The respiratory microbiome in bronchial mucosa and secretions from severe IgE-mediated asthma patients

Altres ajuts: This work was supported by Fundació Catalana de Neumología (FUCAP) and Centro de Investigación Biomédica en Red de Enfermedades Respiratorias(CIBERES). CIBERES is an initiative of the Instituto de Salud Carlos III.The bronchial microbiome in chronic lung diseases presents an abnormal pattern, but its microbial composition and regional differences in severe asthma have not been sufficiently addressed. The aim of the study was to describe the bacterial community in bronchial mucosa and secretions of patients with severe chronic asthma chronically treated with corticosteroids in addition to usual care according to Global Initiative for Asthma. Bacterial community composition was obtained by 16S rRNA gene amplification and sequencing, and functional capabilities through PICRUSt. Thirteen patients with severe asthma were included and provided 11 bronchial biopsies (BB) and 12 bronchial aspirates (BA) suitable for sequence analyses. Bacteroidetes, Firmicutes, Proteobacteria and Actinobacteria showed relative abundances (RAs) over 5% in BB, a cutoff that was reached by Streptococcus and Prevotella at genus level. Legionella genus attained a median RA of 2.7 (interquartile range 1.1-4.7) in BB samples. In BA a higher RA of Fusobacteria was found, when compared with BB [8.7 (5.9-11.4) vs 4.2 (0.8-7.5), p = 0.037], while the RA of Proteobacteria was lower in BA [4.3 (3.7-6.5) vs 17.1 (11.2-33.4), p = 0.005]. RA of the Legionella genus was also significantly lower in BA [0.004 (0.001-0.02) vs. 2.7 (1.1-4.7), p = 0.005]. Beta-diversity analysis confirmed the differences between the microbial communities in BA and BB (R 2 = 0.20, p = 0.001, Adonis test), and functional analysis revealed also statistically significant differences between both types of sample on Metabolism, Cellular processes, Human diseases, Organismal systems and Genetic information processing pathways. The microbiota in the bronchial mucosa of severe asthma has a specific pattern that is not accurately represented in bronchial secretions, which must be considered a different niche of bacteria growth. The online version of this article (doi:10.1186/s12866-017-0933-6) contains supplementary material, which is available to authorized users

Rituximab in the treatment of progressive interstitial lung disease associated with the antisynthetase syndrome

Objective To assess the real-world, long-term effectiveness of rituximab (RTX) as a rescue therapy in patients with antisynthetase syndrome and progressive interstitial lung disease (ASS-ILD). Methods Multicentre observational retrospective longitudinal study of a cohort of patients with ASS-ILD that started treatment with RTX due to recurrent or ongoing progressive ILD despite therapy with glucocorticoids and immunosuppressants. Results Twenty-eight patients were analyzed. Examining the entire study population, before treatment with RTX the mean decline in %pFVC and %pDLCO from the ASS-ILD diagnosis to the initiation of RTX treatment (T0) was -6.44% and -14.85%, respectively. After six months of treatment, RTX reversed the decline in pulmonary function test (PFT) parameters: triangle%pFVC +6.29% (95% CI: -10.07 to 2.51; p=0.002 compared to T0) and triangle%pDLCO +6.15% (95% CI: -10.86 to -1.43; p=0.013). Twenty-four patients completed one year of therapy and 22 two years, maintaining the response in PFT: triangle%pFVC: +9.93% (95% CI: -15.61 to -4.25; p=0.002) and triangle%pDLCO: +7.66% (95% CI: -11.67 to -3.65; p<0.001). In addition, there was a significant reduction in the median dose of prednisone, and it could be suspended in 18% of cases. In 33% of patients who required oxygen therapy at the start of treatment, it could be discontinued. The frequency of adverse events reached 28.5% of cases. Results Twenty-eight patients were analyzed. Examining the entire study population, before treatment with RTX the mean decline in %pFVC and %pDLCO from the ASS-ILD diagnosis to the initiation of RTX treatment (T0) was -6.44% and -14.85%, respectively. After six months of treatment, RTX reversed the decline in pulmonary function test (PFT) parameters: triangle%pFVC +6.29% (95% CI: -10.07 to 2.51; p=0.002 compared to T0) and triangle%pDLCO +6.15% (95% CI: -10.86 to -1.43; p=0.013). Twenty-four patients completed one year of therapy and 22 two years, maintaining the response in PFT: triangle%pFVC: +9.93% (95% CI: -15.61 to -4.25; p=0.002) and triangle%pDLCO: +7.66% (95% CI: -11.67 to -3.65; p<0.001). In addition, there was a significant reduction in the median dose of prednisone, and it could be suspended in 18% of cases. In 33% of patients who required oxygen therapy at the start of treatment, it could be discontinued. The frequency of adverse events reached 28.5% of cases. Conclusion Based on our results, RTX appears to be effective as rescue therapy in most patients with recurrent or progressive ASS-ILD unresponsive to conventional treatment. The use of RTX was well tolerated in the majority of patients

Clinical Outcomes of Severe COVID-19 Patients Admitted to an Intermediate Respiratory Care Unit

Introduction: Many severe COVID-19 patients require respiratory support and monitoring. An intermediate respiratory care unit (IMCU) may be a valuable element for optimizing patient care and limited health-care resources management. We aim to assess the clinical outcomes of severe COVID-19 patients admitted to an IMCU. Methods: Observational, retrospective study including patients admitted to the IMCU due to COVID-19 pneumonia during the months of March and April 2020. Patients were stratified based on their requirement of transfer to the intensive care unit (ICU) and on survival status at the end of follow-up. A multivariable Cox proportional hazards method was used to assess risk factors associated with mortality. Results: A total of 253 patients were included. Of them, 68% were male and median age was 65 years (IQR 18 years). Ninety-two patients (36.4%) required ICU transfer. Patients transferred to the ICU had a higher mortality rate (44.6 vs. 24.2%; p < 0.001). Multivariable proportional hazards model showed that age ≥65 years (HR 4.14; 95%CI 2.31-7.42; p < 0.001); chronic respiratory conditions (HR 2.34; 95%CI 1.38-3.99; p = 0.002) and chronic kidney disease (HR 2.96; 95%CI 1.61-5.43; p < 0.001) were independently associated with mortality. High-dose systemic corticosteroids followed by progressive dose tapering showed a lower risk of death (HR 0.15; 95%CI 0.06-0.40; p < 0.001). Conclusions: IMCU may be a useful tool for the multidisciplinary management of severe COVID-19 patients requiring respiratory support and non-invasive monitoring, therefore reducing ICU burden. Older age and chronic respiratory or renal conditions are associated with worse clinical outcomes, while treatment with systemic corticosteroids may have a protective effect on mortality

Predictors and changes of physical activity in idiopathic pulmonary fibrosis

Background Different clinical predictors of physical activity (PA) have been described in idiopathic pulmonary fibrosis (IPF), but studies are lacking evaluating the potential role of muscle strength and anxiety and depression symptoms in PA limitation. Moreover, little is known about the impact of changes in PA in the course of the disease. The aim of the present study was to investigate the relationship between baseline PA and a wide range of variables in IPF, to assess its longitudinal changes at 12 months and its impact on progression free-survival. Methods PA was assessed by accelerometer and physiological, clinical, psychological factors and health-related quality of life were evaluated in subjects with IPF at baseline and at 12 month follow-up. Predictors of PA were determined at baseline, evolution of PA parameters was described and the prognostic role of PA evolution was also established. Results Forty participants with IPF were included and 22 completed the follow-up. At baseline, subjects performed 5765 (3442) daily steps and spent 64 (44) minutes/day in moderate to vigorous PA. Multivariate regression models showed that at baseline, a lower six-minute walked distance, lower quadriceps strength (QMVC), and a higher depression score in the Hospital Anxiety and Depression scale were associated to lower daily step number. In addition, being in (Gender-Age-Physiology) GAP III stage, having a BMI >= 25 kg/m(2) and lower QMVC or maximum inspiratory pressure were factors associated with sedentary behaviour. Adjusted for age, gender and forced vital capacity (FVC) (%pred.) a lower progression-free survival was evidenced in those subjects that decreased PA compared to those that maintained, or even increased it, at 12 months [HR 12.1 (95% CI, 1.9-78.8); p = 0.009]. Conclusion Among a wide range of variables, muscle strength and depression symptoms have a predominant role in PA in IPF patients. Daily PA behaviour and its evolution should be considered in IPF clinical assessment and as a potential complementary indicator of disease prognosis

Diagnostic delay of associated interstitial lung disease increases mortality in rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease whose main extra-articular organ affected is the lung, sometimes in the form of diffuse interstitial lung disease (ILD) and conditions the prognosis. A multicenter, observational, descriptive and cross-sectional study of consecutive patients diagnosed with RA-ILD. Demographic, analytical, respiratory functional and evolution characteristics were analyzed to evaluate the predictors of progression and mortality. 106 patients were included. The multivariate analysis showed that the diagnostic delay was an independent predictor of mortality (HR 1.11, CI 1.01-1.23, p = 0.035). Also, age (HR 1.33, 95% CI 1.09-1.62, p = 0.0045), DLCO (%) (HR 0.85, 95% CI 0.73-0.98, p = 0.0246), and final SatO2 (%) in the 6MWT (HR 0.62, 95% CI 0.39-0.99, p = 0.0465) were independent predictor variables of mortality, as well as GAP index (HR 4.65, 95% CI 1.59-13.54, p = 0.0051) and CPI index (HR 1.12, 95% CI 1.03-1.22, p = 0.0092). The withdrawal of MTX or LFN after ILD diagnosis was associated with disease progression in the COX analysis (HR 2.18, 95% CI 1.14-4.18, p = 0.019). This is the first study that highlights the diagnostic delay in RA-ILD is associated with an increased mortality just like happens in IPF

Patient Reported Experiences and Delays During the Diagnostic Pathway for Pulmonary Fibrosis: A Multinational European Survey.

Introduction: Pulmonary fibrosis includes a spectrum of diseases and is incurable. There is a variation in disease course, but it is often progressive leading to increased breathlessness, impaired quality of life, and decreased life expectancy. Detection of pulmonary fibrosis is challenging, which contributes to considerable delays in diagnosis and treatment. More knowledge about the diagnostic journey from patients' perspective is needed to improve the diagnostic pathway. The aims of this study were to evaluate the time to diagnosis of pulmonary fibrosis, identify potential reasons for delays, and document patients emotions. Methods: Members of European patient organisations, with a self-reported diagnosis of pulmonary fibrosis, were invited to participate in an online survey. The survey assessed the diagnostic pathway retrospectively, focusing on four stages: (1) time from initial symptoms to first appointment in primary care; (2) time to hospital referral; (3) time to first hospital appointment; (4) time to final diagnosis. It comprised open-ended and closed questions focusing on time to diagnosis, factors contributing to delays, diagnostic tests, patient emotions, and information provision. Results: Two hundred and seventy three participants (214 idiopathic pulmonary fibrosis, 28 sarcoidosis, 31 other) from 13 countries responded. Forty percent of individuals took ≥1 year to receive a final diagnosis. Greatest delays were reported in stage 1, with only 50.2% making an appointment within 3 months. For stage 2, 73.3% reported a hospital referral within three primary care visits. However, 9.9% reported six or more visits. After referral, 76.9% of patients were assessed by a specialist within 3 months (stage 3) and 62.6% received a final diagnosis within 3 months of their first hospital visit (stage 4). Emotions during the journey were overall negative. A major need for more information and support during and after the diagnostic process was identified. Conclusion: The time to diagnose pulmonary fibrosis varies widely across Europe. Delays occur at each stage of the diagnostic pathway. Raising awareness about pulmonary fibrosis amongst the general population and healthcare workers is essential to shorten the time to diagnosis. Furthermore, there remains a need to provide patients with sufficient information and support at all stages of their diagnostic journey

The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.

BACKGROUND AND AIMS Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. APPROACH AND RESULTS C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD + /NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. CONCLUSIONS Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.This work was supported by grants from Ministerio de Ciencia e Innovación, Programa Retos-Colaboración RTC2019-007125-1 (for Jorge Simon and Maria Luz Martinez-Chantar); Ministerio de Economía, Industria y Competitividad, Retos a la Sociedad AGL2017- 86927R (for F.M.); Instituto de Salud Carlos III, Proyectos de Investigación en Salud DTS20/00138 and DTS21/00094 (for Jorge Simon and Maria Luz Martinez-Chantar, and Asis Palazon. respectively); Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-founded by European Regional Development Fund/European Social Fund, “Investing in your future” PI19/00819, “Una manera de hacer Europa” FIS PI20/00765, and PI21/01067 (for Jose J. G. Marin., Pau Sancho-Bru,. and Mario F. Fraga respectively); Departamento de Industria del Gobierno Vasco (for Maria Luz Martinez-Chantar); Asturias Government (PCTI) co-funding 2018-2023/ FEDER IDI/2021/000077 (for Mario F. Fraga.); Ministerio de Ciencia, Innovación y Universidades MICINN: PID2020-117116RB-I00, CEX2021-001136-S PID2020-117941RB-I00, PID2020-11827RB-I00 and PID2019-107956RA-100 integrado en el Plan Estatal de Investigación Científica y Técnica y Innovación, cofinanciado con Fondos FEDER (for Maria Luz Martinez-Chantar, Francisco J Cubero., Yulia A Nevzorova and Asis Palazon); Ayudas Ramón y Cajal de la Agencia Estatal de Investigación RY2013-13666 and RYC2018- 024183-I (for Leticia Abecia and Asis Palazon); European Research Council Starting Grant 804236 NEXTGEN-IO (for Asis Palazon); The German Research Foundation SFB/TRR57/P04, SFB1382-403224013/ A02 and DFG NE 2128/2-1 (for Francisco J Cubero and Yulia A Nevzorova); National Institute of Health (NIH)/National Institute of Alcohol Abuse and Alcoholism (NIAAA) 1U01AA026972-01 (For Pau Sancho-Bru); Junta de Castilla y León SA074P20 (for Jose J. G. Marin); Junta de Andalucía, Grupo PAIDI BIO311 (for Franz Martin); CIBERER Acciones Cooperativas y Complementarias Intramurales ACCI20-35 (for Mario F. Fraga); Ministerio de Educación, Cultura y Deporte FPU17/04992 (for Silvia Ariño); Fundació Marato TV3 201916-31 (for Jose J. G. Marin.); Ainize Pena-Cearra is a fellow of the University of the Basque Country (UPV/ EHU); BIOEF (Basque Foundation for Innovation and Health Research); Asociación Española contra el Cáncer (Maria Luz Martinez-Chantar and Teresa C. Delgado.); Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation) Rare Tumor Calls 2017 (for Maria Luz Martinez-Chantar); La Caixa Foundation Program (for Maria Luz Martinez-Chantar); Proyecto Desarrollo Tecnologico CIBERehd (for Maria Luz Martinez-Chantar); Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III.S

¿Enfermedad o reacción pulmonar intersticial? Investigar hasta encontrar el origen

La neumonía organizativa es un patrón histológico que puede observarse asociado o reactivo en diferentes patologías. Presentamos el caso de una mujer de 67 años con diagnóstico inicial de neumonía organizada criptogénica, sin respuesta a los glucocorticoides y autoinmunidad negativa. Finalmente, la neumonía organizada resultó ser secundaria a neoplasia hematológica. En estos casos es importante insistir en la anamnesis y realizar los procedimientos necesarios para conseguir el diagnóstico definitivo

Comorbidities and Complications in Idiopathic Pulmonary Fibrosis

Though idiopathic pulmonary fibrosis (IPF) is characterized by single-organ involvement, many comorbid conditions occur within other organ systems. Patients with IPF may present during evolution different complications and comorbidities that influence the prognosis and modify the natural course of their disease. In this chapter, we highlight common comorbid conditions encountered in IPF, discuss disease-specific diagnostic modalities, and review the current treatment data for several key comorbidities. The diagnosis and treatment of these comorbidities is a challenge for the pulmonologist specialized in interstitial lung diseases (ILDs). We will focus on pulmonary emphysema, lung cancer, gastroesophageal reflux, pulmonary hypertension, obstructive sleep apnea (sleep disorders), and acute exacerbation of IPF