th2 differentiation, were specifically augmented in T2 Conclusion: Immune-related miRNAs, including miR-21-5p, miR-126-3p, miR-146a-5p and miR-215-5p, can be used as clinically relevant non-invasive biomarkers of the phenotype/endotype and severity of asthma.
MeSH term(s)	Humans ; Exosomes ; Biomarkers ; MicroRNAs/genetics ; Phenotype ; Asthma/diagnosis ; Biomarkers, Tumor
Chemical Substances	Biomarkers ; MicroRNAs ; Biomarkers, Tumor
Language	English
Publishing date	2022-08-29
Publishing country	Denmark
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	391933-x
ISSN	1398-9995 ; 0105-4538
ISSN (online)	1398-9995
ISSN	0105-4538
DOI	10.1111/all.15480
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Article ; Online: iTRAQ-based proteomic analysis reveals potential serum biomarkers of allergic and nonallergic asthma.

Nieto-Fontarigo, Juan José / González-Barcala, Francisco Javier / Andrade-Bulos, Luis Juan / San-José, María Esther / Cruz, María Jesús / Valdés-Cuadrado, Luis / Crujeiras, Rosa María / Arias, Pilar / Salgado, Francisco Javier

Allergy

2020 Volume 75, Issue 12, Page(s) 3171–3183

Abstract: Background: Asthma is heterogeneous disease with different phenotypes, endotypes and severities. Definition of these subgroups requires the identification of biomarkers in biological samples, and serum proteomics is a useful and minimally invasive ... ...

Abstract	Background: Asthma is heterogeneous disease with different phenotypes, endotypes and severities. Definition of these subgroups requires the identification of biomarkers in biological samples, and serum proteomics is a useful and minimally invasive method for this purpose. Therefore, the aim of this study was to detect serum proteins whose abundance is distinctively associated with different asthma phenotypes (allergic vs nonallergic) or severities. Methods: For each group of donors (32 healthy controls, 43 allergic rhinitis patients and 192 asthmatics with different phenotypes and severities), we generated two pools of sera that were analysed by a shotgun MS approach based on combinatorial peptide ligand libraries and iTRAQ-LC-MS/MS. Results: MS analyses identified 18 proteins with a differential abundance. Functional/network study of these proteins identified key processes for asthma pathogenesis, such as complement activation, extracellular matrix organization, platelet activation and degranulation, or post-translational protein phosphorylation. Furthermore, our results highlighted an enrichment of the "Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)" route in allergic asthma and the lectin pathway of complement activation in nonallergic asthma. Thus, several proteins (eg IGFALS, HSPG2, FCN2 or MASP1) displayed a differential abundance between the different groups of donors. Particularly, our results revealed IGFALS as a useful biomarker for moderate-severe allergic asthma. Conclusion: Our data suggest a set of serum biomarkers, especially IGFALS, capable of differentiating allergic from nonallergic asthma. These proteins reveal different pathophysiological mechanisms and may be useful in the future for diagnosis, prognosis or targeted therapy purposes.
MeSH term(s)	Asthma/diagnosis ; Biomarkers ; Chromatography, Liquid ; Humans ; Proteomics ; Tandem Mass Spectrometry
Chemical Substances	Biomarkers
Language	English
Publishing date	2020-07-03
Publishing country	Denmark
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	391933-x
ISSN	1398-9995 ; 0105-4538
ISSN (online)	1398-9995
ISSN	0105-4538
DOI	10.1111/all.14406
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