Clin Chest Med. 2021 Jun;42(2):365-373. doi: 10.1016/j.ccm.2021.03.012.

ABSTRACT

Current therapeutic strategies have succeeded in slowing down the progression of idiopathic pulmonary fibrosis (IPF). Emerging evidence highlights IPF as a disease of aging and impaired regeneration. Novel antiaging and regenerative medicine approaches hold promise to be able to reverse disease and might present hope for a cure. Research focusing on a deeper understanding of lung stem cell populations and how these are regulated and altered in fibrotic disease continues to drive the field, and accompanied by earlier diagnosis, the adaptation of clinically relevant models and readouts for regeneration of diseased lung, ultimately paves the way for translation into clinics.

PMID:34024411 | DOI:10.1016/j.ccm.2021.03.012

Clin Chest Med. 2021 Jun;42(2):357-364. doi: 10.1016/j.ccm.2021.03.011.

ABSTRACT

Management of patients with interstitial lung disease (ILD) requires accurate classification. However, this process relies on subjective interpretation of nonspecific and overlapping clinical features that could hamper clinical care. The development and implementation of objective biomarkers reflective of specific disease states could facilitate precision-based approaches based on patient-level biology to improve the health of ILD patients. Omics-based studies allow for the seemingly unbiased and highly efficient screening of candidate biomarkers and offer unprecedented opportunities for discovery. This review outlines representative major omics-based discoveries in a well-studied condition, idiopathic pulmonary fibrosis, to develop a roadmap to personalized medicine in ILD.

PMID:34024410 | DOI:10.1016/j.ccm.2021.03.011

Clin Chest Med. 2021 Jun;42(2):321-335. doi: 10.1016/j.ccm.2021.03.008.

ABSTRACT

Nonidiopathic pulmonary fibrosis (non-IPF) progressive fibrotic interstitial lung diseases (PF-ILDs) are a heterogeneous group of ILDs, often challenging to diagnose, although an accurate diagnosis has significant implications for both treatment and prognosis. A subgroup of these patients experiences progressive deterioration in lung function, physical performance, and quality of life after conventional therapy. Risk factors for ILD progression include older age, lower baseline pulmonary function, and a usual interstitial pneumonia pattern. Management of non-IPF P-ILD is both pharmacologic and nonpharmacologic. Antifibrotic drugs, originally approved for IPF, have been considered in patients with other fibrotic ILD subtypes, with favorable results in clinical trials.

PMID:34024407 | DOI:10.1016/j.ccm.2021.03.008

Clin Chest Med. 2021 Jun;42(2):287-294. doi: 10.1016/j.ccm.2021.03.006.

ABSTRACT

We are in the midst of transformative innovation in health care delivery and clinical trials in idiopathic pulmonary fibrosis (IPF). Health systems are uniquely positioned at the crossroad of these shifting paradigms, equipped with the resources to expand the research pipeline in IPF through visionary leadership and targeted investments. The authors hope that by prioritizing development of health information technology, supporting a broader range of clinical trial designs, and cultivating broad stakeholder engagement, health systems will generate data to address knowledge-evidence-practice gaps in IPF. This will continue to improve the ability to deliver high-quality, safe, and effective care.

PMID:34024404 | DOI:10.1016/j.ccm.2021.03.006

Clin Chest Med. 2021 Jun;42(2):275-285. doi: 10.1016/j.ccm.2021.03.004.

ABSTRACT

Progress in the past 2 decades has led to widespread use of 2 medications to slow loss of lung function in patients with pulmonary fibrosis. Treatment of individual patients with currently available pharmacotherapies can be limited by side effects, and neither drug has a consistent effect on patient symptoms or function. Several promising new pharmacotherapies are under development. Comprehensive management of pulmonary fibrosis hinges on shared decision making. Patient and caregiver education, and early identification and management of symptoms and comorbidities, can help improve quality of life.

PMID:34024403 | DOI:10.1016/j.ccm.2021.03.004

Clin Chest Med. 2021 Jun;42(2):263-273. doi: 10.1016/j.ccm.2021.03.005.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating disease for patients and their loved ones. Since initial efforts to characterize this disease in the 1960s, understanding of IPF has evolved considerably. Such evolution has continually challenged prior diagnostic and treatment paradigms, ushering in an era of higher confidence diagnoses with less invasive procedures and more effective treatments. This review details how research and clinical experience over the past half century have led to a rethinking of IPF. Here, the evolution in understanding of IPF pathogenesis, diagnostic evaluation and treatment approach is discussed.

PMID:34024402 | DOI:10.1016/j.ccm.2021.03.005

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