Clin Chest Med. 2021 Jun;42(2):229-239. doi: 10.1016/j.ccm.2021.03.001.

ABSTRACT

Interstitial lung diseases (ILDs) are heterogenous and complex chronic lung diseases that even today are challenging to diagnose and classify. The terminology and mechanistic understanding of specific ILDs have evolved substantially over the last centuries and decades, and clinicians, pathologists, radiologists, and researchers are continuously working to untangle the various ILDs of differing causes. Despite many drawbacks and negative clinical trials, the unremitting work of ILD researchers have resulted in great therapeutic successes over the last decade. In this chapter, the authors present historical aspects of ILD and build a foundation to understand current and emerging concepts in ILD.

PMID:34024399 | DOI:10.1016/j.ccm.2021.03.001

Adv Exp Med Biol. 2021;1304:227-258. doi: 10.1007/978-3-030-68748-9_14.

ABSTRACT

Sex differences in the anatomy and physiology of the respiratory system have been widely reported. These intrinsic sex differences have also been shown to modulate the pathophysiology, incidence, morbidity, and mortality of several lung diseases across the life span. In this chapter, we describe the epidemiology of sex differences in respiratory diseases including neonatal lung disease (respiratory distress syndrome, bronchopulmonary dysplasia) and pediatric and adult disease (including asthma, cystic fibrosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, lung cancer, lymphangioleiomyomatosis, obstructive sleep apnea, pulmonary arterial hypertension, and respiratory viral infections such as respiratory syncytial virus, influenza, and SARS-CoV-2). We also discuss the current state of research on the mechanisms underlying the observed sex differences in lung disease susceptibility and severity and the importance of considering both sex and gender variables in research studies' design and analysis.

PMID:34019273 | DOI:10.1007/978-3-030-68748-9_14

Adv Exp Med Biol. 2021;1304:73-94. doi: 10.1007/978-3-030-68748-9_5.

ABSTRACT

Pulmonary manifestations of connective tissue diseases (CTD) carry high morbidity and potential mortality, and the most serious pulmonary type is interstitial lung disease (ILD). Identifying and promptly intervening CTD-ILD with immune suppressor therapy will change the natural course of the disease resulting in survival improvement. Compared to idiopathic pulmonary fibrosis, the most common presentation of idiopathic interstitial pneumonia (IIP), CTD-ILD carries a better prognosis due to the response to immune suppressor therapy. Nonspecific interstitial pneumonia (NSIP) is the most common type of CTD-ILD that is different from the fibrotic classical presentation of IPF, known as usual interstitial pneumonia (UIP). An exception is rheumatoid arthritis that presents more frequently with UIP type. Occasionally, IPF may not have typical radiographic features of UIP, and a full assessment to differentiate IPF from CTD-ILD is necessary, including the intervention of a multidisciplinary team and the histopathology. Interstitial pneumonia with autoimmune features (IPAF) shows promising advantages to identify patients with ILD who have some features of a CTD without a defined autoimmune disease and who may benefit from immune suppressors. A composition of clinical, serological, and morphologic features in patients presenting with ILD will fulfill criteria for IPAF. In summary, the early recognition and treatment of CTD-ILD, differentiation from IPF-UIP, and identification of patients with IPAF fulfill the assessment by the clinician for an optimal care.

PMID:34019264 | DOI:10.1007/978-3-030-68748-9_5

Sichuan Da Xue Xue Bao Yi Xue Ban. 2021 May;52(3):373-379. doi: 10.12182/20210560304.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a type of pulmonary disease that progresses acutely or slowly into irreversible pulmonary diseases, resulting in the end severe damages to patients' lung functions, as well as deaths. At present, the pathogenesis of pulmonary fibrosis is still not clear and there is no effective therapeutic measure available to control the progression of the disease. Research findings indicate that stem cells, being the origin of all cells of organisms, participate in the development of individuals at various stages and play an important role in repairing pulmonary tissue damage. Stem cells are attracting growing attention in the field of regenerative medicine, providing new ideas for treating IPF with transplanted stem cells. Herein, in order to better explore the potential applications of stem cell transplantation in treating IPF, we attempt to summarize preliminary studies of stem cell-mediated pulmonary remodeling after IPF, as well as cutting-edge clinical trials in stem cell-based IPF therapy.

PMID:34018353 | DOI:10.12182/20210560304

Ann Am Thorac Soc. 2021 May 20. doi: 10.1513/AnnalsATS.202103-266OC. Online ahead of print.

ABSTRACT

RATIONALE: Patients with idiopathic pulmonary fibrosis (IPF) frequently suffer from difficult to treat chronic cough, which substantially affects their quality of life. Azithromycin has been demonstrated to relieve chronic cough in some populations, however this has not been investigated in IPF.

OBJECTIVES: To determine the safety and efficacy of azithromycin for the treatment of chronic cough in patients with IPF.

METHODS: In a double-blind randomized controlled cross-over trial, patients with IPF underwent two 12-week intervention periods (azithromycin 500mg or placebo 3 times per week). The primary outcome was change in cough-related quality of life measured by the Leicester cough questionnaire (LCQ). Secondary outcomes included cough severity measured using Visual Analog Scale (VAS), health-related quality of life assessed by the St. George's Respiratory Questionnaire (SGRQ), and objective cough frequency using audiovisual readings from 24h respiratory polygraphy.

RESULTS: 25 patients were randomized (23 men, 2 women), 20 patients completed the study. Mean (standard deviation, SD) age was 67 (8) years, mean (SD) forced vital capacity (FVC) was 65 (16) %-predicted, and diffusion capacity (DLCO) 43 (16) %-predicted. Mean (SD) baseline LCQ was 11.7 (3.7) and 11.3 (3.3) for the azithromycin and the placebo period, respectively, and the corresponding mean (SD) cough VAS 5.6 (2.3) and 5.8 (2.1). There was no significant change in LCQ and VAS with azithromycin or placebo. Similarly, there was no significant difference in change in polygraphy measured cough frequency between the azithromycin and placebo periods. Gastrointestinal adverse effects were more frequent with azithromycin than with placebo (diarrhea 43% vs 5%, p=0.03).

CONCLUSIONS: This randomized controlled trial does not support the use of low dose azithromycin for chronic cough in patients with IPF. Clinical trial registered with ClinicalTrials.gov (NCT02173145).

PMID:34015241 | DOI:10.1513/AnnalsATS.202103-266OC

Int J Mol Med. 2021 Jul;48(1):132. doi: 10.3892/ijmm.2021.4965. Epub 2021 May 20.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a worldwide disease characterized by the chronic and irreversible decline of lung function. Currently, there is no drug to successfully treat the disease except for lung transplantation. Numerous studies have been devoted to the study of the fibrotic process of IPF and findings showed that transforming growth factor‑β1 (TGF‑β1) plays a central role in the development of IPF. TGF‑β1 promotes the fibrotic process of IPF through various signaling pathways, including the Smad, MAPK, and ERK signaling pathways. There are intersections between these signaling pathways, which provide new targets for researchers to study new drugs. In addition, TGF‑β1 can affect the fibrosis process of IPF by affecting oxidative stress, epigenetics and other aspects. Most of the processes involved in TGF‑β1 promote IPF, but TGF‑β1 can also inhibit it. This review discusses the role of TGF‑β1 in IPF.

PMID:34013369 | DOI:10.3892/ijmm.2021.4965

J Thorac Dis. 2021 Apr;13(4):2319-2330. doi: 10.21037/jtd-20-1957.

ABSTRACT

BACKGROUND: Evidence of honeycombing in high-resolution computed tomography (HRCT) is a recognized risk factor for shortened survival in patients with idiopathic pulmonary fibrosis (IPF), but few studies have evaluated the feasibility of exploiting other specific patterns for predicting survival. The aim of this study was to examine the extent of specific HRCT patterns in IPF and determine whether they correlate with clinical features, pulmonary function tests (PFT), and survival.

METHODS: Both the presence and extent of specific HRCT patterns, such as traction bronchiectasis, honeycombing, architectural distortion, reticulation, emphysema, and ground glass opacity, in 129 HRCT examinations were scored semi-quantitatively in three zones of each lung. HRCT examinations were also re-classified according to the 2011 and 2018 international statements. Correlations were calculated between the scores of specific HRCT patterns, clinical features, PFT, and patient survival.

RESULTS: The extent of traction bronchiectasis was found to be an independent risk factor of shortened survival (HR 1.227, P=0.001). Patients with a possible usual interstitial pneumonia (UIP) pattern had a better median survival than the patients with a definite UIP pattern (61 vs. 37 months, P=0.026). The extents of traction bronchiectasis, honeycombing, and architectural distortion displayed an inverse correlation with all PFT values at the time of diagnosis. There were few differences between the radiological classifications of the 2011 and 2018 international statements.

CONCLUSIONS: We conclude that several specific HRCT patterns displayed a correlation with shortened survival in IPF; these may help in evaluating the risk of death in IPF patients.

PMID:34012581 | PMC:PMC8107523 | DOI:10.21037/jtd-20-1957

Ann Thorac Med. 2021 Apr-Jun;16(2):178-187. doi: 10.4103/atm.atm_14_21. Epub 2021 Apr 17.

ABSTRACT

BACKGROUND: Information regarding acute exacerbation (AE) in patients with interstitial lung disease (ILD) is limited.

OBJECTIVES: The objective of the study was to elucidate the clinical features and outcome of AE among ILD patients.

METHODS: We retrospectively analyzed the data of 667 consecutive ILD (nonidiopathic pulmonary fibrosis [IPF] ILD, n = 463; IPF, n = 204) patients. ILD patients meeting the 2016 definition of AE-IPF were identified. Information analyzed included pulmonary function tests, 6-min walk tests, and right heart catheterization data, among others. Cox regression models were used to identify independent predictors of survival.

RESULTS: AE was identified in non-IPF ILD (n = 113) and IPF (n = 74). Compared with AE-IPF patients, non-IPF ILD patients with AE were of younger age, predominantly women, and primarily nonsmokers (all, P < 0.0001). The estimated survival probabilities at 1, 3, and 5 years were 88%, 75%, and 70%, respectively, in the ILD without AE group; 80%, 57%, and 50%, respectively, in the non-IPF ILD with AE group; and 53%, 38%, and 28%, respectively, in the AE-IPF group (P < 0.0001 by log-rank analysis). Age, body mass index, IPF diagnosis, AE, diffusion capacity of the lung for carbon monoxide <35% predicted, 6-min walk distance <300 meters, and cardiac index were independent predictors of survival in the ILD cohort.

CONCLUSIONS: Non-IPF ILD patients with AE have distinct clinical features compared to AE-IPF patients. Importantly, AE is one of many independent risk factors associated with worsened outcomes regardless of the underlying ILD type.

PMID:34012485 | PMC:PMC8109689 | DOI:10.4103/atm.atm_14_21

Nat Commun. 2021 May 19;12(1):2923. doi: 10.1038/s41467-021-23277-8.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) causes progressive fibrosis and worsening pulmonary function. Prognosis is poor and no effective therapies exist. We show that programmed cell death 5 (PDCD5) expression is increased in the lungs of patients with IPF and in mouse models of lung fibrosis. Lung fibrosis is significantly diminished by club cell-specific deletion of Pdcd5 gene. PDCD5 mediates β-catenin/Smad3 complex formation, promoting TGF-β-induced transcriptional activation of matricellular genes. Club cell Pdcd5 knockdown reduces matricellular protein secretion, inhibiting fibroblast proliferation and collagen synthesis. Here, we demonstrate the club cell-specific role of PDCD5 as a mediator of lung fibrosis and potential therapeutic target for IPF.

PMID:34011956 | DOI:10.1038/s41467-021-23277-8

J Hosp Palliat Nurs. 2020 Dec 1;22(6):E29-E30. doi: 10.1097/NJH.0000000000000691.

NO ABSTRACT

PMID:34011863 | DOI:10.1097/NJH.0000000000000691

J Inflamm (Lond). 2021 May 19;18(1):17. doi: 10.1186/s12950-021-00284-6.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is an orphan disease characterized by progressive loss of lung function resulting in shortness of breath and often death within 3-4 years of diagnosis. Repetitive lung injury in susceptible individuals is believed to promote chronic oxidative stress, inflammation, and uncontrolled collagen deposition. Several preclinical and retrospective clinical studies in IPF have reported beneficial outcomes associated with the use of proton pump inhibitors (PPIs) such as esomeprazole. Accordingly, we sought to investigate molecular mechanism(s) by which PPIs favorably regulate the disease process.

METHODS: We stimulated oxidative stress, pro-inflammatory and profibrotic phenotypes in primary human lung epithelial cells and fibroblasts upon treatment with bleomycin or transforming growth factor β (TGFβ) and assessed the effect of a prototype PPI, esomeprazole, in regulating these processes.

RESULTS: Our study shows that esomeprazole controls pro-inflammatory and profibrotic molecules through nuclear translocation of the transcription factor nuclear factor-like 2 (Nrf2) and induction of the cytoprotective molecule heme oxygenase 1 (HO1). Genetic deletion of Nrf2 or pharmacological inhibition of HO1 impaired esomeprazole-mediated regulation of proinflammatory and profibrotic molecules. Additional studies indicate that activation of Mitogen Activated Protein Kinase (MAPK) pathway is involved in the process. Our experimental data was corroborated by bioinformatics studies of an NIH chemical library which hosts gene expression profiles of IPF lung fibroblasts treated with over 20,000 compounds including esomeprazole. Intriguingly, we found 45 genes that are upregulated in IPF but downregulated by esomeprazole. Pathway analysis showed that these genes are enriched for profibrotic processes. Unbiased high throughput RNA-seq study supported antifibrotic effect of esomeprazole and revealed several novel targets.

CONCLUSIONS: Taken together, PPIs may play antifibrotic role in IPF through direct regulation of the MAPK/Nrf2/HO1 pathway to favorably influence the disease process in IPF.

PMID:34011367 | DOI:10.1186/s12950-021-00284-6

Ther Adv Respir Dis. 2021 Jan-Dec;15:17534666211017050. doi: 10.1177/17534666211017050.

ABSTRACT

BACKGROUND: Lung cancer is an important complication of combined pulmonary fibrosis and emphysema (CPFE). Whether the risk of lung cancer is higher in CPFE patients with usual interstitial pneumonia (UIP) than those with idiopathic pulmonary fibrosis (IPF) alone, remains controversial. We conducted this systematic review and meta-analysis to evaluate the prevalence of lung cancer in CPFE patients with UIP compared with IPF patients.

METHODS: We searched the PubMed, Embase, and Cochrane databases for studies that focused on the incidence of lung cancer in CPFE/UIP and IPF groups. We used a fixed-effects model to analyze the odds ratios (ORs) with 95% confidence intervals (CIs) according to data heterogeneity. The cumulative effects based on the publication year and sample size were assessed by cumulative meta-analysis.

RESULTS: A total of nine studies with 933 patients, including 374 CPFE patients with UIP, fulfilled the inclusion criteria. Overall, CPFE patients with UIP have a higher risk of lung cancer than those with IPF alone (OR = 2.69; 95% CI: 1.78-4.05). There were increased risks of lung cancer in CPFE/UIP patients with the presence of emphysema (OR = 2.93; 95% CI: 1.79-4.79) or emphysema in ⩾10% of the lung volume (OR = 2.22; 95% CI: 1.06-4.68).

CONCLUSIONS: Our systematic review and meta-analysis indicated a significantly higher prevalence of lung cancer in CPFE patients with UIP than in patients with IPF alone.The reviews of this paper are available via the supplemental material section.

PMID:34011211 | DOI:10.1177/17534666211017050

Wound Repair Regen. 2021 May 19. doi: 10.1111/wrr.12929. Online ahead of print.

ABSTRACT

Glaucoma is a common progressive optic neuropathy that results in visual field defects and can lead to irreversible blindness. The pathophysiology of glaucoma involves dysregulated extracellular matrix remodelling in both the trabecular meshwork in the anterior chamber and in the lamina cribrosa of the optic nerve head. Fibrosis in these regions leads to raised intraocular pressure and retinal ganglion cell degeneration, respectively. Lysophosphatidic acid (LPA) is a bioactive lipid mediator which acts via six G-protein coupled receptors on the cell surface to activate intracellular pathways that promote cell proliferation, transcription and survival. LPA signalling has been implicated in both normal wound healing and pathological fibrosis. LPA enhances fibroblast proliferation, migration and contraction, and induces expression of pro-fibrotic mediators such as connective tissue growth factor. The LPA axis plays a major role in diseases such as idiopathic pulmonary fibrosis, where it has been identified as an important pharmacological target. In glaucoma, LPA is present in high levels in the aqueous humour, and its signalling has been found to increase resistance to aqueous humour outflow through altered trabecular meshwork cellular contraction and extracellular matrix deposition. LPA signalling may, therefore, also represent an attractive target for treatment of glaucoma. In this review we wish to describe the role of LPA and its related proteins in tissue fibrosis and glaucoma.

PMID:34009724 | DOI:10.1111/wrr.12929

Ann Am Thorac Soc. 2021 May 18. doi: 10.1513/AnnalsATS.202012-1494OC. Online ahead of print.

ABSTRACT

RATIONALE: Patients with Idiopathic Pulmonary Fibrosis (IPF) and their caregivers experience stress, symptom burden, poor quality of life (QOL), and inadequate preparedness for end of life (EOL) care planning as the disease progresses. The hypothesis for this study was early introduction of palliative care in the course of IPF would improve knowledge and preparation for the EOL, patient reported outcomes, and advance care planning in IPF patients and their caregivers.

OBJECTIVES: We sought to determine the feasibility, acceptability and efficacy of a nurse-led early palliative care intervention, entitled "A Program of SUPPORT" in patients with IPF and their caregivers.

METHODS: Patients with Idiopathic Pulmonary Fibrosis, diagnosed in the previous year from their initial center visit, and their caregivers from the University of Pittsburgh Dorothy P. & Richard P. Simmons Center for Interstitial Lung Disease (ILD) at UPMC were randomized to receive the intervention "A Program of SUPPORT" or usual care. This included a total of 3 research visits aligned with their clinic visit over a period of 6-8 months. We measured feasibility, acceptability, and efficacy of this intervention.

RESULTS: 136 patient/caregiver dyads were eligible, and a total of 76 dyads were enrolled and participated. Participants were predominately white males > 65 years old. Thirteen percent did not have an identified caregiver. Feasibility was limited; 56% of eligible dyads were enrolled. Eligible dyads (24%) were interested in participating, but too fatigued to stay after their clinic visit. There was high attrition -(20 % of participants died before the study was completed). "A Program of SUPPORT" was acceptable to participants. Efficacy demonstrated significant improvement in caregiver's knowledge, disease preparedness, and confidence in caring for the patient and an improvement in knowledge and advance care planning completion in patient participants.

CONCLUSIONS: Patients with IPF and their caregivers have unmet needs about knowledge of their disease, self-management strategies, and preparedness for EOL planning. This nurse-led intervention demonstrated acceptability and efficacy on knowledge and advance care plan completion in patients and knowledge, disease preparedness, and confidence in caregivers. Future research should identify additional strategies, including telemedicine resources to reach additional patients and their caregivers earlier in their disease course. Clinical trial is registered with ClinicalTrials.gov (NCT02929017).

PMID:34003726 | DOI:10.1513/AnnalsATS.202012-1494OC

Am J Manag Care. 2021 May;27(7 Suppl):S131-S137. doi: 10.37765/ajmc.2021.88655.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia, a form of interstitial lung disease characterized by abnormal wound healing in the lung that leads to progressive scarring and loss of lung function. Comorbidities are highly prevalent in IPF and often lead to further complications and worse outcomes. In fact, undetected and untreated comorbidities are independently associated with poor outcomes. IPF not only affects patient quality of life (QOL) but also requires significant cost for delivering care. Given the potential for rapid progression of IPF and the associated risk for mortality, early diagnosis is critical for retaining the highest lung function and QOL for as long as possible. Delayed diagnosis of IPF is associated with increased costs in terms of investigations performed, and delayed referral can result in lower survival rates independent of disease severity or associated prognostic factors. Significant progress has been made in understanding IPF pathogenesis, which has, in turn, led to the development of novel therapeutic options that improve outcomes, extend life, and minimize disease burden on patients' daily lives. For patients with IPF in the absence of underlying liver disease, pirfenidone and nintedanib are licensed for the treatment of IPF. Additionally, a number of investigational therapeutic options are currently in development. The extent of clinical effectiveness compared with the cost of therapy has led to a lack of consensus on the cost-vs-benefit analyses for the drugs.

PMID:34003616 | DOI:10.37765/ajmc.2021.88655

Eur Radiol. 2021 May 18. doi: 10.1007/s00330-021-08038-x. Online ahead of print.

ABSTRACT

OBJECTIVES: To determine the accuracy of CT-guided percutaneous transthoracic needle lung biopsy (PTNB) for the diagnosis of malignancy and the associated complication rates in patients with idiopathic pulmonary fibrosis (IPF).

METHODS: This retrospective study included 91 CT-guided PTNBs performed in 80 patients with IPF from April 2003 through December 2016. Data regarding patients, target lesions, procedures, complications, and pathological reports were collected, and the final diagnosis was made. The diagnostic accuracy, sensitivity, specificity, percentage of nondiagnostic results, and complication rates were determined. Multivariable logistic regression analyses were performed to identify risk factors for nondiagnostic results and major complications.

RESULTS: Three biopsies (technical failure [n = 2] and undetermined final diagnosis [n = 1]) were excluded from the diagnostic accuracy calculation. The diagnostic accuracy, sensitivity, and specificity were 89% (78/88), 90% (62/69), and 84% (16/19), respectively. The percentage of nondiagnostic results was 34% (30/88). Lesion size ≤ 3 cm (odds ratio [OR], 8.8; 95% confidence interval [CI], 2.5-31.2; p = 0.001) and needle tip placement outside the target lesion (OR, 13.7; 95% CI, 1.4-132.2; p = 0.02) were risk factors for nondiagnostic results. The overall and major complication rates were 51% (46/91) and 12% (11/91), respectively. The presence of honeycombing along the path of the needle (OR, 11.2; 95% CI, 1.4-89.1; p = 0.02) was an independent risk factor for major complications.

CONCLUSIONS: CT-guided PTNB shows a relatively reasonable accuracy in diagnosing malignancy in patients with IPF. The complication rate may be high, especially when the needle passes through honeycomb lesions.

KEY POINTS: • In patients with idiopathic pulmonary fibrosis (IPF), CT-guided percutaneous transthoracic needle lung biopsy (PTNB) showed a relatively reasonable accuracy for the diagnosis of malignancy. • Target lesion size ≤ 3 cm and biopsy needle tip placement outside the target lesion were risk factors for nondiagnostic results of CT-guided PTNB. • The complication rate may be high, especially in cases where the biopsy needle passes through honeycomb lesions.

PMID:34003347 | DOI:10.1007/s00330-021-08038-x

Diagn Interv Radiol. 2021 May;27(3):329-335. doi: 10.5152/dir.2021.19585.

ABSTRACT

PURPOSE: Mediastinal lymph node (MLN) enlargement detected on chest computed tomography (CT) is frequent in patients with interstitial lung disease (ILD) and is shown in approximately 70% of cases of idiopathic pulmonary fibrosis (IPF). We hypothesized that enlarged MLNs might be a predictor of poor prognosis, associated with lower survival and stronger disease severity.

METHODS: This study included patients with idiopathic pulmonary fibrosis (IPF) or nonspecific interstitial pneumonia (NSIP) from January 2009 to December 2018. Baseline chest CT scan and one-year follow-up scan of the patients were reviewed for the extent of lung fibrosis and MLNs. Two radiologists independently assessed MLN diameter and location. Patients with drug toxicity-related ILD, sarcoidosis, chronic hypersensitivity pneumonitis and other rare idiopathic interstitial pneumonias were excluded. The primary endpoint was survival. Secondary endpoints included number of hospitalizations for respiratory causes, lung function evaluated by forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), and lung fibrosis score determined by CT scan.

RESULTS: We retrospectively reviewed the medical registries of 110 patients with chronic pulmonary fibrosis (mean age 71 years, 60.4% male). Nine participants were excluded because the CT scans were of poor diagnostic quality for the evaluation of the mediastinum or unavailable for review. The analysis of 101 patients showed that enlarged MLNs (short axis diameter ≥10 mm) were present in 50.5% (n=51) and strongly predicted survival (HR= 2.11, 95% CI 1.12-3.96, p = 0.020). Patients with MLN enlargement experienced greater number of hospitalizations for respiratory causes (mean 2.5 vs. 1.8, p = 0.010) and had significantly worse lung function parameters (FVC, 71% vs. 81%, p = 0.018 and DLCO, 40% vs. 50%, p = 0.001) and a higher lung fibrosis score (50% vs. 39%, p = 0.001).

CONCLUSION: In patients with IPF and NSIP, enlarged MLNs predict survival, are associated with increased number of hospitalizations, and show signs of poorer lung function and more severe fibrosis.

PMID:34003121 | DOI:10.5152/dir.2021.19585

Genome Med. 2021 May 17;13(1):83. doi: 10.1186/s13073-021-00904-z.

ABSTRACT

BACKGROUND: While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility.

RESULTS: Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb)) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs associated with both severe COVID-19 and other human traits demonstrated colocalization of the GWAS signal at the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN). This finding points to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity.

CONCLUSIONS: Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches. The iCPAGdb web portal is accessible at http://cpag.oit.duke.edu and the software code at https://github.com/tbalmat/iCPAGdb .

PMID:34001247 | DOI:10.1186/s13073-021-00904-z

Qual Life Res. 2021 May 17. doi: 10.1007/s11136-021-02879-1. Online ahead of print.

ABSTRACT

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a progressive and universally fatal lung disease, characterised by increasing fibrosis of the lung parenchyma. In this study, we aimed to quantify the health state utility values (HSUVs) for Australians with IPF and to identify the factors affecting these HSUVs.

METHODS: Participants of the Australian IPF Registry (AIPFR), with data on EuroQoL five dimension-five level (EQ-5D-5L) profiles were included. Pulmonary function tests (PFTs) were used to assess disease severity using three IPF -based classification systems. Stepwise multivariable linear regression models assessed the relationship between HSUVs and important demographic and clinical parameters.Query RESULTS: A total of 155 participants provided data for the analysis of HSUVs. For our base case, HSUVs ranged from - 0.57 to 1.00. Mean HSUVs for all participants was 0.65 (95% CI 0.61-0.70). In general, HSUVs decreased with increasing disease severity under all disease severity classification systems. Multivariable linear regression demonstrated a negative association between HSUVs, disease severity and having more than 2 comorbidities.

CONCLUSIONS: Our study has shown that EQ-5D-5L has exhibited discriminatory sensitivity for the study population. We have demonstrated that disease severity and having more than two comorbidities was associated with lower HSUVs in Australians with IPF. Our findings support early diagnosis and appropriate evidence-based treatment to slow or prevent IPF progression; and identification and treatment of associated comorbidities to potentially improve health-related quality of life in people with IPF.

PMID:33999322 | DOI:10.1007/s11136-021-02879-1

Expert Opin Emerg Drugs. 2021 May 15. doi: 10.1080/14728214.2021.1931119. Online ahead of print.

ABSTRACT

INTRODUCTION: The enthusiasm generated by the approval of pirfenidone and nintedanib as the first effective therapies for IPF led the IPF scientific community to investigate an increasing number of novel agents in well-designed randomized controlled trials, in the hope to find a cure for these patients.

AREAS COVERED: This review the evidence from IPF phase II trials that were completed or started in 2020 is presented. Literature search was performed using Medline and Clinicaltrials.org databases.

EXPERT OPINION: Randomized clinical trials revolutionized the management of IPF, leading to the discovery of the first therapies capable of slowing down functional deterioration in these patients. The recently published findings of the first successful phase II trials since pirfenidone and nintedanib will hopefully inaugurate a new era in the therapeutic scenario of IPF, where consolidated treatments of proven efficacy and novel targeted agents contribute together to reach the final goal of halting the fibrotic process of this dreadful disease.

PMID:33998354 | DOI:10.1080/14728214.2021.1931119