Cesk Patol. 2023 Spring;59(1):10-17.

ABSTRACT

Histopathological pattern of progressive pulmonary fibrosis could be seen in many different fibrotic lung interstitial diseases. Exact diagnosis is crucial for precise therapy, moreover, different diseases have different prognosis. The most important disorders in this group are idiopatic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis, and their separation is crucial because of totally different treatment of the patients. The aim of this review is to sum up the most important characteristics of usual interstitial pneumonia, histopathological pattern of idiopatic pulmonary fibrosis, and fibrotic hypersensitivity pneumonitis and provide a practical work-up for precise diagnostics of these diseases in the frame of effectively cooperating multidisciplinary team.

PMID:37072274

2023 Mar 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–.

ABSTRACT

Pulmonary hypertension (PH) is defined as a resting mean pulmonary arterial pressure (mPAP) of more than 20 mmHg. Pulmonary hypertension is a complex, heterogeneous disease with multiple etiologies, subtypes, and various methods were used to classify the disease. WHO has categorized pulmonary hypertension into five broad clinical groups based on the underlying etiologies, similarities in pathophysiology, and treatment approach.

WHO group 1 is generally referred to as pulmonary arterial hypertension (PAH). WHO group 2 PH is caused by left heart disease. WHO group 3 is PH related to lung disease and/or hypoxia. WHO group 4 is PH due to pulmonary artery obstructions such as chronic thromboembolic pulmonary hypertension (CTEPH). WHO group 5 PH has unclear and/or multifactorial mechanisms.

Pulmonary veno-occlusive disease (PVOD) is a rare subtype of PAH characterized by progressive obstruction of small pulmonary veins leading to elevated pulmonary arterial pressure and right-sided heart failure. Although PVOD was first described in 1934, the understanding of the disease remains poor.

The clinical features are very non-specific and can resemble congestive heart failure, idiopathic pulmonary arterial hypertension (IPAH), and restrictive lung diseases such as pulmonary fibrosis. The gold standard for diagnosis is a biopsy, which is risky and not advisable in pulmonary hypertension due to a high risk of procedure-related complications such as life-threatening bleeding.

No medical therapy is supported by evidence, and the only curative option is lung transplantation. The prognosis is poor, and life expectancy is two years after symptom onset. This review aims to educate clinicians on this rare, less emphasized, and poorly understood disease.

PMID:36256776 | Bookshelf:NBK585129

Pharmacol Res. 2022 Dec 28:106636. doi: 10.1016/j.phrs.2022.106636. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality and limited therapeutic options. The immune checkpoint PD1/PD-L1 axis is related to the pathogenesis of pulmonary fibrosis, and upregulated expression levels of PD-L1 have been demonstrated in IPF patients. However, the mechanism of PD-L1 in pulmonary fibrosis is not fully understood. Here, we demonstrated upregulated expression of PD-L1 in fibrotic lung tissues and sera of IPF patients. Bleomycin (BLM) treatment induced PD-L1 upregulation, EMT (Epithelial-Mesenchymal Transition) and fibrosis-like morphology changes in human pulmonary alveolar epithelial cells (HPAEpiCs). Silencing PD-L1 attenuated BLM-induced EMT and fibrosis-like morphology changes in HPAEpiCs. In addition, we identified that PD-L1 directly binds to vimentin and inhibits vimentin ubiquitination, thereby increasing vimentin levels in HPAEpiCs. Silencing of vimentin inhibited BLM- and PD-L1-induced fibrosis in HPAEpiCs. The correlation between PD-L1 and EMT or vimentin expression was further confirmed in clinical samples and animal models. Finally, we used BLM- and paraquat-induced pulmonary fibrosis animal models to confirm the anti-pulmonary fibrosis effects of PD-L1 silencing. Taken together, our findings suggest that upregulated PD-L1 stimulates EMT of alveolar epithelial cells by increasing vimentin levels by inhibiting vimentin ubiquitination, thereby contributing to pulmonary fibrosis.

PMID:36586643 | DOI:10.1016/j.phrs.2022.106636

Eur Respir J. 2022 Dec 30:2200604. doi: 10.1183/13993003.00604-2022. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease characterized by aberrant fibroblast/myofibroblast accumulation and excessive collagen matrix deposition in the alveolar areas of lungs. As the first approved IPF medication, pirfenidone (PFD) significantly decelerates lung function decline while its underlying anti-fibrotic mechanism remains elusive. In this study, using transcriptomic and immunofluorescence analyses of primary human IPF tissues, we showed that myocardin related transcription factor (MRTF) signaling is activated in myofibroblasts accumulated in IPF lungs. Furthermore, we showed that PFD inhibits MRTF activation in primary human lung fibroblasts at the clinically achievable concentrations (half-maximal inhibitory concentration (IC50)=50-150 µM, maximal inhibition>90%, maximal concentration of PFD in patients<100 µM). Mechanistically, PFD appears to exert its inhibitory effects by promoting the interaction between MRTF and actin indirectly. Finally, PFD-treated IPF lungs exhibit significantly less MRTF activation in FF areas than naïve IPF lungs. Our results suggest MRTF signaling as a direct target for PFD and implicate that some of the anti-fibrotic effects of PFD may be due to MRTF inhibition in lung fibroblasts.

PMID:36585256 | DOI:10.1183/13993003.00604-2022

J Ethnopharmacol. 2022 Dec 27:116071. doi: 10.1016/j.jep.2022.116071. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Idiopathic pulmonary fibrosis (IPF), characterized by excessive collagen deposition, is a progressive and typically fatal lung disease without effective therapeutic methods. Tanreqing injection (TRQ), a Traditional Chinese Patent Medicine, has been widely used to treat inflammatory respiratory diseases clinically.

AIM OF THE STUDY: The present work aims to elucidate the therapeutic effects and the possible mechanism of TRQ against pulmonary fibrosis.

METHODS: The pulmonary fibrosis murine model were constructed by the intratracheal injection of bleomycin (BLM). 7 days later, TRQ-L (2.6 ml/kg) and TRQ-H (5.2 ml/kg) were administered via intraperitoneal injection respectively for 21 days. The efficacy and underlying molecular mechanism of TRQ were investigated.

RESULTS: Here, we showed that TRQ significantly inhibited BLM-induced lung edema and pulmonary function. TRQ markedly reduced BLM-promoted inflammatory cell infiltration in BALF and inflammatory cytokines release (TNF-α, IL-6, and IL-1β) in serum and lung tissues. Meanwhile, TRQ also alleviated BLM-induced collagen synthesis and deposition. Simultaneously, TRQ attenuated BLM-induced pulmonary fibrosis through regulating the expression of fibrotic hallmarks, manifested by down-regulated α-SMA and up-regulated E-cadherin. Moreover, we found that TRQ significantly prevented STING, p-P65, BIP, p-PERK, p-eIF2α, and ATF4 expression in lung fibrosis mice.

CONCLUSIONS: Taken together, our results indicated that TRQ positively affects inflammatory responses and lung fibrosis by regulating STING-mediated endoplasmic reticulum stress (ERS) signal pathway.

PMID:36584920 | DOI:10.1016/j.jep.2022.116071

West Afr J Med. 2022 Dec 29;39(12):1316-1318.

ABSTRACT

BACKGROUND: Nonspecific interstitial pneumonia is a rare clinical condition and usually precedes the full manifestation of connective tissue disorders, drug-induced interstitial lung disease or chronic hypersensitivity pneumonitis.

OBJECTIVE: This article reports a twenty-eight (28)-year-old Nigerian female with nonspecific interstitial pneumonia (NSIP) complicated by Cor pulmonale. The unusual characteristics of our index case favors NSIP rather than idiopathic pulmonary fibrosis (age of 28 years, female, chest high-resolution computerized tomographic features and response to glucocorticoids).

RESULTS: High-resolution computerized tomography scan of the chest showed honeycombing in the apical lobes and a mixture of reticular changes, ground-glass appearance and fibrotic changes in basal lobes. Echocardiography revealed features of right chamber enlargement with pulmonary hypertension. Due to financial constraint, serological tests for CTDs and lung biopsy could not be done.

CONCLUSION: Being a rare condition, a high index of suspicion with full investigative workup to make early diagnosis and effect prompt treatment is important.

PMID:36583967

Clin Physiol Funct Imaging. 2022 Dec 29. doi: 10.1111/cpf.12809. Online ahead of print.

ABSTRACT

BACKGROUND: Hypoxemia and cardiocirculatory abnormalities may impair muscle oxygen (O2 ) delivery relative to O2 requirements thereby increasing the rate of O2 extraction during incremental exercise in fibrotic interstitial lung disease (f-ILD). Using changes in deoxyhemoglobin concentration ([HHb]) by near-infrared spectroscopy (NIRS) as a proxy of O2 extraction, we investigated whether a simplified (double-linear) approach, previously tested in heart failure, would provide useful estimates of muscle deoxygenation in f-ILD.

METHODS: Twenty-five patients (23 men, 72±8 years, 20 with idiopathic pulmonary fibrosis, lung diffusing capacity for carbon monoxide= 44±11% predicted) and 12 age- and sex-matched healthy controls performed incremental cycling to symptom limitation. Changes in vastus lateralis [HHb] assessed by NIRS were analyzed in relation to work rate (WR) and O2 uptake throughout the exercise.

RESULTS: Patients showed lower exercise capacity than controls (e.g., peak WR= 67±18 vs 105±20% predicted, respectively; p<0.001). The [HHb] response profile was typically S-shaped, presenting three distinct phases. Exacerbated muscle deoxygenation in patients vs controls was evidenced by: i) a steeper mid-exercise [HHb]-WR slope (0.30±0.22 vs 0.11±0.08 μmol/W, p=0.008) (phase 2), and ii) a larger late-exercise increase in [HHb] (p=0.002) (phase 3). Steeper [HHb]-WR slope was associated with lower peak WR (r=-0.70) and greater leg discomfort (r=0.77, p<0.001) in f-ILD. This article is protected by copyright. All rights reserved.

PMID:36582169 | DOI:10.1111/cpf.12809

RMD Open. 2022 Dec;8(2):e002790. doi: 10.1136/rmdopen-2022-002790.

ABSTRACT

BACKGROUND: MUC5B variant rs35705950 is the common and most significant risk variant for rheumatoid arthritis-interstitial lung disease (RA-ILD) in Western populations. However, little is known about its significant association with RA-ILD in Asian populations. We here investigate the association of rs35705950 with Korean patients with RA-ILD.

METHODS: In this cross-sectional study, we genotyped rs35705950 in 2444 patients with RA. Among them, 683 patients with RA who have chest CT were divided into RA-ILD and RA-noILD. RA-ILD was classified as usual interstitial pneumonia (UIP) and other than UIP. The associations of rs35705950 with RA-ILD and its subtype were analysed using multivariable regression adjusted for age at RA diagnosis. Meta-analysis of a previously reported Japanese dataset and Korean dataset obtained for this study was conducted.

RESULTS: The minor allele (T) frequency of rs35705950 was 0.37%, 1.43% and 2.38% in 2444 patients with RA, 105 patients with RA-ILD and 63 patients with UIP, respectively. Genotypic association of rs35705950 with RA-ILD was insignificant (OR 2.49, 95% CI 0.64 to 9.69, p=0.187), but showed significant association with UIP (OR 4.90, 95% CI 1.23 to 19.59, p=0.024) compared with RA-noILD. In meta-analysis (123 UIP and 878 RA-noILD) combining our data with previously reported Japanese data, this variant was found to be significantly associated with UIP (OR 3.51, 95% CI 1.19 to 10.37, p=0.023).

CONCLUSION: MUC5B variant rs35705950 is a rare but significant risk factor for Asian patients with RA-ILD with UIP, suggesting a sharing of the genetic background between Asian and Western populations.

PMID:36581384 | DOI:10.1136/rmdopen-2022-002790

Biomaterials. 2022 Dec 24;293:121960. doi: 10.1016/j.biomaterials.2022.121960. Online ahead of print.

ABSTRACT

Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), are characterized by regional extracellular matrix (ECM) remodeling which contributes to disease progression. Previous proteomic studies on whole decellularized lungs have provided detailed characterization on the impact of COPD and IPF on total lung ECM composition. However, such studies are unable to determine the differences in ECM composition between individual anatomical regions of the lung. Here, we employ a post-decellularization dissection method to compare the ECM composition of whole decellularized lungs (wECM) and specific anatomical lung regions, including alveolar-enriched ECM (aECM), airway ECM (airECM), and vasculature ECM (vECM), between non-diseased (ND), COPD, and IPF human lungs. We demonstrate, using mass spectrometry, that individual regions possess a unique ECM signature characterized primarily by differences in collagen composition and basement-membrane associated proteins, including ECM glycoproteins. We further demonstrate that both COPD and IPF lead to alterations in lung ECM composition in a region-specific manner, including enrichment of type-III collagen and fibulin in IPF aECM. Taken together, this study provides methodology for future studies, including isolation of region-specific lung biomaterials, as well as a dataset that may be applied for the identification of novel ECM targets for therapeutics.

PMID:36580718 | DOI:10.1016/j.biomaterials.2022.121960

Respir Investig. 2022 Nov 15:S2212-5345(22)00142-3. doi: 10.1016/j.resinv.2022.08.009. Online ahead of print.

ABSTRACT

BACKGROUND: Numerous studies investigated patients with IPF; however, only a few examined patients with idiopathic interstitial pneumonias (IIPs).

METHODS: The Japanese Idiopathic Interstitial Pneumonias (JIPS) Registry, which was initiated in December 2016, is a multicenter prospective observational study of patients newly diagnosed with IIPs from 86 facilities treating ILDs. The plan is to enroll more than 600 new patients during the 2-year enrolment period and to follow their progress for 3 years after the last case enrolment. If additional consent is obtained, the study will continue for another 2 years. Research questions mainly focus on identifying the frequency by IIP classification, patient background, and diagnostic methods during enrolment, survival, acute exacerbation rate, changes in high-resolution CT imaging, forced vital capacity, and interstitial pneumonia markers over time. Other research questions, including those regarding disease behavior in patients with progressive fibrosing-ILD and new biomarkers associated with genetic predispositions, will be investigated.

DISCUSSION: The JIPS Registry will provide a comprehensive description of the disease progression, prognosis, treatment status, new biomarkers, and validity of guidelines and central multidisciplinary decisions for IPF and similar diseases that can be differentiated from IPF among IIPs.

ETHICS AND DISSEMINATION: Ethical approval was obtained from the institutional review board of Kanagawa Cardiovascular and Respiratory Center (KCRC-16-0005), and that of Jichi Medical University approved the biobank part (I18-005). Results will be published in peer-reviewed journals and will be presented at national and international conferences.

TRIAL REGISTRATION: ClinTrials.gov Registry (NCT03041623, first posted on February 3, 2017).

PMID:36580379 | DOI:10.1016/j.resinv.2022.08.009

Front Immunol. 2022 Dec 12;13:1049361. doi: 10.3389/fimmu.2022.1049361. eCollection 2022.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease. Many studies suggest that autophagy may be related to disease progression and prognosis in IPF. However, the mechanisms involved have not been fully elucidated.

METHODS: We incorporated 232 autophagy-associated genes (AAGs) and two datasets, GSE28042 and GSE27957, from the GEO database. Univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) regression were used to construct the autophagy-associated prognostic model. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to investigate the functions of these autophagy-associated genes. CIBERSORT algorithm was used to calculate the immune cell infiltration between patients in the high-risk score and low-risk score groups. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was performed to explore the mRNA expression of five genes in the autophagy-associated risk model.

RESULTS: We constructed a 5-autophagy-associated genes signature based on Univariate Cox analysis and LASSO regression. In our autophagy-associated risk model, IPF patients in the high-risk group demonstrated a poor overall survival rate compared to patients in the low-risk group. For 1-, 2-, and 3-year survival rates, the AUC predictive value of the AAG signature was 0.670, 0.787, and 0.864, respectively. These results were validated in the GSE27957 cohort, confirming the good prognostic effect of our model. GO and KEGG pathway analyses enriched immune-related pathways between the high-risk and low-risk groups. And there was also a significant difference in immune cell infiltration between two groups. And the results of qRT-PCR showed that the expression levels of FOXO1, IRGM, MYC, and PRKCQ were significantly decreased in the Peripheral Blood Mononuclear Cell (PBMC) of IPF patient samples.

CONCLUSION: Our study constructed and validated an autophagy-associated risk model based on MYC, MAPK1, IRGM, PRKCQ, and FOXO1. And those five genes may influence the progression of IPF by regulating immune responses and immune cells.

PMID:36578501 | PMC:PMC9791216 | DOI:10.3389/fimmu.2022.1049361

Environ Pollut. 2022 Dec 24:120942. doi: 10.1016/j.envpol.2022.120942. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) whose outcomes are worsened with air pollution exposures. DNA methylation (DNAm) patterns are altered in lungs and blood from patients with IPF, but the relationship between air pollution exposures and DNAm patterns in IPF remains unexplored. This study aimed to evaluate the association of PM2.5 and constituent components with global DNAm in patients with IPF. Patients enrolled in either the University of Pittsburgh Simmons Center for ILD Registry (Simmons) or the U.S.-wide Pulmonary Fibrosis Foundation (PFF) Patient Registry with peripheral blood DNA samples were included. The averages of monthly exposures to PM2.5 and constituents over 1-year and 3-months pre-blood collection were matched to patient residential coordinates using satellite-derived hybrid models. Global DNAm percentage (%5 mC) was determined using the ELISA-based MethylFlash assay. Associations of pollutants with %5 mC were assessed using beta-regression, Cox models for mortality, and linear regression for baseline lung function. Mediation proportion was determined for models where pollutant-mortality and pollutant-%5 mC associations were significant. Inclusion criteria were met by 313 Simmons and 746 PFF patients with IPF. Higher PM2.5 3-month exposures prior to blood collection were associated with higher %5 mC in Simmons (β = 0.02, 95%CI 0.0003-0.05, p = 0.047), with trends in the same direction in the 1-year period in both cohorts. Higher exposures to sulfate, nitrate, ammonium, and black carbon constituents were associated with higher %5 mC in multiple models. Percent 5 mC was not associated with IPF mortality or lung function, but was found to mediate between 2 and 5% of the associations of PM2.5, sulfate, and ammonium with mortality. In conclusion, we found that higher global DNAm is a novel biomarker for increased PM2.5 and anthropogenic constituent exposure in patients with IPF. Mechanistic research is needed to determine if DNAm has pathogenic relevance in mediating associations between pollutants and mortality in IPF.

PMID:36574806 | DOI:10.1016/j.envpol.2022.120942

Am J Physiol Lung Cell Mol Physiol. 2022 Dec 27. doi: 10.1152/ajplung.00248.2022. Online ahead of print.

ABSTRACT

Aberrant vascular remodeling contributes to the progression of many aging-associated diseases, including idiopathic pulmonary fibrosis (IPF), where heterogeneous capillary density, endothelial transcriptional alterations and increased vascular permeability correlate with poor disease outcomes. Thus, identifying disease-driving mechanisms in the pulmonary vasculature may be a promising strategy to limit IPF progression. Here, we identified Ccn3 as an endothelial-derived factor that is upregulated in resolving but not in persistent lung fibrosis in mice, and whose function is critical for vascular homeostasis and repair. Loss and gain of function experiments were carried out to test the role of CCN3 in lung microvascular endothelial function in vitro through RNAi and addition of recombinant human CCN3 protein, respectively. Endothelial migration, permeability, proliferation, and in vitro angiogenesis were tested in cultured human lung microvascular endothelial cells. Loss of CCN3 in lung ECs resulted in transcriptional alterations along with impaired wound healing responses, in vitro angiogenesis, barrier integrity as well as increased pro-fibrotic activity through paracrine signals, whereas the addition of recombinant CCN3 augmented endothelial function. Altogether, our results demonstrate that the matricellular protein CCN3 plays an important role in lung endothelial function and could serve as a promising therapeutic target to facilitate vascular repair and promote lung fibrosis resolution.

PMID:36573684 | DOI:10.1152/ajplung.00248.2022

Qual Life Res. 2022 Dec 26. doi: 10.1007/s11136-022-03331-8. Online ahead of print.

ABSTRACT

PURPOSE: Little is known about the impact of co-morbidities on health-related quality of life (HRQoL) for people with idiopathic pulmonary fibrosis (IPF). We aimed to investigate the relative contribution of co-morbidities to HRQoL of people with IPF.

METHODS: N = 157 participants were recruited from the Australian IPF Registry (AIPFR). Health state utilities (HSUs), and the super-dimensions of physical and psychosocial scores were measured using the Assessment of Quality of Life-8-Dimensions (AQoL-8D). The impact of co-morbidities on HRQoL was investigated using linear regression and general dominance analyses.

RESULTS: A higher number of co-morbidities was associated with lower HSUs (p trend = 0.002). Co-morbidities explained 9.1% of the variance of HSUs, 16.0% of physical super-dimensional scores, and 4.2% of psychosocial super-dimensional scores. Arthritis was associated with a significant reduction on HSUs (β = - 0.09, 95% confidence interval [CI] - 0.16 to - 0.02), largely driven by reduced scores on the physical super-dimension (β = - 0.13, 95% CI - 0.20 to - 0.06). Heart diseases were associated with a significant reduction on HSUs (β = - 0.09, 95% CI - 0.16 to - 0.02), driven by reduced scores on physical (β = - 0.09, 95% CI - 0.16 to - 0.02) and psychosocial (β = -0.10, 95% CI - 0.17 to - 0.02) super-dimensions.

CONCLUSIONS: Co-morbidities significantly impact HRQoL of people with IPF, with markedly negative impacts on their HSUs and physical health. A more holistic approach to the care of people with IPF is important as better management of these co-morbidities could lead to improved HRQoL in people with IPF.

PMID:36572788 | DOI:10.1007/s11136-022-03331-8

BMJ Open Respir Res. 2022 Sep;9(1):e001363. doi: 10.1136/bmjresp-2022-001363.

ABSTRACT

INTRODUCTION: The previous data concerning the prevalence of idiopathic pulmonary fibrosis (IPF) and the frequency of antifibrotic drug use in Finland were based on research registries and medical records whereas nationwide data on the number of patients with IPF in specialised care and those on antifibrotic treatment have not been published.

METHODS: We made an information request to the Finnish National Hospital Discharge Register (Hilmo) covering the whole population of Finland to find out the annual numbers of patients with IPF treated in specialised care in 2016-2021. The numbers of the patients initiating and using pirfenidone and nintedanib were requested from the Social Insurance Institution of Finland (Kela) for the same time period.

RESULTS: The estimated prevalence of IPF in specialised care was 36.0 per 100 000 in 2021, having increased since 2016. The number of antifibrotic drug users and their proportion of outpatients with IPF had also risen during the follow-up period. In 2021, 35% of the patients with IPF used pirfenidone or nintedanib. The number of inpatients treated in specialised care because of IPF had declined during 2016-2021.

CONCLUSIONS: The prevalence of IPF was higher than expected in Finnish specialised care and had increased during the 6-year follow-up time. The increase in the number of patients with IPF using antifibrotic drugs might have diminished the need for IPF-related hospitalisations.

PMID:36571594 | DOI:10.1136/bmjresp-2022-001363

Respirology. 2022 Dec 26. doi: 10.1111/resp.14440. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: The minor T-allele of the MUC5B promoter polymorphism rs35705950 is strongly associated with idiopathic pulmonary fibrosis (IPF). However, conflicting results have been reported on the relationship between the MUC5B minor allele and survival and it is unknown whether a specific subgroup of IPF patients might benefit from MUC5B minor allele carriage. We investigated the association between MUC5B rs35705950, survival and patient characteristics in a real-world population of European IPF patients.

METHODS: In this retrospective study, 1751 patients with IPF from 8 European centres were included. MUC5B rs35705950 genotype, demographics, clinical characteristics at diagnosis and survival data were analysed.

RESULTS: In a multi-variate Cox proportional hazard model the MUC5B minor allele was a significant independent predictor of survival when adjusted for age, sex, high resolution computed tomography pattern, smoking behaviour and pulmonary function tests in IPF. MUC5B minor allele carriers were significantly older at diagnosis (p = 0.001). The percentage of MUC5B minor allele carriers increased significantly with age from 44% in patients aged <56 year, to 63% in patients aged >75. In IPF patients aged <56, the MUC5B minor allele was not associated with survival. In IPF patients aged ≥56, survival was significantly better for MUC5B minor allele carriers (45 months [CI: 42-49]) compared to non-carriers (29 months [CI: 26-33]; p = 4 × 10-12 ).

CONCLUSION: MUC5B minor allele carriage associates with a better median transplant-free survival of 16 months in the European IPF population aged over 56 years. MUC5B genotype status might aid disease prognostication in clinical management of IPF patients.

PMID:36571111 | DOI:10.1111/resp.14440

Cureus. 2022 Dec 22;14(12):e32833. doi: 10.7759/cureus.32833. eCollection 2022 Dec.

ABSTRACT

Aspergillus is a ubiquitous fungus whose clinical manifestations and prognosis after infection depend on the host's immune status. The disease can have an insidious course, making it a challenging diagnosis that should be considered in patients with risk factors. We report the case of a 78-year-old man with a known history of asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome and idiopathic pulmonary fibrosis on long-term therapy with high-dose oral corticosteroids, hypertension, dyslipidemia, type 2 diabetes, and hypo coagulated atrial fibrillation. He was admitted to the Emergency Department (ED) for dyspnea, productive cough, and wasting syndrome. Recent hospitalization due to pneumonia of the left upper lobe (LUE) with no agent isolation is worth mentioning, treated with levofloxacin. Due to slow improvement, he underwent bronchoscopy (BFC), which revealed friable bronchial mucosa, with isolation of Candida albicans in bronchial secretions (BS) but without evidence of neoplastic cells in the pathological anatomy (PA). He completed 14 days of itraconazole. He was discharged after partial clinical improvement. One week later, he was again admitted to a medical ward because of worsening respiratory symptoms and wasting syndrome. Laboratory findings included an elevated C-reactive protein (CRP) and sedimentation rate, hypoosmolar hyponatremia, hypoproteinemia, and hypoalbuminemia. The study of hyponatremia revealed the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and the persistence of respiratory symptoms led us to perform a chest computed tomography (CT), which revealed a subsegmental LUE atelectasis. Due to suspicion of neoplasia, he repeated BFC with isolation of Aspergillus on the bronchoalveolar lavage (BAL) and PA. Subacute invasive pulmonary aspergillosis (IPA) was assumed and voriconazole was started. However, he had an unfavorable evolution with marked cachexia and hemorrhagic shock due to lower gastrointestinal bleeding as a complication of hypocoagulation resulting in death. Chronic exposure to corticosteroids and structural lung disease are recognized risk factors for Aspergillus infection. The presentation as a wasting syndrome associated with respiratory symptoms and SIADH raised suspicion for neoplasia, which was excluded. The PA was fundamental for the definitive diagnosis of IPA. The fatal outcome, probably attributable to late diagnosis, reinforces the importance of high clinical suspicion for Aspergillus infection in patients with risk factors.

PMID:36570116 | PMC:PMC9778411 | DOI:10.7759/cureus.32833

Front Bioeng Biotechnol. 2022 Dec 8;10:1066869. doi: 10.3389/fbioe.2022.1066869. eCollection 2022.

ABSTRACT

The prevalency of lung disease has increased worldwide, especially in the aging population. It is essential to develop novel disease models, that are superior to traditional models. Organoids are three-dimensional (3D) in vitro structures that produce from self-organizing and differentiating stem cells, including pluripotent stem cells (PSCs) or adult stem cells (ASCs). They can recapitulate the in vivo cellular heterogeneity, genetic characteristics, structure, and functionality of original tissues. Drug responses of patient-derived organoids (PDOs) are consistent with that of patients, and show correlations with genetic alterations. Thus, organoids have proven to be valuable in studying the biology of disease, testing preclinical drugs and developing novel therapies. In recent years, organoids have been successfully applied in studies of a variety of lung diseases, such as lung cancer, influenza, cystic fibrosis, idiopathic pulmonary fibrosis, and the recent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. In this review, we provide an update on the generation of organoid models for these diseases and their applications in basic and translational research, highlighting these signs of progress in pathogenesis study, drug screening, personalized medicine and immunotherapy. We also discuss the current limitations and future perspectives in organoid models of lung diseases.

PMID:36568297 | PMC:PMC9772457 | DOI:10.3389/fbioe.2022.1066869

Respir Res. 2022 Dec 24;23(1):377. doi: 10.1186/s12931-022-02277-2.

ABSTRACT

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease that has no cure. Many current research efforts center on diagnostic and therapeutic modalities for IPF while other risk factors affecting disease pathogenesis receive less attention. Emerging data support the clinical importance of weight loss in patients with IPF. However, factors associated with weight loss and the impact of weight loss on mortality remain incompletely explored.

OBJECTIVES: Explore the association between weight loss and transplant-free survival in patients with IPF and identify clinical variables associated with weight loss in this population.

METHODS: Kaplan-Meier and Cox proportional hazard regression analyses were generated and stratified by weight loss or use of antifibrotic medications. Conditional logistic regression was used to evaluate for factors associated with weight loss.

RESULTS: There was a significant increase in mortality in patients who lost ≥ 5% of their body weight loss (HR 2.21, [1.29, 4.43] p = .021). The use of supplemental oxygen (adjusted OR 13.16), and ≥ 200 mL loss of FVC over 1 year (adjusted OR 5.44) were both associated with a ≥ 5% weight loss in the year following a diagnosis of IPF. The use of antifibrotic medication did not significantly change median transplant-free survival in patients who lost more than ≥ 5% of their body mass.

CONCLUSIONS: Weight loss over the first year following a diagnosis of IPF is strongly associated with decreased transplant-free survival. More research is needed to determine the mechanisms surrounding weight loss in patients with IPF.

PMID:36566185 | DOI:10.1186/s12931-022-02277-2

Eur J Intern Med. 2022 Dec 22:S0953-6205(22)00439-3. doi: 10.1016/j.ejim.2022.12.010. Online ahead of print.

NO ABSTRACT

PMID:36564241 | DOI:10.1016/j.ejim.2022.12.010