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/m2 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.

Collagen 3D matrices as a model for the study of cell behavior in pulmonary fibrosis.

Purpose: Idiopathic pulmonary fibrosis (IPF) is a complex progressive chronic lung disease where epithelial to mesenchymal interaction, extracellular matrix (ECM) contact, and pro-fibrotic cytokines dynamics take part in the development of the disease. The study of IPF in the widespread in vitro two-dimensional (2 D) culture fails to explain the interaction of cells with the changing environment that occurs in fibrotic lung tissue. A three-dimensional (3 D) co-culture model might shed light on the pathogenesis of IPF by mimicking the fibrotic environment. Materials and Methods: Fibroblasts from nine IPF were isolated and embedded in collagen matrices with the alveolar epithelial human cell line (A549) on the top. Cells were also cultured in 2 D with and without TGF-ß1 as a conventional model to compare with. Both types of cells were isolated separately. Protein and gene expression of the main fibrotic markers were measured by qPCR, Western blot, and ELISA. Results: IPF fibroblasts to myofibroblasts differentiation was observed in the 3 D model and in cells stimulated with TGF-ß1. In addition, ECM-related genes were highly up-regulated in the 3 D collagen matrix. A549 co-cultured 3 D with IPF fibroblasts showed EMT activation, with down-regulation of E-cadherin (CDH1). However, other pro-fibrotic genes as VIM, TGFB1, and MMP7 were up-regulated in A549 co-cultured 3 D with fibroblasts. Conclusions: 3 D-collagen matrices might induce fibroblasts' fibrotic phenotype as in the classic TGF-ß1 model, by up-regulating genes associated with matrix production. In addition, IPF lung fibroblasts seem to exert a pro-fibrotic influence in A549 cells when they are co-cultured. These results suggest that an improved 3 D co-culture model might serve as an important tool to study the fibrotic process and its regulation.

Effects of Early Physical Therapy and Follow-Up in Acute Severe Coronavirus Disease 2019 Pneumonia: A Retrospective Observational Study.

Background: Rehabilitation in subjects with severe coronavirus disease 2019 (COVID-19) pneumonia has been widely recommended. However, data regarding the starting time of rehabilitation, subjects and healthcare workers' safety, as well as rehabilitation program features are limited. We aimed to assess the safety and characterize the effect of early and non-early physiotherapy on severe COVID-19 pneumonia subjects. Methods: A retrospective cohort study, including a consecutive sample of surviving subjects admitted to an acute care hospital due to severe COVID-19 pneumonia from March 13th to May 15th of 2020, is made. Subjects were separated into three groups: non-physical therapy, early physiotherapy (onset <7 days of admission), and non-early physiotherapy. Subject and therapist safety and length of hospital stay were the main evaluated outcomes. Results: A total of 159 subjects were included (72% men; median age 62 years). Rehabilitation was performed on 108 subjects (32 early and 76 non-early physiotherapies). The length of hospital stay was 19 [interquartile range (IQR) 36.25] and 34 days (IQR 27.25) (p = 0.001) for early and non-early physiotherapy groups, respectively. No physiotherapist was infected and no subject adverse effect was identified. Multivariate analysis of subjects receiving physiotherapy during admission identified obesity [odds ratio (OR) 3.21; p-value 0.028], invasive mechanical ventilation (OR 6.25; p-value <0.001), and non-early physiotherapy (OR 3.54; p-value 0.017) as independent factors associated with a higher risk of prolonged hospital stay. Survivors' follow-up after hospital discharge at 8 weeks was completed by 54% of subjects. Conclusion: Rehabilitation in acute severe COVID-19 pneumonia is safe for subjects and healthcare workers and could reduce the length of hospitalization stay, especially in those that may start early.

Different Faces of Idiopathic Pulmonary Fibrosis With Preserved Forced Vital Capacity.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is progressive and irreversible. Some discrepancies about IPF staging exists, especially in mild phases. Forced vital capacity (FVC) higher than 80% has been considered early or mild IPF even for the design of clinical trials. METHODS: Spanish multicentre, observational, retrospective study of IPF patients diagnosed between 2012 and 2016, based on the ATS/ERS criteria, which presented FVC greater or equal 80% at diagnosis. Clinical and demographic characteristics, lung function, radiological pattern, treatment, and follow-up were analyzed. RESULTS: 225 IPF patients were included, 72.9% were men. The mean age was 69.5 years. The predominant high-resolution computed tomography (HRCT) pattern was consistent usual interstitial pneumonia (UIP) (51.6%). 84.7% of patients presented respiratory symptoms (exertional dyspnea and/or cough) and 33.33% showed oxygen desaturation below 90% in the 6min walking test (6MWT). Anti-fibrotic treatment was initiated at diagnosis in 55.11% of patients. Median FVC was 89.6% (IQR 17) and 58.7% of patients had a decrease of diffusion lung capacity for carbon monoxide (DLCO) below 60% of theoretical value; most of them presented functional progression (61.4%) and higher mortality at 3 years (20.45%). A statistically significant correlation with the 3-years mortality was observed between DLCO <60% and consistent UIP radiological pattern. CONCLUSIONS: Patients with preserved FVC but presenting UIP radiological pattern and moderate-severe DLCO decrease at diagnosis associate an increased risk of progression, death or lung transplantation. Therefore, in these cases, preserved FVC would not be representative of early or mild IPF.

Management of Acute Exacerbation of Idiopathic Pulmonary Fibrosis in Specialised and Non-specialised ILD Centres Around the World.

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a severe complication associated with a high mortality. However, evidence and guidance on management is sparse. The aim of this international survey was to assess differences in prevention, diagnostic and treatment strategies for AE-IPF in specialised and non-specialised ILD centres worldwide. Material and Methods: Pulmonologists working in specialised and non-specialised ILD centres were invited to participate in a survey designed by an international expert panel. Responses were evaluated in respect to the physicians' institutions. Results: Three hundred and two (65%) of the respondents worked in a specialised ILD centre, 134 (29%) in a non-specialised pulmonology centre. Similarities were frequent with regards to diagnostic methods including radiology and screening for infection, treatment with corticosteroids, use of high-flow oxygen and non-invasive ventilation in critical ill patients and palliative strategies. However, differences were significant in terms of the use of KL-6 and pathogen testing in urine, treatments with cyclosporine and recombinant thrombomodulin, extracorporeal membrane oxygenation in critical ill patients as well as antacid medication and anaesthesia measures as preventive methods. Conclusion: Despite the absence of recommendations, approaches to the prevention, diagnosis and treatment of AE-IPF are comparable in specialised and non-specialised ILD centres, yet certain differences in the managements of AE-IPF exist. Clinical trials and guidelines are needed to improve patient care and prognosis in AE-IPF.

Lung Transplant Improves Survival and Quality of Life Regardless of Telomere Dysfunction.

Introduction: Fibrotic interstitial lung diseases (ILDs) are the first indication for lung transplantation (LT). Telomere dysfunction has been associated with poor post-transplant outcomes. The aim of the study was to evaluate the morbi-mortality and quality of life in fibrotic ILDs after lung transplant depending on telomere biology. Methods: Fibrotic ILD patients that underwent lung transplant were allocated to two arms; with or without telomere dysfunction at diagnosis based on the telomere length and telomerase related gene mutations revealed by whole-exome sequencing. Post-transplant evaluation included: (1) short and long-term mortality and complications and (2) quality of life. Results: Fifty-five percent of patients that underwent LT carried rare coding mutations in telomerase-related genes. Patients with telomere shortening more frequently needed extracorporeal circulation and presented a higher rate of early post-transplant hematological complications, longer stay in the intensive care unit (ICU), and a higher number of long-term hospital admissions. However, post-transplant 1-year survival was higher than 80% regardless of telomere dysfunction, with improvement in the quality of life and oxygen therapy withdrawal. Conclusions: Post-transplant morbidity is higher in patients with telomere dysfunction and differs according to elapsed time from transplantation. However, lung transplant improves survival and quality of life and the associated complications are manageable.

Methylprednisolone Pulses Plus Tacrolimus in Addition to Standard of Care vs. Standard of Care Alone in Patients With Severe COVID-19. A Randomized Controlled Trial.

Introduction: Severe lung injury is triggered by both the SARS-CoV-2 infection and the subsequent host-immune response in some COVID-19 patients. Methods: We conducted a randomized, single-center, open-label, phase II trial with the aim to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) vs. SoC alone, in hospitalized patients with severe COVID-19. The primary outcome was time to clinical stability within 56 days after randomization. Results: From April 1 to May 2, 2020, 55 patients were prospectively included for subsequent randomization; 27 were assigned to the experimental group and 28 to the control group. The experimental treatment was not associated with a difference in time to clinical stability (hazard ratio 0.73 [95% CI 0.39-1.37]) nor most secondary outcomes. Median methylprednisolone cumulative doses were significantly lower (360 mg [IQR 360-842] vs. 870 mg [IQR 364-1451]; p = 0.007), and administered for a shorter time (median of 4.00 days [3.00-17.5] vs. 18.5 days [3.00-53.2]; p = 0.011) in the experimental group than in the control group. Although not statistically significant, those receiving the experimental therapy showed a numerically lower all-cause mortality than those receiving SoC, especially at day 10 [2 (7.41%) vs. 5 (17.9%); OR 0.39 (95% CI 0.05-2.1); p = 0.282]. The total number of non-serious adverse events was 42 in each the two groups. Those receiving experimental treatment had a numerically higher rate of non-serious infectious adverse events [16 (38%) vs. 10 (24%)] and serious infectious adverse events [7 (35%) vs. 3 (23%)] than those receiving SoC. Conclusions: The combined use of methylprednisolone pulses plus tacrolimus, in addition to the SoC, did not significantly improve the time to clinical stability or other secondary outcomes compared with the SoC alone in severe COVID-19. Although not statistically significant, patients receiving the experimental therapy had numerically lower all-cause mortality than those receiving SoC, supporting recent non-randomized studies with calcineurin inhibitors. It is noteworthy that the present trial had a limited sample size and several other limitations. Therefore, further RCTs should be done to assess the efficacy and safety of tacrolimus to tackle the inflammatory stages of COVID-19. Clinical Trial Registration: Identifier [NCT04341038/EudraCT: 2020-001445-39].

Idiopathic pulmonary fibrosis cluster analysis highlights diagnostic delay and cardiovascular comorbidity association with outcome.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) prognosis is heterogeneous despite antifibrotic treatment. Cluster analysis has proven to be a useful tool in identifying interstitial lung disease phenotypes, which has yet to be performed in IPF. The aim of this study is to identify phenotypes of IPF with different prognoses and requirements. METHODS: Observational retrospective study including 136 IPF patients receiving antifibrotic treatment between 2012 and 2018. Six patients were excluded due to follow-up in other centres. Cluster analysis of 30 variables was performed using approximate singular value-based tensor decomposition method and comparative statistical analysis. RESULTS: The cluster analysis identified three different groups of patients according to disease behaviour and clinical features, including mortality, lung transplant and progression-free survival time after 3-year follow-up. Cluster 1 (n=60) was significantly associated (p=0.02) with higher mortality. Diagnostic delay was the most relevant characteristic of this cluster, as 48% of patients had ≥2 years from first respiratory symptoms to antifibrotic treatment initiation. Cluster 2 (n=22) had the longest progression-free survival time and was correlated to subclinical patients evaluated in the context of incidental findings or familial screening. Cluster 3 (n=48) showed the highest percentage of disease progression without cluster 1 mortality, with metabolic syndrome and cardiovascular comorbidities as the main characteristics. CONCLUSION: This cluster analysis of IPF patients suggests that diagnostic and treatment delay are the most significant factors associated with mortality, while IPF progression was more related to metabolic syndrome and cardiovascular comorbidities.

Mapping IPF helps identify geographic regions at higher risk for disease development and potential triggers.

BACKGROUND AND OBJECTIVE: The relationship between IPF development and environmental factors has not been completely elucidated. Analysing geographic regions of idiopathic pulmonary fibrosis (IPF) cases could help identify those areas with higher aggregation and investigate potential triggers. We hypothesize that cross-analysing location of IPF cases and areas of consistently high air pollution concentration could lead to recognition of environmental risk factors for IPF development. METHODS: This retrospective study analysed epidemiological and clinical data from 503 patients registered in the Observatory IPF.cat from January 2017 to June 2019. Incident and prevalent IPF cases from the Catalan region of Spain were graphed based on their postal address. We generated maps of the most relevant air pollutant PM2.5 from the last 10 years using data from the CALIOPE air quality forecast system and observational data. RESULTS: In 2018, the prevalence of IPF differed across provinces; from 8.1 cases per 100 000 habitants in Barcelona to 2.0 cases per 100 000 in Girona. The ratio of IPF was higher in some areas. Mapping PM2.5 levels illustrated that certain areas with more industry, traffic and shipping maintained markedly higher PM2.5 concentrations. Most of these locations correlated with higher aggregation of IPF cases. Compared with other risk factors, PM2.5 exposure was the most frequent. CONCLUSION: In this retrospective study, prevalence of IPF is higher in areas of elevated PM2.5 concentration. Prospective studies with targeted pollution mapping need to be done in specific geographies to compile a broader profile of environmental factors involved in the development of pulmonary fibrosis.

Rituximab as a rescue treatment added on mycophenolate mofetil background therapy in progressive systemic sclerosis associated interstitial lung disease unresponsive to conventional immunosuppression.

OBJECTIVE: To test whether the use of rituximab (RTX) is effective and safe as a rescue therapy add-on treatment to mycophenolate (MMF) in patients with progressive systemic sclerosis-associated interstitial lung disease (SSc-ILD) in whom conventional immunosuppressants (IS) have failed. METHODS: Longitudinal retrospective observational study of a cohort of patients with SSc-ILD that started treatment with RTX due to ongoing lung function impairment despite treatment with glucocorticoids and IS (cyclophosphamide and/or MMF). All patients were treated with 2 or more cycles of RTX and evaluated for at least 12 months. RESULTS: Twenty-four patients were included. Before initiation of RTX the mean decline in%pFVC and %pDLCO during the previous 2 years (delta) was -12.9% and -12.5%, respectively. After 1 year of treatment with RTX, a significant improvement in %pFVC (∆+8.8% compared to baseline, 95% CI: -13.7 to -3.9; p = 0.001) and%pDLCO (∆+4.6%, 95% CI: -8.2 to -0.8; p = 0.018) was observed. In addition, there was a significant reduction in the median dose of prednisone and it could be suspended in 25% of patients. At 2 years of treatment, RTX had been discontinued in 9 patients (due to adverse events in 3 cases and inefficacy in 6). In the 15 patients (62.5%) that completed 24 months of therapy, the statistically significant amelioration in pulmonary function test parameters was maintained: ∆%pFVC: +11.1% (95% CI: -17.6 to -4.5; p = 0.003) and ∆%pDLCO: +8.7% (95% CI: -13.9 to -8.3; p = 0.003). CONCLUSION: Based on our results, RTX's use as an add-on treatment to MMF appears to be effective as a rescue therapy in patients with a more aggressive SSc-ILD phenotype.

Real-world clinical effectiveness of rituximab rescue therapy in patients with progressive rheumatoid arthritis-related interstitial lung disease.

OBJECTIVE: To assess the real-world, long-term effectiveness of rituximab (RTX) as a rescue therapy in patients with progressive rheumatoid arthritis-related interstitial lung disease (RA-ILD) in whom more conventional therapy has failed. METHODS: Longitudinal retrospective observational study of a cohort of patients with RA-ILD that started treatment with RTX due to ongoing progressive ILD despite treatment with glucocorticoids and csDMARDs or immunosuppressants (IS). All patients were treated with two or more cycles of RTX and evaluated for at least 12 months. Ongoing therapy with csDMARDs or IS remained unchanged. RESULTS: Thirty-one patients were analyzed. Before initiation of RTX the mean decline (delta) in %pFVC and %pDLCO from the ILD diagnosis (median 21 months) was -16.5% and -19.7%, respectively. After 1 year of treatment, RTX was able to reverse the decline of pulmonary function test (PFTs) parameters: ∆%pFVC +8.06% compared to baseline (95% CI: -10.9 to -5.2; p<0.001) and ∆%pDLCO +12.7% (95% CI: -16.3 to -9.1; p<0.001). In addition, there was a significant reduction in the median dose of prednisone, and it could be suspended in 26% of cases. Dividing the population into UIP and non-UIP patterns, we observed a significant increase in PFTs parameters in both groups. In the 25 patients (80.6%) that completed 2 years of treatment, the statistically significant amelioration in PFTs parameters observed at one year was maintained: ∆%pFVC +11.2% (95% CI: -15.6 to -6.8; p<0.001) and ∆%pDLCO +14.8% (95% CI: -19.3 to -10.3; p<0.001). At the end of the follow-up period (median 32 months; IQR 25th-75th 26-64), only 23 of the 31 patients (74.2%) were still undergoing treatment with RTX: in 3 cases (10%) it was stopped due to adverse events, in another 3 (10%) treatment failed ultimately requiring a lung transplant, and 2 patients (6%) died due to progression of the ILD and infectious complications. The frequency of adverse events reached 32% of cases. CONCLUSION: Based on our results, RTX appears to be effective as rescue therapy in a considerable proportion of patients with progressive RA-ILD unresponsive to conventional treatment.