Pathol Int. 2021 Oct 13. doi: 10.1111/pin.13176. Online ahead of print.

ABSTRACT

Pneumocyte injury is a crucial factor influencing the severity of interstitial lung disease (ILD). In this study, we investigated the potential of hepatocyte nuclear factor α (HNF4α) as an immunohistochemical marker to detect pneumocyte injury and as a prognostic marker. Surgical lung biopsy specimens were collected from 309 patients with different types of ILDs (61 idiopathic pulmonary fibrosis (IPF), 173 non-IPF, and 75 unclassifiable ILD). HNF4α expression were examined and the frequency of positive cells (per mm2 ) was calculated. HNF4α was strongly expressed in regenerating pneumocytes present on fibroblastic foci, Masson bodies/organizing alveoli. In the non-IPF and unclassifiable ILD groups, cases with high frequency expression showed significantly poorer outcome. Particularly, in the unclassifiable ILD group, the prognostic impact was more significant (death due to ILD, log-rank test, p < 0.0001), with a 10-year survival rate (hazard ratio 11.1, Wald test, p = 0.0003), as compared to the non-IPF group (log-rank test, p = 0.0269; hazard ratio 2.7, Wald test, p = 0.0334). Multivariable analysis focusing on the unclassifiable ILD group confirmed that the frequent HNF4α expression was an independent prognostic factor (hazard ratio 28.6; Wald test, p = 0.0033). Thus, HNF4α can be utilized as an immunohistochemical marker for pneumocyte injury and have prognostic impact particularly in unclassifiable ILD.

PMID:34643024 | DOI:10.1111/pin.13176

medRxiv. 2021 Oct 6:2021.05.18.21257396. doi: 10.1101/2021.05.18.21257396. Preprint.

ABSTRACT

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n=35) or hospitalization (n=42) due to severe COVID-19 using genome-wide association summary from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (n rs495828 = 53 and n rs505922 =59); strongest association with venous embolism, odds ratio (OR rs495828 1.33 (p=1.32 × 10 -199 ), and thrombosis OR rs505922 1.33, p=2.2 x10 -265 . Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p=4.12 × 10 -191 ; CRHR1 ( rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p=2.26× 10 -12 . The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p=6.48 x10 -23 , lupus OR 0.84, p=3.97 × 10 -06 . PheWAS stratified by genetic ancestry demonstrated differences in genotype-phenotype associations across ancestry. LMNA (rs581342) associated with neutropenia OR 1.29 p=4.1 × 10 -13 among Veterans of African ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.

PMID:34642702 | PMC:PMC8509103 | DOI:10.1101/2021.05.18.21257396

Int J Environ Res Public Health. 2021 Sep 23;18(19):10016. doi: 10.3390/ijerph181910016.

ABSTRACT

We investigated the usefulness and effectiveness of tele-rehabilitation on exercise capacity in patients with idiopathic pulmonary fibrosis (IPF). A randomized study was carried out, including stable patients with IPF for 3 months of tele-rehabilitation: video and chat consultations with a physiotherapist and workout sessions with a virtual physiotherapist agent (VAPA). Moreover, 6-min walk test distance (6MWTD), forced vital capacity (FVC), diffusion capacity for carbon monoxide (DLCO), 7 days pedometry, Saint George Respiratory Questionnaire for interstitial lung disease, The King's Brief Interstitial Lung Disease Questionnaire, and General Anxiety Disorder 7 Questionnaire were tested before and after 3 months of tele-rehabilitation, as well as after 3 and 6 months follow-up. Patient satisfaction and adherence were also measured for tele-rehabilitation with VAPA. Twenty-nine patients aged 70.9 ± 8.6 years, male 72.4%, FVC% 83.5 ± 17.7, DLCO% 50.6 ± 13.0, 6MWTD 468.4 ± 14.8 were included. Fifteen patients were randomized to tele-rehabilitation with VAPA and 14 to the control group. Differences in 6MWTD between groups were at baseline (+10 m (p = 0.11)) and after 3 (+39.5 m (p = 0.03)), 6 (+34.3 m (p = 0.02)), and 9 months (+40.5 m (p = 0.15)) follow-up. No difference was observed in pedometry and quality of life. Adherence was above 63%. Patient satisfaction was high. Tele-rehabilitation with VAPA appears to be useful in patients with IPF. Exercise capacity was better at follow up at 3 and 6 months compared with the control group. There was no change in quality of life or pedometry. Adherence and patient satisfaction were all high.

PMID:34639313 | DOI:10.3390/ijerph181910016

Int J Mol Sci. 2021 Sep 28;22(19):10447. doi: 10.3390/ijms221910447.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), one of the most common fibrosing interstitial lung diseases (ILD), is a chronic-age-related respiratory disease that rises from repeated micro-injury of the alveolar epithelium. Environmental influences, intrinsic factors, genetic and epigenetic risk factors that lead to chronic inflammation might be implicated in the development of IPF. The exact triggers that initiate the fibrotic response in IPF remain enigmatic, but there is now increasing evidence supporting the role of chronic exposure of viral infection. During viral infection, activation of the NLRP3 inflammasome by integrating multiple cellular and molecular signaling implicates robust inflammation, fibroblast proliferation, activation of myofibroblast, matrix deposition, and aberrant epithelial-mesenchymal function. Overall, the crosstalk of the NLRP3 inflammasome and viruses can activate immune responses and inflammasome-associated molecules in the development, progression, and exacerbation of IPF.

PMID:34638790 | DOI:10.3390/ijms221910447

Clin Pharmacol Drug Dev. 2021 Oct 11. doi: 10.1002/cpdd.1021. Online ahead of print.

ABSTRACT

Ziritaxestat is a novel inhibitor of autotaxin, an enzyme responsible for the production of lysophosphatidic acid, the downstream signaling of which mediates responses to tissue injury and has been implicated in the pathogenesis of fibrotic conditions such as idiopathic pulmonary fibrosis and systemic sclerosis. This study (Clinical Trial Registration: NCT03787186) was designed to assess the absorption, distribution, metabolism, and excretion of orally administered 600-mg ziritaxestat labeled with a carbon-14 tracer (14 C-ziritaxestat). To understand the absolute bioavailability of ziritaxestat, an intravenous 100-μg microdose, labeled with a microtracer amount of 14 C radiation, was administered in a separate part of the study, following an unlabeled 600-mg therapeutic oral dose of ziritaxestat. Six healthy male subjects completed each study part. The majority of the labeled oral dose was recovered in feces (77%), with a total mass balance of 84%. The absolute bioavailability of ziritaxestat was 54%. Ziritaxestat was the main (76%) circulating drug-related product. There were 7 treatment-emergent adverse events, all of which were considered mild and not considered to be related to the study drug.

PMID:34633152 | DOI:10.1002/cpdd.1021

Front Vet Sci. 2021 Sep 23;8:732133. doi: 10.3389/fvets.2021.732133. eCollection 2021.

ABSTRACT

West Highland white terriers (WHWTs) affected with canine idiopathic pulmonary fibrosis (CIPF) are at risk of developing precapillary pulmonary hypertension (PH). In humans, thoracic computed tomography angiography (CTA) is commonly used to diagnose and monitor patients with lower airway diseases. In such patients, CTA helps to identify comorbidities, such as PH, that could negatively impact prognosis. Diameter of the pulmonary trunk (PT), pulmonary trunk-to-aorta ratio (PT/Ao), and right ventricle-to-left ventricle ratio (RV/LV) are CTA parameters commonly used to assess the presence of PH. Pulmonary vein-to-right pulmonary artery ratio (PV/PA) is a new echocardiographic parameter that can be used in dogs to diagnose PH. The primary aim of this study was to evaluate the use of various CTA parameters to diagnose PH. An additional aim was to evaluate the correlation of RV/LV measurements between different CTA planes. CTA and echocardiography were prospectively performed on a total of 47 WHWTs; 22 affected with CIPF and 25 presumed healthy control dogs. Dogs were considered to have PH if pulmonary vein-to-right pulmonary artery ratio (PV/PA) measured on 2D-mode echocardiography was less than to 0.7. WHWTs affected with CIPF had higher PT/Ao compared with control patients. In WHWTs affected with CIPF, PT size was larger in dogs with PH (15.4 mm) compared with dogs without PH (13 mm, p = 0.003). A cutoff value of 13.8 mm predicted PH in WHWTs affected with CIPF with a sensitivity of 90% and a specificity of 87% (AUC = 0.93). High correlations were observed between the different CTA planes of RV/LV. Results suggest that diameter of the PT measured by CTA can be used to diagnose PH in WHWTs with CIPF.

PMID:34631858 | PMC:PMC8495013 | DOI:10.3389/fvets.2021.732133

Front Med (Lausanne). 2021 Sep 24;8:736485. doi: 10.3389/fmed.2021.736485. eCollection 2021.

ABSTRACT

Familial pulmonary fibrosis (FPF) is a monogenic disease most commonly involving telomere- (TERT) or surfactant- (SFTP) related mutations. These mutations have been shown to alter lymphocytic inflammatory responses, and FPF biopsies with histological lymphocytic infiltrates have been reported. Recently, a model of a surfactant mutation in mice showed that the disease initially started with an inflammatory response followed by fibrogenesis. Since inflammation and fibrogenesis are targeted by different drugs, we investigated whether the degree of these two features co-localize or occur independently in different entities of FPF, and whether they influence survival. We quantified the number of lymphocyte aggregates per surface area, the extent of diffuse lymphocyte cell infiltrate, the number of fibroblast foci per surface area, and the percentage of fibrotic lung surface area in digitally scanned hematoxylin and eosin (H&E) sections of diagnostic surgical biopsies of patients with TERT-related FPF (TERT-PF; n = 17), SFTP-related FPF (SFTP-PF; n = 7), and sporadic idiopathic pulmonary fibrosis (sIPF; n = 10). For comparison, we included biopsies of patients with cellular non-specific interstitial pneumonia (cNSIP; n = 10), an inflammatory interstitial lung disease with high lymphocyte influx and usually responsive to immunosuppressive therapy. The degree of inflammatory cell infiltrate and fibrosis in TERT-PF and SFTP-PF was not significantly different from that in sIPF. In comparison with cNSIP, the extent of lymphocyte infiltrates was significantly lower in sIPF and TERT-PF, but not in SFTP-PF. However, in contrast with cNSIP, in sIPF, TERT-PF, and SFTP-PF, diffuse lymphocyte cell infiltrates were predominantly present and lymphocyte aggregates were only present in fibrotic areas (p < 0.0001). Furthermore, fibroblast foci and percentage of fibrotic lung surface were associated with survival (p = 0.022 and p = 0.018, respectively), while this association was not observed for lymphocyte aggregates or diffuse lymphocytic infiltration. Inflammatory cells in diagnostic lung biopsies of TERT-PF, SFTP-PF, and sIPF were largely confined to fibrotic areas. However, based on inflammation and fibrosis, no differences were found between FPF and sIPF, substantiating the histological similarities between monogenic familial and sporadic disease. Furthermore, the degree of fibrosis, rather than inflammation, correlates with survival, supporting that fibrogenesis is the key feature for therapeutic targeting of FPF.

PMID:34631753 | PMC:PMC8497799 | DOI:10.3389/fmed.2021.736485

Front Pharmacol. 2021 Sep 24;12:713572. doi: 10.3389/fphar.2021.713572. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is one of the most common and devastating interstitial lung diseases with poor prognosis. Currently, few effective drugs are available for IPF. Hence, we sought to explore the role of mefunidone (MFD), a newly synthesized drug developed by our team, in lung fibrosis. In this study, MFD was found to attenuate bleomycin (BLM) -induced lung fibrosis and inflammation in mice according to Ashcroft and alveolitis scoring. The protein contents and total cell counts in bronchoalveolar lavage fluids of BLM-treated mice were also lowered by MFD. Moreover, the elevation of TGF-β/Smad2 and phosphorylation of MAPK pathways was repressed by MFD. Additionally, MFD attenuated the swelling and vacuolization of mitochondria, lowered the ratio of apoptotic cells, restored the mitochondrial membrane potential, and reversed the expression of cleaved-caspase 3, Bcl-2 and Bax. Meanwhile, the level of epithelial marker, E-cadherin, was restored by MFD, while the levels of mesenchymal markers such as Snail and vimentin were down-regulated by MFD. Besides, MFD inhibited the expression of fibronectin and α-smooth muscle actin in TGF-β treated normal human lung fibroblasts. Thus, our findings suggested that MFD could ameliorate lung fibrosis, cell apoptosis and EMT potentially via suppression of TGF-β/Smad2 and MAPK pathways.

PMID:34630088 | PMC:PMC8499630 | DOI:10.3389/fphar.2021.713572

Rev Mal Respir. 2021 Oct 7:S0761-8425(21)00365-X. doi: 10.1016/j.rmr.2021.07.004. Online ahead of print.

ABSTRACT

EPIDemio study is a multicenter, prospective and observational study. The objective is to estimate the prevalence and incidence of fibrosing interstitial lung diseases (ILDs) in the department of Haute Garonne (31) in France. Fifty-five pulmonologists from the Toulouse university hospital and 8 private establishments participated in this study. Two hundred and fifty-six cases of fibrosing ILDs were reported (gross overall prevalence: 22.8/100,000 and estimated 30.1/100,000. Idiopathic ILDs represent 55.8% of fibrosing ILDs ahead of systemic disease-related ILDs (24.6%) and ILDs associated with environmental exposure (13.3%). Idiopathic pulmonary fibrosis (IPF) represents 35.9% of fibrosing ILDs, which corresponds to a minimal prevalence of 8.2/100,000 and an estimated prevalence of 11.2/100,000. This study confirms epidemiological data collected in France and Europe.

PMID:34629221 | DOI:10.1016/j.rmr.2021.07.004

Respiration. 2021 Oct 8:1-9. doi: 10.1159/000519214. Online ahead of print.

ABSTRACT

BACKGROUND: The overall incidence of interstitial lung disease and disease-associated mortality have been found on the rise. Hospitalizations for interstitial lung disease are typically caused by airway infection or the acute exacerbation of the underlying disease. Seasonal variance in ambient air pollution has recently been linked to exacerbation and mortality. We sought to examine the seasonal pattern of hospitalizations in Germany, use of mechanical ventilation, and in-hospital mortality on a year-by-year basis to identify their overall trend and to characterize seasonal patterns.

METHODS: The national in-patient database of the federal statistical office of Germany was searched for cases of interstitial lung disease.

RESULTS: A total of 130,366 hospitalizations for ILD occurred from 2005 to 2015. Time series data were examined for seasonality using X-11 statistics. The incidence of hospitalizations, mechanical ventilation, and in-hospital mortality show clear seasonal peaks in the cold season. The observed seasonality cannot be attributed to the variance of selected comorbidities. Also, there is a significant overall upward trend regarding hospitalization counts, especially in the use of non-invasive ventilation.

CONCLUSION: Time series analysis of in-hospital data shows an ILD-related rise of hospitalizations, in-hospital mortality, and non-invasive ventilation. This emphasizes a growing importance of interstitial lung diseases for health-care systems. Strong seasonality is seen in these variables. Data therefore support previous studies of ILD exacerbation. More research on infectious causes and environmental factors is warranted.

PMID:34628406 | DOI:10.1159/000519214

Orphanet J Rare Dis. 2021 Oct 9;16(1):419. doi: 10.1186/s13023-021-02043-5.

ABSTRACT

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) has a variable disease course with dismal prognosis in the majority of patients with no validated drug therapy. This study is to evaluate the effect of nintedanib in patients with idiopathic and secondary PPFE. Patients admitted to a tertiary care center (2010-2019) were included into this retrospective analysis if they had a multidisciplinary diagnosis of PPFE, had been followed-up for 3 months or more, and had lung function tests and chest CTs available for review. Changes in pulmonary function tests were assessed using non-parametric tests and linear mixed effect model. Lung volumes were measured with lobar segmentation using chest CT.

RESULTS: Out of 21 patients with PPFE, nine had received nintedanib, six had received another treatment and another six patients were monitored without drug therapy. Annual FVC (% of predicted) relative decline was - 13.6 ± 13.4%/year before nintedanib and - 1.6 ± 6.02%/year during nintedanib treatment (p = 0.014), whereas no significant change in FVC% relative decline was found in patients receiving another treatment (- 13.25 ± 34 before vs - 16.61 ± 36.2%/year during treatment; p = 0.343). Using linear mixed effect model, the slope in FVC was - 0.97%/month (95% CI: - 1.42; - 0.52) before treatment and - 0.50%/month (95% CI: - 0.88; 0.13) on nintedanib, with a difference between groups of + 0.47%/month (95% CI: 0.16; 0.78), p = 0.004. The decline in the upper lung volumes measured by CT was - 233 mL/year ± 387 mL/year before nintedanib and - 149 mL/year ± 173 mL/year on nintedanib (p = 0.327). Nintedanib tolerability was unremarkable.

CONCLUSION: In patients with PPFE, nintedanib treatment might be associated with slower decline in lung function, paving the way for prospective, controlled studies.

PMID:34627338 | DOI:10.1186/s13023-021-02043-5

Eur Respir J. 2021 Oct 8:2003721. doi: 10.1183/13993003.03721-2020. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that is characterised by aberrant proliferation of activated myofibroblasts and pathological remodelling of the extracellular matrix. Previous studies have revealed that the intermediate filament protein Nestin plays key roles in tissue regeneration and wound healing in different organs. Whether Nestin plays a critical role in the pathogenesis of IPF needs to be clarified.Nestin expression in lung tissues from bleomycin-treated mice and IPF patients was determined. Transfection with Nestin shRNA vectors in vitro that regulated TGF-β/Smad signalling was conducted. Biotinylation assays to observe plasma membrane TβRI, TβRI endocytosis and TβRI recycling after Nestin knockdown were performed. Adeno-associated virus serotype 6 (AAV6)-mediated Nestin knockdown was assessed in vivoWe found that Nestin expression was increased in a murine pulmonary fibrosis model and IPF patients, and that the upregulated protein primarily localised in lung α-SMA+ myofibroblasts. Mechanistically, we determined that Nestin knockdown inhibited TGF-β signalling by suppressing recycling of TβRI to the cell surface and that Rab11 was required for the ability of Nestin to promote TβRI recycling. In vivo, we found that intratracheal administration of adeno-associated virus serotype 6 (AAV6)-mediated Nestin knockdown significantly alleviated pulmonary fibrosis in multiple experimental mice models.In conclusion, our findings reveal a pro-fibrotic function of Nestin partially through facilitating Rab11-dependent recycling of TβRI and shed new light on pulmonary fibrosis treatment.

PMID:34625478 | DOI:10.1183/13993003.03721-2020

J Cardiothorac Vasc Anesth. 2021 Sep 17:S1053-0770(21)00835-1. doi: 10.1053/j.jvca.2021.09.021. Online ahead of print.

ABSTRACT

OBJECTIVES: To determine the incidence and predictive factors of acute kidney injury (AKI) after off-pump lung transplantation.

DESIGN: A retrospective cohort study.

SETTING: The operating room and intensive care unit.

PARTICIPANTS: Adult patients who underwent lung transplant without cardiopulmonary bypass or extracorporeal membrane oxygenator between 2006 and 2016 at the Vanderbilt University Medical Center.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: The presence of postoperative AKI was assessed by the Kidney Disease: Improving Global Outcomes criteria in the first seven postoperative days. Multivariate logistic regression analysis was used to determine the independent predictive factors of AKI. One hundred forty-eight patients were included in the final analysis, of whom 63 (42.6%) subsequently developed AKI: 43 (29.0%) stage 1, ten (6.8%) stage 2, and ten (6.8%) stage 3. Patients who had AKI had a longer hospital length of stay (12 days [interquartile range (IQR): 10-17] vs ten days [IQR: 8-12], p < 0.001). For every one-year increase in age, the odds of AKI decreased by 8% (odds ratio [OR] 0.92, 95% confidence interval [CI]: 0.87-0.98, p = 0.008). The odds of having AKI in patients with bilateral lung transplant was lower than patients with unilateral transplant (OR 0.09, 95% CI: 0.01-0.63, p = 0.015). Additionally, a diagnosis of chronic obstructive pulmonary disease increased the odds of AKI by four-fold compared with a diagnosis of idiopathic pulmonary fibrosis (OR 4.73, 95% CI: 1.44-15.56, p = 0.011).

CONCLUSIONS: AKI is a common complication after off-pump lung transplantation and is associated with increased hospital length of stay. Younger age, unilateral lung transplant, and diagnosis of chronic obstructive pulmonary disease are independently associated with AKI.

PMID:34625351 | DOI:10.1053/j.jvca.2021.09.021

J Clin Imaging Sci. 2021 Sep 30;11:52. doi: 10.25259/JCIS_143_2021. eCollection 2021.

ABSTRACT

OBJECTIVES: The objectives of the study were to estimate the impact of high matrix image reconstruction on chest computed tomography (CT) compared to standard image reconstruction.

MATERIAL AND METHODS: This retrospective study included patients with interstitial or parenchymal lung disease, airway disease, and pulmonary nodules who underwent chest CT. Chest CT images were reconstructed using high matrix (1024 × 1024) or standard matrix (512 × 512), with all other parameters matched. Two radiologists, blinded to reconstruction technique, independently examined each lung, viewing image sets side by side and rating the conspicuity of imaging findings using a 5-point relative conspicuity scale. The presence of pulmonary nodules and confidence in classification of internal attenuation was also graded. Overall image quality and subjective noise/artifacts were assessed.

RESULTS: Thirty-four patients with 68 lungs were evaluated. Relative conspicuity scores were significantly higher using high matrix image reconstruction for all imaging findings indicative of idiopathic lung fibrosis (peripheral airway visualization, interlobular septal thickening, intralobular reticular opacity, and end-stage fibrotic change; P ≤ 0.001) along with emphysema, mosaic attenuation, and fourth order bronchi for both readers (P ≤ 0.001). High matrix reconstruction did not improve confidence in the presence or classification of internal nodule attenuation for either reader. Overall image quality was increased but not subjective noise/artifacts with high matrix image reconstruction for both readers (P < 0.001).

CONCLUSION: High matrix image reconstruction significantly improves the conspicuity of imaging findings reflecting interstitial lung disease and may be useful for diagnosis or treatment response assessment.

PMID:34621597 | PMC:PMC8492437 | DOI:10.25259/JCIS_143_2021

Respirology. 2021 Oct 5. doi: 10.1111/resp.14154. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease that requires ongoing care and is associated with considerable socioeconomic burden. We evaluated the IPF care pathway from symptom recognition to treatment. We describe the impact of IPF on healthcare resource use (HCRU), quality of life (QoL) and work impairment, and report differences in patient and physician perspectives using real-world data from France, Germany, Japan and the United States.

METHODS: Quantitative, point-in-time data were collected as part of the Adelphi IPF II Disease Specific Programme™. Physician-reported data (patient demographics, medical history, diagnoses, treatment) were matched to patient-reported data (HCRU, QoL, work impairment). HCRU was measured as physician visits and hospitalizations. QoL and work impairment were measured using the EuroQol-5 Dimensions (EQ-5D) and Work Productivity and Activity Impairment questionnaires.

RESULTS: Overall, 244 physicians reported data on 1249 patients, 739 of whom self-reported data. Diagnostic delays of 0.8 (Germany) to 2.0 (Japan) years after symptom onset were reported; treatment initiation was further delayed. In all countries, patients more often reported symptoms in the survey than did their physicians. On average, patients underwent 7-10 clinical tests before diagnosis. Antifibrotic use increased from 57% (2016) to 69% (2019); only 50% of patients with moderate/severe IPF were satisfied with their treatment. The 12-month hospitalization rates were 24% (Japan) to 64% (United States). Patients reported low QoL (mean EQ-5D visual analogue scale: 61.7/100).

CONCLUSION: Patients with IPF experience considerable diagnostic and treatment delays. More effective therapies and management are needed to reduce the disease burden.

PMID:34611971 | DOI:10.1111/resp.14154

Respir Res. 2021 Oct 5;22(1):259. doi: 10.1186/s12931-021-01853-2.

ABSTRACT

BACKGROUND: Health-related quality of life (HRQL) is impaired in patients with idiopathic pulmonary fibrosis (IPF). HRQL is often measured using the St. George's Respiratory Questionnaire (SGRQ) despite the development of an IPF-specific version (SGRQ-I). Using data from a real-world cohort of patients with IPF, we aimed to transform SGRQ into a derived version of SGRQ-I, SGRQ-Ider, to examine the cross-sectional and longitudinal validity of SGRQ-Ider and to compare SGRQ-Ider to SGRQ-I.

METHODS: Based on results from SGRQ, SGRQ-Ider was derived applying the algorithm used to develop SGRQ-I. Of the 50 items in SGRQ, 34 items were retained in SGRQ-Ider. Response options for seven items were collapsed and minor adjustments were made to the weights of two items after correspondence with the developers of SGRQ-I. Cross-sectional validation, responsiveness and minimal clinically important difference (MCID) were assessed by comparison to other HRQL instruments, pulmonary function tests and 6-min walk test performed at baseline, 6 and 12 months. Furthermore, the association between SGRQ-Ider scores and mortality was examined.

RESULTS: A total of 150 IPF patients participated and 124 completed follow-up at 12 months. SGRQ-Ider performed comparably to SGRQ-I with a high concurrent validity, good test-retest reliability and high known-groups validity. SGRQ-Ider was responsive to change in HRQL and physiological anchors. MCID of SGRQ-Ider for improvement and deterioration was 3.5 and 5.7, respectively. SGRQ-Ider scores were associated with mortality in both univariate (HR 1.82, 95% CI 1.42-2.34 per 20-point increase) and multivariate analyses (HR 1.57, 95% CI 1.20-2.05 per 20-point increase).

CONCLUSIONS: The SGRQ-Ider is a valid, reliable and responsive HRQL instrument in patients with IPF and has psychometric properties comparable to SGRQ-I. Thus, SGRQ results can reliably be transformed into the SGRQ-Ider. The MCID estimates were calculated for improvement and deterioration separately. Increasing SGRQ-Ider score was associated with increased mortality.

PMID:34610840 | DOI:10.1186/s12931-021-01853-2

Respiration. 2021 Oct 5:1-13. doi: 10.1159/000518855. Online ahead of print.

ABSTRACT

BACKGROUND: Weight loss is frequently reported in patients with idiopathic pulmonary fibrosis (IPF) and may be associated with worse outcomes in these patients.

OBJECTIVE: The aim of this study was to investigate the relationships between body mass index (BMI) and weight loss, and outcomes over 1 year in patients with IPF.

METHODS: Data were included from placebo patients enrolled in ASCEND (NCT01366209) and CAPACITY (NCT00287716 and NCT00287729), and all patients in INSPIRE (NCT00075998) and RIFF Cohort A (NCT01872689). An additional analysis included data from pirfenidone-treated patients. Outcomes (annualized change in percent predicted forced vital capacity [%FVC], percent predicted carbon monoxide diffusing capacity, 6-min walk distance, St. George's Respiratory Questionnaire total score, hospitalization, mortality, and serious adverse events) were analyzed by baseline BMI (<25 kg/m2, 25 kg/m2-<30 kg/m2, or ≥30 kg/m2) and annualized percent change in body weight (no loss, >0-<5% loss, or ≥5% loss).

RESULTS: Placebo-treated patients with a baseline BMI <25 kg/m2 or annualized weight loss may experience worse outcomes versus those with a baseline BMI ≥25 kg/m2 or no weight loss. The proportion of placebo-treated patients who experienced a relative decline of ≥10% in %FVC or death up to 1 year post-randomization was highest in patients with a baseline BMI <25 kg/m2. Pirfenidone-treated patients with an annualized weight loss ≥5% may also experience worse outcomes versus those with no weight loss.

CONCLUSIONS: Patients with a baseline BMI <25 kg/m2 or annualized weight loss of >0-<5% or ≥5% may experience worse outcomes over 1 year versus those with a baseline BMI ≥25 kg/m2 or no weight loss.

PMID:34610600 | DOI:10.1159/000518855

Chron Respir Dis. 2021 Jan-Dec;18:14799731211033925. doi: 10.1177/14799731211033925.

ABSTRACT

BACKGROUND: Various patient reported outcome measures (PROMs) are used in idiopathic pulmonary fibrosis (IPF). We aimed to describe their psychometric properties, assess their relationship with 1-year mortality and determine their minimal clinically important differences (MCIDs).

METHODS: In a prospective multicentre study, participants with IPF completed the King's Brief Interstitial Lung Disease Questionnaire (K-BILD), the modified Medical Research Council (mMRC) dyspnoea scale, St George's Respiratory Questionnaire (SGRQ) and University of California, San Diego shortness of breath questionnaire (UCSD-SOBQ) three-monthly intervals over a 12-month period. Forced vital capacity (FVC) was matched with questionnaires and mortality was captured. Anchor- and distribution-based methods were used to derive MCID.

RESULTS: Data were available from 238 participants. All PROMs had good internal consistency and high degree of correlations with other tools (except UCSD-SOBQ correlated poorly with FVC). There were significant associations with mortality for K-BILD (hazard ratio 16.67; 95% CI 2.38-100) and SGRQ (hazard ratio 4.65; 95% CI 1.32-16.62) but not with the other PROMs or FVC. The median MCID (range) for K-BILD was 6.3 (4.1-7.0), SGRQ was 7.0 (3.8-9.6), mMRC was 0.4 (0.1-0.5) and UCSD-SOBQ was 9.6 (4.1-14.2).

CONCLUSIONS: The K-BILD was related to other severity measures and had the strongest relationship with mortality.

PMID:34609156 | DOI:10.1177/14799731211033925

Am J Health Syst Pharm. 2021 Oct 5:zxab375. doi: 10.1093/ajhp/zxab375. Online ahead of print.

ABSTRACT

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PURPOSE: This article summarizes the appropriate use and pharmacology of treatments for fibrosing interstitial lung diseases, with a specific focus on the antifibrotic agents nintedanib and pirfenidone.

SUMMARY: The interstitial lung diseases are a heterogenous group of parenchymal lung disorders with a common feature-infiltration of the interstitial space with derangement of the normal capillary-alveolar anatomy. Diseases characterized by fibrosis of the interstitial space are referred to as the fibrosing interstitial lung diseases and often show progression over time: idiopathic pulmonary fibrosis is the most common fibrotic interstitial lung disease. Historically, therapies for fibrosing lung diseases have been limited in number, questionable in efficacy, and associated with potential harms. Food and Drug Administration (FDA) approval of the antifibrotic agents nintedanib and pirfenidone for idiopathic pulmonary fibrosis in 2014 heralded an era of reorganization of therapy for the fibrotic interstitial lung diseases. Subsequent investigations have led to FDA approval of nintedanib for systemic sclerosis-associated interstitial lung disease and interstitial lung diseases with a progressive phenotype. Although supportive care and pulmonary rehabilitation should be provided to all patients, the role(s) of immunomodulators and/or immune suppressing agents vary by the underlying disease state. Several agents previously used to treat fibrotic lung diseases (N-acetylcysteine, anticoagulation, pulmonary vasodilators) lack efficacy or cause harm.

CONCLUSION: With the introduction of effective pharmacotherapy for fibrosing interstitial lung disease, pharmacists have an increasingly important role in the interdisciplinary team managing these patients.

PMID:34608488 | DOI:10.1093/ajhp/zxab375

Pharmacol Res. 2021 Oct 1:105923. doi: 10.1016/j.phrs.2021.105923. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) induces significant morbidity and mortality, for which there are limited therapeutic options available. Here, we found that tetraethylthiuram disulphide (disulfiram, DSF), a derivative of thiuram, used in the treatment of alcohol abuse, has an inhibitory effect on bleomycin (BLM)-induced pulmonary fibrosis via the attenuation of the fibroblast-to-myofibroblast transition, migration, and proliferation of fibroblasts. Furthermore, DSF inhibited the activation of primary pulmonary fibroblasts and fibroblast cell line under transforming growth factor-β 1 (TGF-β1) challenge. Mechanistically, the anti-fibrotic effect of DSF on fibroblasts depends on the inhibition of TGF-β signalling. We further determined that DSF interrupts the interaction between SMAD3 and TGF-β receptor Ι (TBR Ι), and identified that DSF directly binds with SMAD3, in which Trp326, Thr330, and Cys332 of SMAD3 are critical binding sites for DSF. Collectively, our results reveal a powerful anti-fibrotic function of DSF in pulmonary fibrosis through the inhibition of TGF-β/SMAD signalling in pulmonary fibroblasts, indicating that DSF is a promising therapeutic candidate for IPF.

PMID:34607006 | DOI:10.1016/j.phrs.2021.105923