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

Int J Nurs Sci. 2021 Mar 4;8(2):175-180. doi: 10.1016/j.ijnss.2021.02.004. eCollection 2021 Apr 10.

ABSTRACT

OBJECTIVE: This study aimed to explore the lived experiences of the disease journey and patients' care needs with idiopathic pulmonary fibrosis (IPF).

METHODS: Face-to-face semi-structured interviews were conducted with a purposive sampling of IPF patients admitted to the department of respiratory medicine in a tertiary hospital in Beijing. Interview data were analyzed using the thematic analysis method. In the end, 16 patients were interviewed.

RESULTS: Four themes emerged from the qualitative data included the long and confusing journey to reach a diagnosis, living with the disease, understanding the disease and treatment and desire for continuity of care. A series of subthemes were also identified, including uncertainty of diagnosis, delaying the process, living with physical symptoms, living with emotional distress, loss of independence, uncertainty with the prognosis, questioning the cause of the disease, concerning the side effects of treatments, lacking continuity of care, and wanting a better quality of healthcare in community hospitals.

CONCLUSIONS: Based on the findings, there is an urgent need to improve the care delivery to this vulnerable population in China. To meet their health needs, it is of paramount importance to develop effective education programs for health professionals and IPF patients and improve care models of healthcare systems, especially in remote areas, to enhance care continuity in the communities.

PMID:33997131 | PMC:PMC8105533 | DOI:10.1016/j.ijnss.2021.02.004

Front Nutr. 2021 Apr 29;8:548076. doi: 10.3389/fnut.2021.548076. eCollection 2021.

ABSTRACT

Ninjin'yoeito, a Kampo prescription, was administered to two patients with idiopathic pulmonary fibrosis (IPF) over a period of 12 weeks to improve loss of appetite and lassitude. In Case 1, improvements were observed in appetite, lassitude, and breathlessness, as well as increases or increasing tendencies in body weight, blood albumin level, and hemoglobin (Hb) level. Case 2 showed no changes in appetite but improvements in lassitude and no deterioration of breathlessness. His body weight and his blood albumin and Hb levels increased or showed increasing trends. In both cases, a trend for improvement of respiratory function was observed. In summary, ninjin'yoeito trended to improve the subjective symptoms and nutritional status of a patient with pulmonary fibrosis.

PMID:33996870 | PMC:PMC8116530 | DOI:10.3389/fnut.2021.548076

Front Immunol. 2021 Apr 30;12:664109. doi: 10.3389/fimmu.2021.664109. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most devastating progressive interstitial lung disease that remains refractory to treatment. Pathogenesis of IPF relies on the aberrant cross-talk between injured alveolar cells and myofibroblasts, which ultimately leads to an aberrant fibrous reaction. The contribution of the immune system to IPF remains not fully explored. Recent evidence suggests that both innate and adaptive immune responses may participate in the fibrotic process. Dendritic cells (DCs) are the most potent professional antigen-presenting cells that bridge innate and adaptive immunity. Also, they exert a crucial role in the immune surveillance of the lung, where they are strategically placed in the airway epithelium and interstitium. Immature DCs accumulate in the IPF lung close to areas of epithelial hyperplasia and fibrosis. Conversely, mature DCs are concentrated in well-organized lymphoid follicles along with T and B cells and bronchoalveolar lavage of IPF patients. We have recently shown that all sub-types of peripheral blood DCs (including conventional and plasmacytoid DCs) are severely depleted in therapy naïve IPF patients. Also, the low frequency of conventional CD1c+ DCs is predictive of a worse prognosis. The purpose of this mini-review is to focus on the main evidence on DC involvement in IPF pathogenesis. Unanswered questions and opportunities for future research ranging from a better understanding of their contribution to diagnosis and prognosis to personalized DC-based therapies will be explored.

PMID:33995394 | PMC:PMC8121252 | DOI:10.3389/fimmu.2021.664109

Front Immunol. 2021 Apr 22;12:663203. doi: 10.3389/fimmu.2021.663203. eCollection 2021.

ABSTRACT

The immune system is receiving increasing attention for interstitial lung diseases, as knowledge on its role in fibrosis development and response to therapies is expanding. Uncontrolled immune responses and unbalanced injury-inflammation-repair processes drive the initiation and progression of idiopathic pulmonary fibrosis. The regulatory immune system plays important roles in controlling pathogenic immune responses, regulating inflammation and modulating the transition of inflammation to fibrosis. This review aims to summarize and critically discuss the current knowledge on the potential role of regulatory immune cells, including mesenchymal stromal/stem cells, regulatory T cells, regulatory B cells, macrophages, dendritic cells and myeloid-derived suppressor cells in idiopathic pulmonary fibrosis. Furthermore, we review the emerging role of regulatory immune cells in anti-fibrotic therapy and lung transplantation. A comprehensive understanding of immune regulation could pave the way towards new therapeutic or preventive approaches in idiopathic pulmonary fibrosis.

PMID:33995390 | PMC:PMC8120991 | DOI:10.3389/fimmu.2021.663203

Front Pharmacol. 2021 Apr 29;12:669227. doi: 10.3389/fphar.2021.669227. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis is a chronic and progressive fibrotic lung disease, and current treatments are limited by their side effects. Proliferation of human lung fibroblasts in the pulmonary interstitial tissue is a hallmark of this disease and is driven by prolonged ERK signalling in the nucleus in response to growth factors such as platelet-derived growth factor (PDGF). Agents that increase cAMP have been suggested as alternative therapies, as this second messenger can inhibit the ERK cascade. We previously examined a panel of eight Gαs-cAMP-coupled G protein-coupled receptors (GPCRs) endogenously expressed in human lung fibroblasts. Although the cAMP response was important for the anti-fibrotic effects of GPCR agonists, the magnitude of the acute cAMP response was not predictive of anti-fibrotic efficacy. Here we examined the reason for this apparent disconnect by stimulating the Gαs-coupled prostacyclin receptor and measuring downstream signalling at a sub-cellular level. MRE-269 and treprostinil caused sustained cAMP signalling in the nucleus and complete inhibition of PDGF-induced nuclear ERK and fibroblast proliferation. In contrast, iloprost caused a transient increase in nuclear cAMP, there was no effect of iloprost on PDGF-induced ERK in the nucleus, and this agonist was much less effective at reversing PDGF-induced proliferation. This suggests that sustained elevation of cAMP in the nucleus is necessary for efficient inhibition of PDGF-induced nuclear ERK and fibroblast proliferation. This is an important first step towards understanding of the signalling events that drive GPCR inhibition of fibrosis.

PMID:33995100 | PMC:PMC8116805 | DOI:10.3389/fphar.2021.669227

Cancer Genomics Proteomics. 2021 May-Jun;18(3 Suppl):451-459. doi: 10.21873/cgp.20271.

ABSTRACT

BACKGROUND/AIM: The prevalence of idiopathic pulmonary fibrosis (IPF) increases with age and is associated with senescence of alveolar epithelial cells (AECs). AEC senescence in pulmonary cells mediates IPF. We herein aimed to determine if YAP1 gene knockdown, a member of the Hippo/YAP signal pathway, in the bleomycin (BLM)-induced mouse model of IPF, inhibits onset of senescence of AECs and alleviates IPF.

MATERIALS AND METHODS: Adeno-associated viruses (AAVs) expressing Yes-associated protein 1 (YAP1) short hairpin RNA (shRNA) were delivered into the lung of BLM-induced IPF mice via intratracheal injection, to knockdown the YAP1 gene in AECs. The mice were assigned to 4 groups: G1: control (normal mice); G2: IPF mice; G3: IPF + AAV/YAP1; G4: IPF + AAV/scramble. After 28 days, AECs were examined for senescence using H&E staining, Masson's trichrome Staining, senescence-associated ß-galactosidase (SA-β-gal) staining, western blotting and co-immunofluorescence staining, to determine the expression of YAP1, Smad-3 and p21, in order to determine the induction of senescence of ACEs.

RESULTS: The severity of IPF determined by H&E staining, Masson's staining and immunofluorescence (IF) staining was positively correlated with the senescence of AECs. Down-regulation of YAP1 expression of the Hippo-signaling pathway, determined by western blotting in AECs, alleviated pulmonary fibrosis as determined by Masson's staining. Down regulation of YAP1 expression reduced the senescence of AECs as determined by ß-galactosidase (SA-β-gal) staining, which alleviated the clinical symptoms of IPF mice, as determined by body weight and lung index.

CONCLUSION: Down-regulation of YAP1 expression in AECs inhibited AEC senescence which is thought to be the cause of IPF. Therefore, future studies can focus on inhibiting YAP1 to effectively treat IPF.

PMID:33994367 | DOI:10.21873/cgp.20271

Respir Investig. 2021 May 13:S2212-5345(21)00075-7. doi: 10.1016/j.resinv.2021.04.005. Online ahead of print.

ABSTRACT

BACKGROUND: Phase IV clinical trials in Western countries have reported that combined therapy with pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF) has a manageable safety profile. However, data on the long-term safety and tolerability of this combination treatment in the real-world setting in Japan are limited.

METHODS: The retrospective data of 46 patients with IPF who received combination therapy with pirfenidone and nintedanib were obtained from 16 institutes in Japan. Adverse events and adverse drug reactions (ADRs) were reported through a retrospective review of medical records.

RESULTS: Nintedanib and pirfenidone were added to preceding treatment with antifibrotic drugs in 32 (69.6%) and 13 (28.3%) patients, respectively. In one patient (2.1%), the two drugs were concurrently initiated. The mean duration of monotherapy before initiating the combination was 26.3 months. In 26 of 38 patients (68.4%), the Gender-Age-Physiology index stage was II or III. Thirty-three patients (71.7%) had some ADRs, and 14 patients (30.4%) permanently discontinued either drug or both drugs owing to the development of ADRs during the observation period (mean: 59 weeks). The percentage of grade III or IV IPF according to the Japanese Respiratory Society severity classification was higher in patients who permanently discontinued either drug or both drugs than in those who continued both drugs (90.9% [10/11; 3 undetermined grade] vs. 61.1% [11/18; 1 undetermined grade]). Decreased appetite (18/46, 39.1%) and diarrhea (16/46, 34.8%) were frequently observed ADRs. Two patients (4.3%) had serious ADRs (liver toxicity and pneumothorax).

CONCLUSIONS: Real-world data imply that combination therapy with pirfenidone and nintedanib for IPF has a manageable safety/tolerability profile.

PMID:33994347 | DOI:10.1016/j.resinv.2021.04.005

Respir Med. 2021 May 4:106432. doi: 10.1016/j.rmed.2021.106432. Online ahead of print.

ABSTRACT

BACKGROUND: Recognition of Anti-tRNA synthetase (ARS) related interstitial lung disease (ILD) is key to ensuring patients have prompt access to immunosuppressive therapies. The purpose of this retrospective cohort study was to identify factors that may delay recognition of ARS-ILD.

METHODS: Patients seen at Vanderbilt University Medical Center between 9/17/2017-10/31/2018 were included in this observational cohort. Clinical and laboratory features were obtained via chart abstraction. Kruskal-Wallis ANOVA, Mann-Whitney U, and Fisher's exact t tests were utilized to determine statistical significance.

RESULTS: Patients with ARS were found to have ILD in 51.9% of cases, which was comparable to the frequency of ILD in systemic sclerosis (59.5%). The severity of FVC reduction in ARS (53.2%) was comparable to diffuse cutaneous systemic sclerosis (56.8%, p = 0.48) and greater than dermatomyositis (66.9%, p = 0.005) or limited cutaneous systemic sclerosis (71.8%, p = 0.005). Frank honeycombing was seen with ARS antibodies but not other myositis autoantibodies. ARS patients were more likely to first present to a pulmonary provider in a tertiary care setting (53.6%), likely due to fewer extrapulmonary manifestations. Only 33% of ARS-ILD were anti-nuclear antibody, rheumatoid factor, or anti-cyclic citrullinated peptide positive. Patients with ARS-ILD had a two-fold longer median time to diagnosis compared to other myositis-ILD patients (11.0 months, IQR 8.5-43 months vs. 5.0 months, IQR 3.0-9.0 months, p = 0.003).

CONCLUSIONS: ARS patients without prominent extra-pulmonary manifestations are at high risk for not being recognized as having a connective tissue disease related ILD and miscategorized as usual interstitial pneumonia/idiopathic pulmonary fibrosis without comprehensive serologies.

PMID:33994288 | DOI:10.1016/j.rmed.2021.106432

Rheumatology (Oxford). 2021 May 16:keab441. doi: 10.1093/rheumatology/keab441. Online ahead of print.

ABSTRACT

OBJECTIVES: Pulmonary manifestations in rheumatoid arthritis (RA) are common comorbidities. Interstitial lung disease (ILD), both idiopathic and in RA has been associated with several genetic variants. We assessed pulmonary fibrosis (PF) in an inception cohort of RA patients in relation to genetic variants and disease-related factors.

METHODS: 1466 early RA patients were consecutively included and followed prospectively from index date until death or December 31, 2016. Clinical, and laboratory data and treatment were continuously registered according to Swedish Rheumatology quality register. DNA was available from 1184 patients and 571 151 genome-wide-single-nucleotide polymorphism were analysed (GSA, Illumina, deCode, Island). Thirteen identified genetic variants were extracted. At follow-up the patients answered a questionnaire regarding disease progression and lung involvement, which was validated by reviewing medical records and analysing radiological examinations.

RESULTS: The prevalence of PF was 5.6%, and the annualized incidence rate was 5.0/1000 (95%CI 3.80, 6.54). Four SNPs were associated with PF in RA; rs35705950 (MUC5B), OR = 2.5 (95%CI 1.5, 4.0), adjusted p-value = 0.00016 and q-value = 0.0021, rs111521887 (TOLLIP) OR = 1.9 (95%CI 1.3, 2.8), adjusted p-value = 0.0014 and q-value = 0.0092; rs2609255 (FAM13A) (OR = 1.7 (95%CI 1.1, 2.5), adjusted p-value = 0.013 and q-value = 0.055) and rs2736100 (TERT) OR = 1.5 (1.0, 2.2), adjusted p-value = 0.046, q-value was 0.15. Older age and rheumatoid factor-positivity were associated with increased risk, whilst methotrexate treatment was associated with a lower risk of PF.

CONCLUSIONS: Development of PF in an inception cohort of RA patients was associated with four of 12 ILD risk genes. RA-related factors except for age at diagnosis and RF-positivity were of limited importance in PF development.

PMID:33993221 | DOI:10.1093/rheumatology/keab441

Transplant Rev (Orlando). 2021 May 4;35(3):100626. doi: 10.1016/j.trre.2021.100626. Online ahead of print.

ABSTRACT

Chronic lung allograft dysfunction (CLAD) is the major long-term cause of morbidity and mortality after lung transplantation. Both bronchiolitis obliterans syndrome and restrictive lung allograft syndrome, two main types of CLAD, lead to fibrosis in either the small airways or alveoli and pleura. Pathological pathways in CLAD and other types of fibrosis, for example idiopathic pulmonary fibrosis, are assumed to overlap and therefore fibrosis biomarkers could aid in the early detection of CLAD. These biomarkers could help to differentiate between different phenotypes of CLAD and could, in comparison to biomarkers of inflammation, possibly distinguish an infectious event from CLAD when a decline in lung function is present. This review gives an overview of known CLAD specific biomarkers, describes new promising fibrosis biomarkers currently investigated in other types of fibrosis, and discusses the possible use of these fibrosis biomarkers for CLAD.

PMID:33992914 | DOI:10.1016/j.trre.2021.100626

Respir Med. 2021 May 4:106437. doi: 10.1016/j.rmed.2021.106437. Online ahead of print.

ABSTRACT

Pleuroparenchymal fibroelastosis (PPFE) is a rare, generally idiopathic form of interstitial pneumonia with unique clinical, radiological and histopathological features. It is named after the presence of upper lobe pleural and subjacent parenchymal fibrosis, with accompanying elastic fibers. Although it is usually an idiopathic disease, it has been linked to other co-existent diseases. Diagnostic suspicion of PPFE is based on the identification of typical abnormalities on chest CT scan, which are prevailingly located in the upper lobes, adjacent to the apex of the lungs. Diagnosis can be confirmed by histological analysis, although biopsy is not always feasible. The disease is generally progressive, but not uniformly. The course of the disease is frequently slow and involves a progressive loss of upper lobe volume, which results in platythorax, associated with a significant reduction of body mass. PPFE concomitant to other interstitial lung diseases is associated with a poorer prognosis. The disease occasionally progresses rapidly causing irreversible respiratory insufficiency, which leads to death. Currently, there is no effective pharmacological therapy available, and lung transplantation is the best therapeutic option. The purpose of this review is to draw the attention to PPFE, describe its clinical, radiological and histopathological features, analyze its diagnostic criteria, and provide an update on the management of the disease.

PMID:33992495 | DOI:10.1016/j.rmed.2021.106437

Rev Mal Respir. 2021 May 12:S0761-8425(21)00236-9. doi: 10.1016/j.rmr.2021.04.015. Online ahead of print.

ABSTRACT

We present data on prognostic factors in a Tunisian cohort of people with Idiopathic pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) has a poor prognosis, with a median survival in patients with the condition of only 3 to 5 years. Previous studies have identified a number of prognostic factors in this chronic pulmonary disease.

METHODS: We conducted a retrospective study, including patients with idiopathic pulmonary fibrosis (IPF) who were diagnosed at the Pneumology Department of the University Hospital Fattouma-Bourguiba, Monastir, between 1991 and 2014. The aim of this study was to compare clinical, radiological, pulmonary functional predictors of survival in IPF in a Tunisian cohort with those of previous studies.

RESULTS: This study included 126 patients. Their mean age was 66 years, with a male predominance (68.3%). Respiratory function tests revealed a restrictive ventilatory deficit in 72.6% of cases. The median survival of our study population was 22.5 months [6.7-49.5]. In univariate analysis, factors associated with a poor prognosis were: lower baseline values of TLC, FCV and DLco, level of dyspnea assessed by mMRC scale, hypoxemia at diagnosis, the degree of desaturation during exercise, a higher annual decline of FVC and DLco, acute respiratory distress and also the GAP score. In multivariate analysis, independent prognostic factors were: baseline DLco, level of dyspnea, desaturation at exertion and the annual decline of the DLco.

CONCLUSION: Lower baseline DLco, the level of dyspnea, desaturation on exercise, and annual decline in DLco are all associated with a poor prognosis in IPF.

PMID:33992493 | DOI:10.1016/j.rmr.2021.04.015

BMC Pulm Med. 2021 May 15;21(1):165. doi: 10.1186/s12890-021-01530-6.

ABSTRACT

BACKGROUND: Nintedanib is effective for treating idiopathic pulmonary fibrosis (IPF), but some patients may exhibit a suboptimal response and develop on-treatment acute exacerbation (AE-IPF), hepatic injury, or mortality. It remains unclear which patients are at risk for these adverse outcomes.

METHODS: We analysed the demographic and clinical data, baseline plasma levels of Krebs von den Lungen-6 (KL-6) and surfactant protein A (SPA), and longitudinal clinical courses of a real-world cohort of IPF patients who received nintedanib ≥ 14 days between March 2017 and December 2020. Cox proportional-hazards regression, subdistribution hazards regression, and sensitivity analyses were performed to investigate the association between baseline predictors and AE-IPF, mortality, and nintedanib-related hepatic injury. The relationship between baseline predictors and pulmonary function decline was determined.

RESULTS: Fifty-seven patients were included, of whom 24 (42%) developed hepatic injury, 20 (35%) had AE-IPF, and 16 (28%) died on-treatment. A baseline plasma KL-6 level ≥ 2.5 ng/mL, and diffusion capacity for carbon monoxide (DLCO) < 55% predicted, were associated with increased risk of hepatic injury (adjusted hazard ratio [aHR] was 3.46; 95% CI 1.13-10.60; p = 0.029 for KL-6, and 6.05; 95% CI 1.89-19.32; p = 0.002 for DLCO). Both factors also predicted severe and recurrent hepatic injury. Patients with baseline KL-6 ≥ 2.5 ng/mL also had a higher risk of AE-IPF (aHR 4.52; 95% CI 1.63-12.55; p = 0.004). For on-treatment mortality, baseline KL-6 ≥ 3.5 ng/mL and SPA ≥ 600 pg/mL were significant predictors (aHR 5.39; 95% CI 1.16-24.97; p = 0.031 for KL-6, and aHR 12.28; 95% CI 2.06-73.05; p = 0.006 for SPA). Results from subdistribution hazard regression and sensitivity analyses supported these findings. Patients with elevated baseline plasma KL-6 levels also exhibited a trend towards faster pulmonary function decline.

CONCLUSIONS: For patients with IPF who are receiving nintedanib, we have identified baseline predictors, in particular plasma KL-6 levels, for the risk of adverse outcomes. Patients with these predictors may require close monitoring for unfavourable responses during treatment. Our findings also support the prognostic role of molecular markers like KL-6 and may contribute to future formulation of more individualized therapeutic strategies for IPF.

PMID:33992083 | DOI:10.1186/s12890-021-01530-6

Exp Mol Med. 2021 May 14. doi: 10.1038/s12276-021-00618-7. Online ahead of print.

ABSTRACT

Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that are rapidly metabolized into diols by soluble epoxide hydrolase (sEH). sEH inhibition has been shown to increase the biological activity of EETs, which are known to have anti-inflammatory properties. However, the role of EETs in pulmonary fibrosis remains unexplored. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to analyze EETs in the lung tissues of patients with idiopathic pulmonary fibrosis (IPF, n = 29) and controls (n = 15), and the function of 11,12-EET was evaluated in in vitro and in vivo in pulmonary fibrosis models. EET levels in IPF lung tissues, including those of 8,9-EET, 11,12-EET, and 14,15-EET, were significantly lower than those in control tissues. The 11,12-EET/11,12-DHET ratio in human lung tissues also differentiated IPF from control tissues. 11,12-EET significantly decreased transforming growth factor (TGF)-β1-induced expression of α-smooth muscle actin (SMA) and collagen type-I in MRC-5 cells and primary fibroblasts from IPF patients. sEH-specific siRNA and 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU; sEH inhibitor) also decreased TGF-β1-induced expression of α-SMA and collagen type-I in fibroblasts. Moreover, 11,12-EET and TPPU decreased TGF-β1-induced p-Smad2/3 and extracellular-signal-regulated kinase (ERK) expression in primary fibroblasts from patients with IPF and fibronectin expression in Beas-2B cells. TPPU decreased the levels of hydroxyproline in the lungs of bleomycin-induced mice. 11,12-EET or sEH inhibitors could inhibit pulmonary fibrosis by regulating TGF-β1-induced profibrotic signaling, suggesting that 11,12-EET and the regulation of EETs could serve as potential therapeutic targets for IPF treatment.

PMID:33990688 | DOI:10.1038/s12276-021-00618-7