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Background: Peptidyl arginine deiminases (PADs) and citrullinated H3 histone (H3Cit) play a crucial role in the inflammatory response. These components determine various clinical situations in COVID-2019 associated pneumonia. Single nucleotide polymorphisms (SNPs) in the genes PADI2 and PADI4 may influence the outcome of poorer patient outcomes. We analyze the association of circulating levels NETs biomarkers (PAD2, PAD4, and H3Cit) and the SNPs on PADI2 (rs1005753 and rs2235926) and PADI4 (rs11203366, rs11203367, and rs874881) in hospitalized patients with severe acute respiratory distress syndrome (ARDs) by SARS-CoV-2 pneumonia., Methods: A cross-sectional study in 160 hospitalized patients with ARDs by SARS-CoV-2 pneumonia. The plasma levels of PAD2, PAD4, and H3Cit were determined by ELISA method. The SNPs were determined by qPCR using TaqMan probes. Logistic regression models and receiver operating characteristics (ROC) curve were used to assess the association and predictive value of PAD2, PAD4, and H3Cit plasma levels in outcome by ARDs by SARS-CoV-2 pneumonia., Results: PAD2, PAD4, and H3Cit concentrations were predictors of invasive mechanical ventilation (IMV) requirement and non-survival. PAD2 were associated with non-survival, while PAD4 and H3Cit were associated with requirement IMV. In addition, PAD2 and PAD4 concentrations were related with inflammation markers such as NLR, MLR, dNLR, SII, SIRI, AISI, and NHL. In the carriers of TT genotype of rs1005753 of PADI2 were associated with increased of H3Cit, while, the carriers of GTG/GTG haplotype of PADI4 was related to the presence of increased of PAD4 circulating levels., Conclusion: SNPs in PADI2 and PADI4 have a significant influence on concentrations of PAD2, PAD4, and H3Cit, which are predictor markers of requirement IMV and non-survival in severe ARDS by SARS-CoV-2 pneumonia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors did not receive financial support for the development of this research., (Copyright © 2025. Published by Elsevier B.V.)

The present study aimed to identify in patients with severe COVID-19 and acute respiratory distress syndrome (ARDS) the association between rs3804099 and rs3804100 ( TLR2 ) and evaluate the expression of TLR-2 on the cell surface of innate and adaptive cells of patients' carriers of C allele in at least one genetic variant. We genotyped 1018 patients with COVID-19 and ARDS. According to genotype, a subgroup of 12 patients was selected to stimulate peripheral blood mononuclear cells (PBMCs) with spike and LPS + spike. We evaluated soluble molecules in cell culture supernatants. The C allele in TLR2 (rs3804099, rs3804100) is not associated with a risk of severe COVID-19; however, the presence of the C allele (rs3804099 or rs3804100) affects the TLR-2 ability to respond to a spike of SARS-CoV-2 correctly. The reference group (genotype TT) downregulated the frequency of non-switched TLR-2+ B cells in response to spike stimulus; however, the allele's C carriers group is unable to induce this regulation, but they produce high levels of IL-10, IL-6, and TNF-α by an independent pathway of TLR-2. Findings showed that TT genotypes (rs3804099 and rs3804100) affect the non-switched TLR-2+ B cell distribution. Genotype TT (rs3804099 and rs3804100) affects the TLR-2's ability to respond to a spike of SARS-CoV-2. However, the C allele had increased IL-10, IL-6, and TNF-α by stimulation with spike and LPS.

Hypersensitivity pneumonitis (HP) is an immune-mediated inflammatory interstitial lung disease that may evolve to pulmonary fibrosis, a progressive disorder with a poor prognosis characterized by fibroblast activation and extracellular matrix accumulation. In HP lung fibroblasts, the gene expression of proteins involved in the interaction with the immune response, their isoforms, and how they influence their phenotype have yet to be elucidated. We analyzed the expression and splicing variants of 16 target genes involved in the interaction between HP fibroblasts and immune signaling and evaluated possible correlations with clinical data. The comparison of HP and control fibroblasts revealed distinct gene expression patterns. HP lung fibroblasts displayed an increased expression of IFI27 and PDFGRA and a downregulation of IL17RC and TGFBR3. IFI27 immunoreactive protein was markedly increased in HP lung tissues and normal fibroblasts treated with TGF-β. Furthermore, IFI27 overexpression in normal fibroblasts increased α-SMA and decreased cell number over time. The isoform analysis showed similar expression patterns for most genes, except for the AGER receptor with increased soluble variants relative to full-length AGER in HP fibroblasts. These findings indicate important differences in the expression of genes related to the immune response by HP fibroblasts, highlighting their unique characteristics and providing further insight into a possible profibrotic role of IFI27 in the disease., (© 2024. The Author(s).)

Introduction: Background: changes in body composition (BC) are common in interstitial lung disease, which leads to an increased risk of complications and infections, and are associated with poor quality of life and worse outcomes. BC assessment is important to identify malnutrition and sarcopenia. However, gold-standard techniques are not available in all clinical settings. Aims: this study aimed to evaluate the agreement and reliability of body composition estimated by bioelectric impedance analysis (BIA) and measured using dual-energy X-ray absorptiometry (DEXA) in women with interstitial lung disease. Methods: this is a cross-sectional study. BC (fat mass and appendicular skeletal muscle mass) were assessed using BIA multifrequency and DEXA in standardized conditions. Agreement and reliability between techniques were evaluated using Bland-Altman plots and the intraclass correlation coefficient (ICC). Results: a total of 50 women were evaluated. No differences were observed for FM (BIA, 25.8 ± 10.2 kg and DEXA, 26.3 ± 10.0 kg, p = 0.77) and ASMM (BIA, 14.1 ± 2.7 kg and DEXA, 13.9 ± 2.3 kg, p = 0.83). Based on ICC, good reliability was observed for FM (ICC, 0.98) and ASMM (ICC, 0.93). Conclusion: BC estimated by BIA showed good agreement and reliability with DEXA measurements. In the absence of this method, BIA can replace the DEXA technique for body composition assessment.

Background: COVID-19 survivors who were hospitalised continue to experience long-term multisystemic sequelae and symptoms, impacting their health-related quality of life (HRQoL). The complexity of post-COVID-19 conditions underscores the importance of adopting a multidisciplinary, patient-centric approach to ensure ongoing care. This study aims to assess HRQoL and post-COVID symptoms in a cohort of severe COVID-19 survivors depending on their participation in a multidisciplinary programme., Methods: This prospective study was conducted in a post-COVID clinic staffed by a multidisciplinary team (physical rehabilitator, nutritionist, psychologist, including experts in pulmonary rehabilitation, nutrition, psychology and others). Subjects over 18 years old who were hospitalised due to severe COVID-19 during the acute phase and had attended the post-COVID clinic within the first 3 months following discharge were included. Subjects who were unable or unwilling to provide informed consent to participate in the protocol were excluded. Linear mixed-effect models were employed to examine changes in 12-Item Short-Form Health Survey (SF-12) component scores. The resolution of post-COVID symptom clusters was compared using the Cox model., Results: A total of 730 patients were included, with a mean±sd age of 55.78±15.43 years; 60.55% were male and 90.62% required mechanical ventilation during hospitalisation. Programme attendants demonstrated improved SF-12 physical and mental component scores at 3 and 12 months. A reduction in the prevalence of post-COVID symptoms was observed in both groups, with greater reductions in those attending the programme., Conclusion: Our study showed that patients enrolled on the multidisciplinary programme experienced improvements in fatigue, musculoskeletal, gastrointestinal, neuropsychiatric and respiratory symptoms, along with enhanced SF-12 mental and physical component scores., Competing Interests: Conflict of interest: All the authors have nothing to disclose., (Copyright ©The authors 2024.)

The HLA-G 14-bp indel (rs371194629) variant is associated with IMV requirement in COVID-19 and with exercise-induced desaturation in the post-COVID-19 condition https://bit.ly/3THdx1D., Competing Interests: Conflict of interest: On behalf of all authors, we declare that there are no conflicts of interest and that the present text has not been previously published or submitted elsewhere for review. There has been no ghostwriting, and all authors are listed. All authors have approved the manuscript for submission, (Copyright ©The authors 2024.)

COVID-19 is characterized by a wide range of clinical manifestations, where aging, underlying diseases, and genetic background are related to worse outcomes. In the present study, the differential expression of seven genes related to immunity, IRF9 , CCL5 , IFI6 , TGFB1 , IL1B , OAS1 , and TFRC , was analyzed in individuals with COVID-19 diagnoses of different disease severities. Two-step RT-qPCR was performed to determine the relative gene expression in whole-blood samples from 160 individuals. The expression of OAS1 ( p < 0.05) and IFI6 ( p < 0.05) was higher in moderate hospitalized cases than in severe ones. Increased gene expression of OAS1 (OR = 0.64, CI = 0.52-0.79; p = 0.001), IRF9 (OR = 0.581, CI = 0.43-0.79; p = 0.001), and IFI6 (OR = 0.544, CI = 0.39-0.69; p < 0.001) was associated with a lower risk of requiring IMV. Moreover, TGFB1 (OR = 0.646, CI = 0.50-0.83; p = 0.001), CCL5 (OR = 0.57, CI = 0.39-0.83; p = 0.003), IRF9 (OR = 0.80, CI = 0.653-0.979; p = 0.03), and IFI6 (OR = 0.827, CI = 0.69-0.991; p = 0.039) expression was associated with patient survival. In conclusion, the relevance of OAS1 , IRF9 , and IFI6 in controlling the viral infection was confirmed.

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19). The disease has a wide range of clinical manifestations, from asymptomatic to severe. Ancestral contribution, sex, immune response, and genetic factors influence the presentation of the disease. The objective of the present study was to validate these genetic variants in patients with severe COVID-19 who died and in survivor patients. Methods: Single nucleotide variants (SNVs) in six genes: ATPase plasma membrane Ca 2+ transporting 2 ( ATP2B2), transmembrane serine protease 2 (TMPRSS2), dedicator of cytokinesis 2 (DOCK2), (interferon alpha and beta receptor subunit 2) IFNAR2, tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), and tumor necrosis factor receptor superfamily, member 1B ( TNFRSF1B) , were explored in two groups: the first consisted of severe COVID-19-related patients (familial cases from 58 families, n = 130), and the second group of unrelated severe COVID-19 patients (n = 1045). In each study group, death was evaluated as the outcome., Results: In non-related patients with severe COVID-19, carriers of GG genotype (rs2289274) in the ATP2B2 gene showed a high-risk probability of non-surviving (OR = 1.43). Survival analysis to 75 days indicates that carriers of GG have a higher risk than GA or AA genotypes (p = 0.0059). The haplotype GG (rs2289273-rs2289274) in ATP2B2 was found to be associated with a high risk of death in severe non-related COVID-19 patients. No significant associations were found between severe COVID-19-related patients and SNVs in ATP2B2, TMPRSS2, DOCK2, IFNAR2, TNFRSF1A, or TNFRSF1B ., Conclusions: Unrelated patients with severe COVID-19 that carry the GG genotype (rs2289274) in ATP2B2 showed a high death risk. Survival analysis to 75 days indicates that carriers of GG have a higher risk of non-survival compared to GA or AA genotypes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Enzymes of the peptidylarginine deiminase family (PADs) play a relevant role in the pathogenesis of COVID-19. However, the association of single nucleotide polymorphisms (SNPs) in their genes with COVID-19 severity and death is unknown., Methodology: We included 1045 patients who were diagnosed with COVID-19 between October 2020 and December 2021. All subjects were genotyped for PADI2 (rs1005753 and rs2235926) and PADI4 (rs11203366, rs11203367, and rs874881) SNPs by TaqMan assays and their associations with disease severity, death, and inflammatory biomarkers were evaluated., Results: 291 patients presented had severe COVID-19 according to PaO 2 /FiO 2 , and 393 had a non-survival outcome. Carriers of the rs1005753 G/G genotype in the PADI2 gene presented susceptibility for severe COVID-19, while the heterozygous carriers in rs11203366, rs11203367, and rs874881 of the PADI4 gene showed risk of death. The GTACC haplotype in PADI2 - PADI4 was associated with susceptibility to severe COVID-19, while the GCACC haplotype was a protective factor. The GCGTG haplotype was associated with severe COVID-19 but as a protective haplotype for death. Finally, the GTACC haplotype was associated with platelet-to-lymphocyte ratio (PLR), the GCACC haplotype with neutrophil-to-hemoglobin and lymphocyte and the GCGTG haplotype as a protective factor for the elevation of procalcitonin, D-dimer, CRP, LCRP, NHL, SII, NLR, and PLR., Conclusions: Our results suggest that the haplotypic combination of GTACC and some individual genotypes of PADI2 and PADI4 contribute to the subjects' susceptibility for severity and death by COVID-19., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Aim: To characterize the lung microbiome in the bronchoalveolar lavage fluid (BALF) of patients with Antisynthetase Syndrome (ASSD) according to anti-Jo1 autoantibody positivity and evaluate the correlation with differential cell count and other bacterial genera in BALF., Methods: We sequenced the 16S ribosomal RNA gene in the BALF of anti-Jo1-positive (JoP, n=6) and non-Jo1-positive (NJo, n=17) patients, and the differential cell count in BALF was evaluated. The Spearman's correlation was calculated for the quantitative variables and abundance of bacterial species., Results: The Veillonella genus showed a significant decrease (p<0.01) in JoP (2.2%) in comparison to NJo (4.1%) patients. The correlation analysis showed several high (rho ≥ ± 0.7) and significant (p < 0.05) correlations. We analyzed the results obtained for the Veillonella genera and other study variables. The JoP group showed that the abundance of Veillonella had a high negative correlation with macrophages (rho = - 0.77) and a positive correlation with eosinophils (rho = 0.77), lymphocytes (rho = 0.77), and Prevotella (rho = 1)., Conclusions: The lung microbiome in ASSD patients differs and may affect cell composition, contributing to lung damage mechanisms. The presence of anti-Jo1 autoantibodies showed a low abundance of Veillonella . This genus had a strong and positive correlation with Prevotella abundance and levels of eosinophils and lymphocytes, and it showed a strong negative correlation with the percentage of macrophages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Quintero-Puerta, Lira-Lucio, Falfán-Valencia, Vega-Sánchez, Márquez-García, Mejía, Bautista-Becerril, Rojas-Serrano, Ramos-Martínez, Buendía-Roldán and Pérez-Rubio.)

Background: Since the first case of severe COVID-19, its effect on patients with previous interstitial lung disease (ILD) has been uncertain. We aimed to describe baseline clinical characteristics in ILD patients hospitalized by critical COVID and compare mortality during hospitalization., Methods: We studied patients with ILD with COVID-19 and a control group matched by age, 1:2 ratio with COVID-19 without previous lung disease. On admission, laboratory tests and sociodemographic variables were evaluated. We evaluated patients critically ill and compared baseline characteristics and mortality in each group. Additionally, we performed a sub-analysis of ILD patients who died versus survivors., Results: Forty-one patients and 82 controls were analyzed. In the group of ILD with COVID-19 there was a predominance of women (65 versus 33%: p < 0.001); lower leukocytes (9 ± 6 versus 11 ± 7, p = 0.01) and neutrophils (8 ± 5 versus 10 ± 6, p = 0.02). The most common ILD was secondary to autoimmune diseases. Patients with ILD and critical COVID-19 showed a significantly higher mortality compared with those without previous ILD (63 versus 33%, p = 0.007). Patients who died in this group had higher BMI (28 ± 6 versus 25 ± 4 kg/m 2 , p = 0.05), less extended hospital stay (20 ± 17 versus 36 ± 27 days, p = 0.01), and fewer days of evolution (9 ± 7 versus 16 ± 16, p = 0.05)., Conclusions: We found higher mortality in patients with ILD with critical COVID-19. Higher BMI and comorbidities were present in the non-survivors., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Tobacco smoking is the leading risk factor for many respiratory diseases. Several genes are associated with nicotine addiction, such as CHRNA5 and ADAM33 . This research aims to evaluate the association of the polymorphisms rs16969968 ( CHRNA5 ) and rs3918396 ( ADAM33 ) in patients who developed severe COVID-19. We included 917 COVID-19 patients hospitalized with critical disease and oxygenation impairment. They were divided into two groups, tobacco-smoking ( n = 257) and non-smoker ( n = 660) patients. The genotype and allele frequencies of two single nucleotide variants, the rs16969968 ( CHRNA5 ) and rs3918396 ( ADAM33 ), were evaluated. The rs3918396 in ADAM33 does not show a significative association. We analyzed the study population according to the rs16969968 genotype (GA + AA, n = 180, and GG, n = 737). The erythrocyte sedimentation rate (ESR) shows statistical differences; the GA + AA group had higher values than the GG group ( p = 0.038, 32 vs. 26 mm/h, respectively). The smoking patients and GA or AA genotype carriers had a high positive correlation ( p < 0.001, rho = 0.753) between fibrinogen and C-reactive protein. COVID-19 patients and smokers carriers of one or two copies of the risk allele (rs16969968/A) have high ESR and a positive correlation between fibrinogen and C-reactive protein.

Anti-synthetase syndrome (ASSD) is an autoimmune disorder characterized by inflammatory interstitial lung disease (ILD). The main objective of this work was to quantify the concentrations of cytokines and molecules associated with inflammasome activation in bronchoalveolar lavage (BAL) of patients with ASSD and a comparison group of systemic sclerosis (SSc) patients. Cytokines and lactate dehydrogenase (LDH) were determined using the concentrated BAL protein. The activity of caspase-1 and concentration of NLRP3 with the protein purified from the cell pellet in each group of patients. We found higher caspase-1 levels in ASSD vs. SSc, 1.25 RFU vs. 0.75 RFU p = 0.003, and LDH levels at 0.15 OD vs. 0.09 OD p < 0.001. A significant difference was observed in molecules associated with inflammasome activation, IL-18: 1.42 pg/mL vs. 0.87 pg/mL p = 0.02 and IFN-γ: 0.9 pg/mL vs. 0.86 pg/mL, p = 0.01. A positive correlation was found between caspase-1 and LDH in the patients with ASSD Rho 0.58 ( p = 0.008) but not in the SSc group. In patients with ASSD, greater caspase-1 and higher LDH activity were observed in BAL, suggesting cell death due to pyroptosis and activation of the inflammasome pathway.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and frequently fatal disease. Currently there are national and multinational registries in Europe, United States, Australia and China to better understand the magnitude of the problem and the characteristics of the IPF patients. However, there are no national or regional registries in Latin America, so the objective of this study was to carry out a Latin American registry that would allow the identification of IPF patients in our region., Methodology: A system consisting of 3 levels of control was designed, ensuring that patients met the diagnostic criteria for IPF according to international guidelines ATS/ERS/ALAT/JRS 2011. Demographic, clinical, serological, functional, tomographic, histological and treatment variables were recorded through a digital platform., Results: 761 IPF patients from 14 Latin American countries were included for analysis, 74.7% were male, with a mean age of 71.9+8.3 years. In general there was a long period of symptoms before definitive diagnosis (median 1 year). In functional tests, an average reduction of FVC (70.9%) and DLCO (53.7%) was detected. 72% received at least one antifibrotic drug (pirfenidone or nintedanib) and 11.2% of the patients had an acute exacerbation, of which 38 (45.2%) died from this cause., Conclusions: Like other registries, we found that there is difficulty in the recognition and excessive delay in the diagnosis of IPF in Latin America. Most of the patients in REFIPI received antifibrotics; these were well tolerated and associated with fewer adverse events than those reported in clinical trials., (Copyright © 2022 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: The systemic viral disease caused by the SARS-CoV-2 called coronavirus disease 2019 (COVID-19) continues to be a public health problem worldwide., Objective: This study is aimed to evaluate the association and predictive value of indices of systemic inflammation with severity and non-survival of COVID-19 in Mexican patients., Materials and Methods: A retrospective study was carried out on 807 subjects with a confirmed diagnosis of COVID-19. Clinical characteristics, acute respiratory distress syndrome (ARDS), severity according to PaO 2 /FiO 2 ratio, invasive mechanical ventilation (IMV), and non-survival outcome were considered to assess the predictive value and the association of 11 systemic inflammatory indices derived from hematological parameters analyzed at the hospital admission of patients. The receiver operating characteristics curve was applied to determine the thresholds for 11 biomarkers, and their prognostic values were assessed via the Kaplan-Meier method., Results: 26% of the studied subjects showed COVID-19 severe (PaO 2 /FiO 2 ratio ≤ 100), 82.4% required IMV, and 39.2% were non-survival. The indices NHL, NLR, RDW, dNLR, and SIRI displayed predictive values for severe COVID-19 and non-survival. NHL, SIRI, and NLR showed predictive value for IMV. The cut-off values for RDW (OR = 1.85, p < 0.001), NHL (OR = 1.67, p = 0.004) and NLR (OR = 1.56, p = 0.012) were mainly associated with severe COVID-19. NHL (OR = 3.07, p < 0.001), AISI (OR = 2.64, p < 0.001) and SIRI (OR = 2.51, p < 0.001) were associated with IMV support, while for non-survival the main indices associated were NHL (OR = 2.65, p < 0.001), NLR (OR = 2.26, p < 0.001), dNLR (OR = 1.92, p < 0.001), SIRI (OR = 1.67, p = 0.002) and SII (OR = 1.50, p = 0.010). The patients with an RDW, PLR, NLR, dNLR, MLR, SII, and NHL above the cut-off had a survival probability of COVID-19 50% lower, with an estimated mean survival time of 40 days., Conclusion: The emergent systemic inflammation indices NHL, NLR, RDW, SII, and SIRI have a predictive power of severe COVID-19, IMV support, and low survival probability during hospitalization by COVID-19 in Mexican patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gutiérrez-Pérez, Buendía-Roldán, Pérez-Rubio, Chávez-Galán, Hernández-Zenteno, Aguilar-Duran, Fricke-Galindo, Zaragoza-García, Falfán-Valencia and Guzmán-Guzmán.)

Background: The impact of genetic variants in the expression of tumor necrosis factor-α (TNF-α) and its receptors in coronavirus disease 2019 (COVID-19) severity has not been previously explored. We evaluated the association of TNF (rs1800629 and rs361525), TNFRSF1A (rs767455 and rs1800693), and TNFRSF1B (rs1061622 and rs3397) variants with COVID-19 severity, assessed as invasive mechanical ventilation (IMV) requirement, and the plasma levels of soluble TNF-α, TNFR1, and TNFR2 in patients with severe COVID-19., Methods: The genetic study included 1353 patients. Taqman assays were used to assess the genetic variants. ELISA was used to determine soluble TNF-α, TNFR1, and TNFR2 in plasma samples from 334 patients., Results: Patients carrying TT (TNFRSF1B rs3397) exhibited lower PaO2/FiO2 levels than those with CT + CC genotypes. Differences in plasma levels of TNFR1 and TNFR2 were observed according to the genotype of TNFRSF1B rs1061622, TNF rs1800629, and rs361525. According to the studied genetic variants, there were no differences in the soluble TNF-α levels. Higher soluble TNFR1 and TNFR2 levels were detected in patients with COVID-19 requiring IMV., Conclusions: Genetic variants in TNF and TNFRSFB1 influence the plasma levels of soluble TNFR1 and TNFR2, implicated in COVID-19 severity., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: During follow-up, patients severely affected by coronavirus disease 2019 (COVID-19) requiring invasive mechanical ventilation (IMV), show symptoms of Post-Intensive Care Syndrome (PICS) such as cognitive impairment, psychological disability, and neuromuscular deconditioning. In COVID-19 pandemic, it is a priority to develop multidisciplinary post-acute care services to address the long-term multisystemic impact of COVID-19., Research Question: Which are the most relevant multisystemic sequelae in severe post-COVID-19 patients?, Study Design and Methods: Observational chart review study that included adult patients discharged from a referral hospital for respiratory diseases in Mexico after recovering from severe COVID-19 disease from December 23, 2020, to April 24, 2021. Data were collected from 280 of 612 potentially eligible patients to evaluate persistent symptoms and compare sequelae in patients who required intubation, using a standardized questionnaire of symptoms, in addition to findings reported during the face-to-face health assessment. Univariable and multivariate analyses were performed for the association among the requirement of IMV and the long-term persistence of symptoms., Results: 280 patients were included. The median age was 55 (range, 19 to 86) years, and 152 (54.3%) were men. The mean length of hospital stay was 19 (SD, 14.1) days. During hospitalization 168 (60%) participants received IMV. A large proportion of these patients reported fatigue (38.7%), paresthesia (35.1%), dyspnea (32.7%) and headache (28%); meanwhile only 3 (1.8%) of them were asymptomatic. Patients who required intubation were more likely to have neuropsychiatric (67.3% vs 55.4%; OR, 1.79 [95% CI, 1.08 to 2.97]) and musculoskeletal involvement (38.7% vs. 25.9%; OR, 1.92 [95% CI, 1.12 to 3.27]), adjusted for age,sex and hospitalization time., Interpretation: The proportion of patients requiring intubation was 60%, reporting persistent symptoms in 98% of them. Neuropsychiatric and musculoskeletal symptoms were the most predominant symptoms in these patients, with a significant difference. Post-COVID-19 syndrome is a frequent problem in patients who required IVM. Physicians in ICU and in care of COVID-19 patients should be aware of this syndrome in order to avoid more complications., Competing Interests: The authors have declared that no competing interests exist.

Background: Patients with anti-tRNA autoantibodies are characterized by arthritis, mechanic´s hands, fever, Raynaud´s phenomenon, and interstitial lung disease (ILD), in at least two clinical scenarios: the antisynthetase syndrome (ASSD) and interstitial pneumonia with autoimmune features (IPAF). The anti-tRNA-ILD treatment is centered on the administration of corticosteroids and a wide variety of immunosuppressive drugs; however, the effectiveness of the treatment depends on factors not fully understood. This research work aimed to quantify the serum levels of two molecules related to pulmonary fibrosis and explore their relationship with the progression of ILD associated with ASSD METHODOLOGY: Serum levels of sCD163 and TGF-β1 from baseline and after six months of treatment of ILD patients' positives to anti-tRNA were included in the current study. At six months, patients were classified as with or without ILD progression RESULTS: Forty patients were included (anti-Jo1, anti-PL7, anti-PL12, and anti-Ej). Five patients (12.5%) had ILD progression and were characterized by higher levels of sCD163 at baseline. Baseline sCD163 serum levels showed good discriminatory capacity in patients with ILD progression. On the other hand, at follow-up, serum TGF-β1 levels significantly increased in both patients' groups, with and without progression CONCLUSION: Basal levels of sCD163 were higher in patients who later developed ILD progression and kinetics of both molecules suggests the participation of M2 macrophages in the development of ILD., (Copyright © 2022. Published by Elsevier B.V.)

Interferons (IFNs) are a group of cytokines with antiviral, antiproliferative, antiangiogenic, and immunomodulatory activities. Type I IFNs amplify and propagate the antiviral response by interacting with their receptors, IFNAR1 and IFNAR2. In COVID-19, the IFNAR2 (interferon alpha and beta receptor subunit 2) gene has been associated with the severity of the disease, but the soluble receptor (sIFNAR2) levels have not been investigated. We aimed to evaluate the association of IFNAR2 variants (rs2236757, rs1051393, rs3153, rs2834158, and rs2229207) with COVID-19 mortality and to assess if there was a relation between the genetic variants and/or the clinical outcome, with the levels of sIFNAR2 in plasma samples from hospitalized individuals with severe COVID-19. We included 1,202 subjects with severe COVID-19. The genetic variants were determined by employing Taqman ® assays. The levels of sIFNAR2 were determined with ELISA in plasma samples from a subgroup of 351 individuals. The rs2236757, rs3153, rs1051393, and rs2834158 variants were associated with mortality risk among patients with severe COVID-19. Higher levels of sIFNAR2 were observed in survivors of COVID-19 compared to the group of non-survivors, which was not related to the studied IFNAR2 genetic variants. IFNAR2, both gene, and soluble protein, are relevant in the clinical outcome of patients hospitalized with severe COVID-19., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fricke-Galindo, Martínez-Morales, Chávez-Galán, Ocaña-Guzmán, Buendía-Roldán, Pérez-Rubio, Hernández-Zenteno, Verónica-Aguilar, Alarcón-Dionet, Aguilar-Duran, Gutiérrez-Pérez, Zaragoza-García, Alanis-Ponce, Camarena, Bautista-Becerril, Nava-Quiroz, Mejía, Guzmán-Guzmán and Falfán-Valencia.)

Background: Genetic susceptibility to infectious diseases is partly due to the variation in the human genome, and COVID-19 is not the exception. This study aimed to identify whether risk alleles of known genes linked with emphysema ( SERPINA1 ) and pulmonary fibrosis ( MUC5B ) are associated with severe COVID-19, and whether plasma mucin 5B differs according to patients' outcomes., Materials and Methods: We included 1258 Mexican subjects diagnosed with COVID-19. We genotyped rs2892474 and rs17580 of the SERPINA1 gene and rs35705950 of MUC5B . Based on the rs35705950 genotypes, mucin 5B plasma protein levels were quantified., Results: Homozygous for the risk alleles of the three polymorphisms were found in less than 5% of the study population, but no statistically significant difference in the genotype or allele association analysis. At the protein level, non-survivors carrying one or two copies of the risk allele rs35705950 in MUC5B (GT + TT) had lower levels of mucin 5B compared to the survivors (0.0 vs. 0.17 ng/mL, p = 0.0013)., Conclusion: The polymorphisms rs28929474 and rs17580 of SERPINA1 and rs35705950 of MUC5B are not associated with the risk of severe COVID-19 in the Mexican population. COVID-19 survivor patients bearing one or two copies of the rs35705950 risk allele have higher plasma levels of mucin 5B.

Background and Objectives: ILD patients can be positive to highly specific autoantibodies of connective tissue diseases (CTD). Among them stand out myositis-specific and associated autoantibodies (MSA/MAA). There is limited knowledge about treatment response and prognosis of ILD patients positive to MSA/MAA (MSA/MAA-ILD). Our aim was to describe clinical, radiological and pulmonary function (PF) of MSA/MAA-ILD Latin-American patients and risk factors associated to PF at onset and long term follow up., Methods: Multicentric retrospective study of MSA/MAA-ILD patients evaluated between 2016 and 2018 in 3 ILD clinics in Latin America. Clinical, functional and tomographic variables were described. Variables associated with poor baseline PF and associated with functional improvement (FI) were analyzed in a multivariate logistic regression model., Results: We included 211 patients, 77.4% female, mean age 57 years old. Most frequent MSA/MAA were Ro-52 and Jo-1. Poor baseline PF was associated to ILD as initial diagnosis and NSIP/OP HRCT pattern. 121 patients were included in the follow up PF analysis: 48.8% remained stable and 33% had a significant FI. In multivariate analysis, OP pattern on HRCT was associated with FI. Systemic symptoms from the beginning and the absence of sclerodactyly showed a trend to be associated with FI., Conclusions: Worse baseline PF could be related to the absence of extra-thoracic symptoms and "classic" antibodies in CTD (ANA), which causes delay in diagnosis and treatment. In contrast, FI could be related to the presence of extra-thoracic signs that allow timely diagnosis and therapy, and more acute and subacute forms of ILD, such as OP pattern., (Copyright © 2021 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease of unknown etiology. Myofibroblasts are organized in peculiar subepithelial fibroblasts foci (FF), where they abnormally persist and exclude lymphocytes by unclear mechanisms. FF are the source of an excessive extracellular matrix, which results in progressive stiffening and destruction of the lung architecture. We hypothesized that the absence of T cells inside the FF could be related, at least partially, to an inefficient function of lymphocytes induced by IPF fibroblasts. Here, we evaluated the effect of a supernatant from IPF fibroblasts on T-cell apoptosis and migration capacity. Data showed that IPF fibroblasts secrete pro-apoptotic molecules (both from extrinsic and intrinsic pathways), generating a microenvironment that induces apoptosis of T cells at 3 h of culture, despite a weak anti-apoptotic profile exhibited by these T cells. At 24 h of culture, the supernatants from both IPF and control fibroblasts provoked T-cell death. However, at this time of culture, IPF fibroblasts caused a marked decrease in T-cell migration; in contrast, control lung fibroblasts induced an increase of T-cell migration. The reduction of T-cell migratory capacity provoked by IPF fibroblasts was associated with a negative regulation of RHOA and ROCK, two essential GTPases for migration, and was independent of the expression of chemokine receptors. In conclusion, our findings demonstrate that IPF fibroblasts/myofibroblasts induce apoptosis and affect T-cell migration, revealing a mechanism involved in the virtual absence of T lymphocytes inside the FF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chavez-Galan, Becerril, Ruiz, Ramon-Luing, Cisneros, Montaño, Salgado, Ramos, Buendía-Roldán, Pardo and Selman.)

Angiotensin-Converting Enzyme 2 (ACE2) is an 805 amino acid protein encoded by the ACE2 gene expressed in various human cells, especially in those located in the epithelia. The primary function of ACE2 is to produce angiotensin (1-7) from angiotensin II (Ang II). The current research has described the importance of ACE2 and Ang (1-7) in alternative routes of the renin-angiotensin system (RAS) that promote the downregulation of fibrosis, inflammation, and oxidative stress processes in a great variety of diseases, such as hypertension, acute lung injury, liver cirrhosis, and kidney abnormalities. Investigations into the recent outbreak of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have revealed the importance of ACE2 during infection and its role in recognizing viral binding proteins through interactions with specific amino acids of this enzyme. Additionally, the ACE2 expression in several organs has allowed us to understand the clinical picture related to the infection caused by SARS-CoV-2. This review aims to provide context for the functions and importance of ACE2 with regards to SARS-CoV-2 in the general clinical aspect and its impact on other diseases, especially respiratory diseases.

Background: Around 8-10% of individuals over 50 years of age present interstitial lung abnormalities (ILAs), but their risk factors are uncertain., Methods: From 817 individuals recruited in our lung ageing programme at the Mexican National Institute of Respiratory Diseases, 80 (9.7%) showed ILAs and were compared with 564 individuals of the same cohort with normal high-resolution computed tomography to evaluate demographic and functional differences, and with 80 individuals randomly selected from the same cohort for biomarkers. We evaluated MUC5B variant rs35705950, telomere length, and serum levels of matrix metalloproteinase (MMP)-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, interleukin (IL)-6, surfactant protein (SP)-D, α-Klotho and resistin., Results: Individuals with ILAs were usually males (p<0.005), older than controls (p<0.0001), smokers (p=0.01), with a greater frequency of MUC5B rs35705950 (OR 3.5, 95% CI 1.3-9.4; p=0.01), and reduced diffusing capacity of the lung for carbon monoxide and oxygen saturation. Resistin, IL-6, SP-D, MMP-1, MMP-7 and MMP-13 were significantly increased in individuals with ILAs. Resistin (12±5 versus 9±4 ng·mL -1 ; p=0.0005) and MMP-13 (357±143 versus 298±116 pg·mL -1 ; p=0.004) were the most increased biomarkers. On follow-up (24±18 months), 18 individuals showed progression which was associated with gastro-oesophageal reflux disease (OR 4.1, 95% CI 1.2-12.9; p=0.02) and in females with diabetes mellitus (OR 5.3, 95% CI 1.0-27.4; p=0.01)., Conclusions: Around 10% of respiratory asymptomatic individuals enrolled in our lung ageing programme show ILAs. Increased serum concentrations of pro-inflammatory molecules and MMPs are associated with ILAs., Competing Interests: Conflict of interest: I. Buendía-Roldán has nothing to disclose. Conflict of interest: R. Fernandez has nothing to disclose. Conflict of interest: M. Mejía has nothing to disclose. Conflict of interest: F. Juarez has nothing to disclose. Conflict of interest: G. Ramirez-Martinez has nothing to disclose. Conflict of interest: E. Montes has nothing to disclose. Conflict of interest: A.K.S. Pruneda has nothing to disclose. Conflict of interest: K. Martinez-Espinosa has nothing to disclose. Conflict of interest: A. Alarcon-Dionet has nothing to disclose. Conflict of interest: I. Herrera has nothing to disclose. Conflict of interest: C. Becerril has nothing to disclose. Conflict of interest: L. Chavez-Galan has nothing to disclose. Conflict of interest: M. Preciado has nothing to disclose. Conflict of interest: A. Pardo has nothing to disclose. Conflict of interest: M. Selman has nothing to disclose., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Healthcare workers (HCWs) constitute a population which is significantly affected by SARS-CoV-2 infection worldwide. In Mexico, the Instituto Nacional de Enfermedades Respiratorias (INER) is the principal national reference of respiratory diseases. Aim: To evaluate the efficiency of the INER-POL-TRAB-COVID19 program to mitigate the SARS-CoV-2 infection risk among the INER-healthcare workers (INER-HCW). Methods: Currently, the INER has 250 beds and 200 respiratory ventilators to support COVID-19 patients in critical condition. On March 1st, 2020, the INER-POL-TRAB-COVID19 program was launched to mitigate the SARS-CoV-2 infection risk among the INER-HCW. Findings: From March 1st to October 1st, 2020, 71.5% of INER-HCWs were tested for SARS-CoV-2 infection, and 77% of them were frontline workers. Among the tested INER-HCWs, 10.4% were positive for SARS-CoV-2 infection. Nonetheless, nosocomial infection represented only 3.8% of the cases and the mortality was null. Fifty-three of INER-HCWs positive to SARS-CoV-2 had a negative test 42-56 days post-diagnosis and were returned to service. Finally, although a change in the PPE implemented on May 11th, 2020, the incidence of SARS-CoV-2 infection was not affected. Conclusion: INER has a lower incidence of HCWs infected with SARS-CoV-2 as compared to the mean of the national report. The implementation of the INER-POL-TRAB-COVID19 program is efficient to decrease the risk of infection among the HCWs. Our findings suggest that the implementation of a similar program at a national level can be helpful to provide a safe environment to HCWs and to prevent the collapse of health institutions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Salazar, Chavez-Galan, Castorena-Maldonado, Mateo-Alonso, Diaz-Vazquez, Vega-Martínez, Martínez-Orozco, Becerril-Vargas, Sosa-Gómez, Patiño-Gallegos, Alonso-Martínez, López-Segundo, Vidal, Velasco-González, Pérez-Pulido, Santillán-Doherty, Regalado-Pineda, Salas-Hernández and Buendía-Roldán.)

Antisynthetase syndrome (ASSD) is a rare multisystemic connective tissue disease affecting the skin, joints, muscles, and lungs, characterized by anti-aminoacyl transfer-RNA-synthetases (anti-tRNA) autoantibodies production, being anti-Jo1 the most frequent. We included one-hundred twenty-one ASSD patients and 340 healthy subjects (HS), and also, we divided the case group into anti-Jo1 and non-anti-Jo1. Two single nucleotide polymorphisms (SNPs) in the IL17A gene were evaluated. Anti-Jo1 was the most common anti-tRNA antibody in our cohort, and the most frequent tomographic pattern was non-specific interstitial pneumonia (NSIP). Anti-Jo1 ASSD patients had higher levels of creatine phosphokinase than the non-anti-Jo1 group. Significant differences in genotype frequencies with rs8193036/CC between anti-Jo1 vs. non-anti-Jo1 ASSD patients ( p < 0.001), maintaining the association after Bonferroni correction ( p = 0.002). Additionally, in the anti-Jo1 group vs. HS comparison, we found a statistically significant difference with the same SNP ( p = 0.018, OR = 2.91, 95% CI = 1.15-7.35), maintaining the association after Bonferroni correction ( p = 0.036). The rs8193036/CC genotype in IL17A is associated with ASSD patients with anti-Jo1. Also, anti-Jo1 and non-anti-Jo1 patients display differences in genotype frequencies.

Background and Objectives: ILD patients can be positive to highly specific autoantibodies of connective tissue diseases (CTD). Among them stand out myositis-specific and associated autoantibodies (MSA/MAA). There is limited knowledge about treatment response and prognosis of ILD patients positive to MSA/MAA (MSA/MAA-ILD). Our aim was to describe clinical, radiological and pulmonary function (PF) of MSA/MAA-ILD Latin-American patients and risk factors associated to PF at onset and long term follow up., Methods: Multicentric retrospective study of MSA/MAA-ILD patients evaluated between 2016 and 2018 in 3 ILD clinics in Latin America. Clinical, functional and tomographic variables were described. Variables associated with poor baseline PF and associated with functional improvement (FI) were analyzed in a multivariate logistic regression model., Results: We included 211 patients, 77.4% female, mean age 57 years old. Most frequent MSA/MAA were Ro-52 and Jo-1. Poor baseline PF was associated to ILD as initial diagnosis and NSIP/OP HRCT pattern. 121 patients were included in the follow up PF analysis: 48.8% remained stable and 33% had a significant FI. In multivariate analysis, OP pattern on HRCT was associated with FI. Systemic symptoms from the beginning and the absence of sclerodactyly showed a trend to be associated with FI., Conclusions: Worse baseline PF could be related to the absence of extra-thoracic symptoms and "classic" antibodies in CTD (ANA), which causes delay in diagnosis and treatment. In contrast, FI could be related to the presence of extra-thoracic signs that allow timely diagnosis and therapy, and more acute and subacute forms of ILD, such as OP pattern., (Copyright © 2021 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Background: Hemodynamic response to supplemental oxygen in idiopathic pulmonary fibrosis (IPF) is still not well known., Objective: To determine and compare the effect of low-flow acute supplemental oxygen on the hemodynamics of IPF patients and matched healthy subjects., Methods: Descriptive and comparative study in 20 IPF-patients and 19 Control-subjects, (60-80 years old) breathing ambient air followed by acute nasal low-flow (3 L/min) supplemental oxygen. Non-invasive methods were used during the supine position to evaluate oxygen saturation, heart rate, stroke volume index, cardiac output index, total peripheral resistance and arterial blood pressure., Results: Breathing ambient air, IPF (vs. Control) presented lower values in stroke volume index (38.7 [29.4-43.2] vs. 45.4 [38.4-50.9] mL•kg-1•m 2 ; p=0.009) and cardiac output index (2.484 [2.268 - 2.946] vs. 2.857 [2.628 - 3.054] L•min -1 •m -2 ; p=0.028), with higher total peripheral resistance (1644 [1559-2076] vs. 1505 [1366-1784] dyne•s•cm -5 ; p=0.017). During supplemental oxygen (vs. ambient air), both groups increased oxygen saturation above 94% (p<0.001) while heart rate decreased about 6 to 8% (p<0.001); stroke volume index increased around 7% in the Control-group (p=0.004) but only 1% in the IPF-group (p=0.017). In addition, IPF showed increments in total peripheral resistance (1644 [1559-2076] vs. 1706 [1554-2278] dyne•s•cm -5 ; p=0.017) with subsequent decrements in cardiac output index (2.484 [2.268 - 2.946] vs. 2.362 [2.139 - 2.664] L•min -1 •m -2 ; p<0.001)., Conclusion: Low-flow acute supplemental oxygen in IPF causes a meaningful decrement in cardiac output due to greater reduction in heart rate and increment in total peripheral resistance than matched healthy subjects. Knowing the hemodynamic profile of IPF patients may be helpful in determining their management with supplemental oxygen., Competing Interests: Declaration of Interest statement None, (Copyright © 2020 Elsevier Inc. All rights reserved.)

The antisynthetase syndrome (ASSD) is an autoimmune disorder characterized by myositis, arthritis, mechanic's hands, fever, Raynaud phenomenon, and interstitial lung disease (ILD). We aimed to evaluate single-nucleotide polymorphisms in the interleukin 1B ( IL1B ) gene and their association between ILD with antisynthetase autoantibodies, as well as IL-1β serum levels. The most frequent antisynthetase autoantibody was anti-Jo1. The most frequent tomographic pattern was non-specific interstitial pneumonia, whereas in the anti-Jo1 subjects, it was organized pneumonia. Anti-Jo1 patients tend to have more significant arthritis, and Raynaud phenomenon have higher levels of creatinine phosphokinase. In the IL1B gene, the GG genotype and G allele of rs1143634 [odds ratio (OR) = 2.21 and OR = 2.60, respectively, p < 0.05] are associated with an increased risk, as well as with the dominant and recessive models ( p < 0.05). This finding is maintained after logistic regression analysis adjusting for potential confounding variables ( p < 0.05). Subjects with the rs16944/AG heterozygous genotype had higher serum levels of IL-1β compared to homozygous ( p < 0.05). In conclusion, rs1143634 is associated with a higher risk of ASSD. Also, the GA genotype is associated with higher levels of IL-1β in ASSD patients., (Copyright © 2020 Ponce-Gallegos, Ramos-Martínez, García-Carmona, Mejía, Nava-Quiroz, Pérez-Rubio, Ambrocio-Ortiz, González-Pérez, Buendía-Roldán, Rojas-Serrano and Falfán-Valencia.)

Idiopathic pulmonary fibrosis is a chronic and progressive disease of unknown cause. It is characterized by the aberrant activation of the bronchioalveolar epithelium, the formation of fibroblast foci and the excessive production extracellular matrix. The cellular and molecular mechanisms that contribute to the pathobiology of the disease are unclear. The CX3CL1-CX3CR1 axis regulates cellular responses that are known to be relevant in IPF, such as proliferation and collagen production. In this study, we characterize for the first time the expression of CX3CL1 and its receptor in lung tissue from patients with IPF; and its effect on collagen production in IPF fibroblasts. We found that CX3CL1-CX3CR1 axis has a modified expression in the lung tissue, importantly this axis is expressed on fibroblasts, and CX3CL1 decreased the collagen production in pulmonary fibroblasts derived from IPF patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Hypersensitivity pneumonitis is an immune-mediated disease triggered by exposure to organic particles in susceptible individuals. It has been reported that a subgroup of patients with hypersensitivity pneumonitis develops autoantibodies with or without clinical manifestations of autoimmune disease. However, the mechanisms involved in this process and the effect of the autoantibodies on clinical course in hypersensitivity pneumonitis is unknown. We evaluated the association between human leukocyte antigen (HLA) class II alleles and hypersensitivity pneumonitis patients with and without autoantibodies., Methods: 170 hypersensitivity pneumonitis patients were included. We analysed the presence of antinuclear antibodies, rheumatoid factor, anti-SSA/Ro, anti-SSB/La and anti-CCP at the time of diagnosis. In addition, in a subset of patients we evaluated anti-Scl-70, anti-neutrophil cytoplasmic antibody, and anti-DNA. HLA typing was performed using PCR sequence-specific primers in a high-resolution modality, including HLA-DRB1 and HLA-DQB1 loci. Statistical analysis was performed employing Epi-Info v7 and SPSS v20., Results: 60 hypersensitivity pneumonitis patients showed sera autoantibodies (HPAbs + ), and 110 hypersensitivity pneumonitis patients did not (HPAbs - ). The frequency of the allele HLA-DRB1*03:01 was remarkably increased in the HPAbs + group (10.8% versus 0.45%; OR 30.14, 95% CI 3.83-237.1; p=1.65×10 -4 after Bonferroni's correction). Likewise, we found that the haplotype DRB1*03:01-DQB1*02:01 , which is part of the 8.1 ancestral haplotype, a major genetic determinant of autoimmune diseases, confers significant risk to develop autoantibodies (OR 19.23, 95% CI 2.37-155.9; p=0.0088 after Bonferroni's correction). In addition, the HLA-DRB1*03:01 allele was associated with higher mortality in patients with hypersensitivity pneumonitis (adjusted OR 5.9, 95% CI 1.05-33.05; p=0.043)., Conclusions: A subset of hypersensitivity pneumonitis patients presents circulating autoantibodies and higher mortality that are associated with some alleles of 8.1 ancestral haplotype., Competing Interests: Conflict of interest: I. Buendía-Roldán has nothing to disclose. Conflict of interest: L. Santiago-Ruiz has nothing to disclose. Conflict of interest: G. Pérez-Rubio has nothing to disclose. Conflict of interest: M. Mejía has nothing to disclose. Conflict of interest: J. Rojas-Serrano has nothing to disclose. Conflict of interest: E. Ambrocio-Ortiz has nothing to disclose. Conflict of interest: G. Benítez-Valdez has nothing to disclose. Conflict of interest: M. Selman has nothing to disclose. Conflict of interest: R. Falfán-Valencia has nothing to disclose., (Copyright ©ERS 2020.)

Fibrosing diseases are causes of morbidity and mortality around the world, and they are characterized by excessive extracellular matrix (ECM) accumulation. The bHLH transcription factor scleraxis (SCX) regulates the synthesis of ECM proteins in heart fibrosis. SCX expression was evaluated in lung fibroblasts and tissue derived from fibrotic disease patients and healthy controls. We also measured SCX in sera from 57 healthy controls, and 56 Idiopathic Pulmonary Fibrosis (IPF), 40 Hypersensitivity Pneumonitis (HP), and 100 Systemic Sclerosis (SSc) patients. We report high SCX expression in fibroblasts and tissue from IPF patients versus controls. High SCX-serum levels were observed in IPF (0.663 ± 0.559 ng/mL, p < 0.01) and SSc (0.611 ± 0.296 ng/mL, p < 0.001), versus controls (0.351 ± 0.207 ng/mL) and HP (0.323 ± 0.323 ng/mL). Serum levels of the SCX heterodimerization partner, TCF3, did not associate with fibrotic illness. IPF patients with severely affected respiratory capacities and late-stage SSc patients presenting anti-topoisomerase I antibodies and interstitial lung disease showed the highest SCX-serum levels. SCX gain-of-function induced the expression of alpha-smooth muscle actin (α-SMA/ACTA2) in fibroblasts when co-overexpressed with TCF3. As late and severe stages of the fibrotic processes correlated with high circulating SCX, we postulate it as a candidate biomarker of fibrosis and a potential therapeutic target.

The lung microbiome composition has critical implications in the regulation of innate and adaptive immune responses. Next-generation sequencing techniques have revolutionized the understanding of pulmonary physiology and pathology. Currently, it is clear that the lung is not a sterile place; therefore, the investigation of the participation of the pulmonary microbiome in the presentation, severity, and prognosis of multiple pathologies, such as asthma, chronic obstructive pulmonary disease, and interstitial lung diseases, contributes to a better understanding of the pathophysiology. Dysregulation of microbiota components in the microbiome-host interaction is associated with multiple lung pathologies, severity, and prognosis, making microbiome study a useful tool for the identification of potential therapeutic strategies. This review integrates the findings regarding the activation and regulation of the innate and adaptive immune response pathways according to the microbiome, including microbial patterns that could be characteristic of certain diseases. Further studies are required to verify whether the microbial profile and its metabolites can be used as biomarkers of disease progression or poor prognosis and to identify new therapeutic targets that restore lung dysbiosis safely and effectively.

Interstitial lung abnormalities (ILA) are observed in around 9% of older respiratory asymptomatic subjects, mainly smokers. Evidence suggests that ILA may precede the development of interstitial lung diseases and may evolve to progressive fibrosis. Identifying biomarkers of this subclinical status is relevant for early diagnosis and to predict outcome. We aimed to identify circulating microRNAs (miRNAs) associated to ILA in a cohort of respiratory asymptomatic subjects older than 60 years. We identified 81 subjects with ILA from our Lung-Aging Program in Mexico City ( n = 826). We randomly selected 112 subjects without ILA (Ctrl) from the same cohort. Using polymerase chain reaction PCR-Array technology (24 ILA and 24 Ctrl, screening cohort) and reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) (57 ILA and 88 Ctr, independent validation cohort) we identified seven up-regulated miRNAs in serum of ILA compared to Ctrl (miR-193a-5p, p < 0.0001; miR-502-3p, p < 0.0001; miR-200c-3p, p = 0.003; miR-16-5p, p = 0.003; miR-21-5p, p = 0.002; miR-126-3p, p = 0.004 and miR-34a-5p, p < 0.005). Pathways regulated by these miRNAs include transforming growth factor beta (TGF-β), Wnt, mammalian target of rapamycin (mTOR), Insulin, mitogen-activated protein kinase (MAPK) signaling, and senescence. Receiver operator characteristic (ROC) curve analysis indicated that miR-193a-5p (area under the curve AUC: 0.75) and miR-502-3p (AUC 0.71) have acceptable diagnostic value. This is the first identification of circulating miRNAs associated to ILA in respiratory asymptomatic subjects, providing potential non-invasive biomarkers and molecular targets to better understand the pathogenic mechanisms associated to ILA.

Anti-tRNA autoantibodies are associated with interstitial lung disease (ILD), in at least two clinical scenarios: the anti-synthetase syndrome (ASSD) and interstitial pneumonia with autoimmune features (IPAF). Under pathological conditions, cytokines indicate the participating elements and the course of inflammatory phenomena. We aimed to quantify serum concentrations of different inflammatory cytokines profiles in patients with anti-tRNA associated ILD (anti-tRNA-ILD) and estimate the association between these and ILD improvement and progression. Serum levels of 18 cytokines from baseline and after six months of treatment of ILD patients' positives to anti-tRNA were included in the current study. At six months, patients were classified as with or without ILD progression. A total of 39 patients were included (10 anti-Jo1, eight anti-PL7, 11 anti-PL12, and 10 anti-Ej). Three patients (7.6%) had ILD progression (progressors patients, PP) and showed statistically higher levels in IL-4, IL-10, IL-17A, IL-22, GM-CSF, IL-1β, IL-6, IL-12, IL-18, and TNF-α, compared to patients without disease progression (no progressors patients, NPP). IL-17A, IL-1β, and IL-6 (T-helper-lymphocyte (Th)17 inflammatory cytokine profile) were elevated and had a high discriminatory capacity in distinguishing ILD PP of those NPP at follow-up. Overall, there is an association between the cytokines of the Th17 inflammatory profile and the ASSD progression.