ResearchPad - interstitial-lung-disease https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Acute exacerbation of idiopathic interstitial pneumonias related to chemotherapy for lung cancer: nationwide surveillance in Japan]]> https://www.researchpad.co/article/elastic_article_16162 The Japanese are at high risk of acute exacerbation of IPF. Therefore, chemotherapy for Japanese lung cancer patients with IIPs is challenging. However, appropriate chemotherapy may give a survival benefit, despite the risk of acute deterioration of IIPs. http://bit.ly/3cROaCy

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<![CDATA[Prognostic impact of pre-existing interstitial lung disease in non-HIV patients with <i>Pneumocystis</i> pneumonia]]> https://www.researchpad.co/article/elastic_article_12763 Pre-existing interstitial lung disease (ILD) is an independent prognostic risk factor for non- HIV Pneumocystis pneumonia (PCP). Prophylaxis for PCP is needed in patients with pre-existing ILD under immunosuppression. http://bit.ly/37BGZuK

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<![CDATA[Efficacy of recombinant thrombomodulin for poor prognostic cases of acute exacerbation in idiopathic interstitial pneumonia: secondary analysis of the SETUP trial]]> https://www.researchpad.co/article/elastic_article_12521 Acute exacerbation (AE) in idiopathic pulmonary fibrosis and other idiopathic interstitial pneumonias (IIPs) are poor prognostic events although they are usually treated with conventional therapy with corticosteroids and immunosuppressants. Previously, we demonstrated the safety and efficacy of recombinant human soluble thrombomodulin (rhTM) for AE-IIP in the SETUP trial. Here, we aimed to clarify the efficacy of rhTM for poor-prognosis cases of AE-IIP.MethodsIn this study, we included 85 patients, in whom fibrin degradation product (FDP)/d-dimer was evaluated at AE, from the 100 patients in the SETUP trial. The AE-IIP patients in the rhTM arm (n=39) were diagnosed using the Japanese criteria from 2014 to 2016 and treated with intravenous rhTM for 6 days in addition to the conventional therapy. The AE-IIP patients in the control arm (n=46) were treated with the conventional therapy without rhTM between 2011 and 2013. The subjects were classified into higher and lower FDP/d-dimer groups based on the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation scoring system. A multivariate Cox proportional hazard regression analysis with stepwise selection was performed to reveal the prognostic factors of AE-IIP.ResultsWe developed a prognostic scoring system using two significant prognostic factors, higher FDP/d-dimer at AE and prednisolone therapy before AE, with 3 and 2 points assigned for each parameter, respectively. The prognostic scores ranged from 0 to 5. Survival of AE-IIP patients with a prognostic score=0 was significantly better than that of patients with score ≥2. Survival was improved with the rhTM therapy (p<0.05) in the poor prognostic cases (score ≥2), but not in the good prognostic cases (score=0).ConclusionsTreatment with rhTM might improve survival in AE-IIP cases with poor prognoses.Trial registration numberUMIN000014969, date: 28 August 2014. ]]> <![CDATA[Ranking Self-reported Gastrointestinal Side Effects of Pharmacotherapy in Sarcoidosis]]> https://www.researchpad.co/article/N7e211b88-355b-48da-a397-a8130beb3a02

Background

Clinical manifestations of sarcoidosis vary widely, depending on the intensity of the inflammation and the organ systems affected. So far, no curative treatment exists; the disease can only be suppressed. All treatment options cause side effects affecting quality of life. The aim of this study was to establish and rank the prevalence of self-reported gastrointestinal side effects of drugs used in the treatment of sarcoidosis.

Methods

A cross-sectional web-based anonymous survey about complaints and side effects was conducted among sarcoidosis patients in the Netherlands, United Kingdom, and United States of America.

Results

Of the participants, 70% were being treated with one or more drugs. The most important reported side effect was weight gain, associated with increased appetite among prednisone users (as monotherapy as well as in combination with other drugs). Methotrexate (MTX) users especially experienced nausea, with monotherapy as well as combination therapy. Vomiting and weight loss were most prominent among azathioprine and mycophenolate mofetil (MMF) users, whereas diarrhoea was frequently mentioned by MMF and MTX users. The reported side effects of hydroxychloroquine were generally rather mild.

Conclusion

The current study ranked the gastrointestinal side effects associated with pharmacotherapy in sarcoidosis patients. Pharmacotherapy does have multiple gastrointestinal side effects. The strongest association between a reported side effect and drug use was that of weight gain associated with increased appetite among prednisone users. It would therefore be useful for future research to look further into dietary interventions to counter these side effects and reduce their burden.

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<![CDATA[How consistently do physicians diagnose and manage drug-induced interstitial lung disease? Two surveys of European ILD specialist physicians]]> https://www.researchpad.co/article/N7b39363e-f269-4f81-ba00-bda0f90d72ee

Introduction

Currently there are no general guidelines for diagnosis or management of suspected drug-induced (DI) interstitial lung disease (ILD). The objective was to survey a sample of current European practice in the diagnosis and management of DI-ILD, in the context of the prescribing information approved by regulatory authorities for 28 licenced drugs with a recognised risk of DI-ILD.

Methods

Consultant physicians working in specialist ILD centres across Europe were emailed two surveys via a website link. Initially, opinion was sought regarding various diagnostic and management options based on seven clinical ILD case vignettes and five general questions regarding DI-ILD. The second survey involved 29 statements regarding the diagnosis and management of DI-ILD, derived from the results of the first survey. Consensus agreement was defined as 75% or greater.

Results

When making a diagnosis of DI-ILD, the favoured investigations used (other than computed tomography) included pulmonary function tests, bronchoscopy and blood tests. The preferred method used to decide when to stop treatment was a pulmonary function test. In the second survey, the majority of the statements were accepted by the 33 respondents, with only four of 29 statements not achieving consensus when the responses “agree” and “strongly agree” were combined as one answer.

Conclusion

The two surveys provide guidance for clinicians regarding an approach to the diagnosis and management of DI-ILD in which the current evidence base is severely lacking, as demonstrated by the limited information provided by the manufacturers of the drugs associated with a high risk of DI-ILD that we reviewed.

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<![CDATA[Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study]]> https://www.researchpad.co/article/Nc37a7aa3-4d2f-449b-9abe-9a659eea3349

In patients with primary or secondary lung tumour treated with immune checkpoint inhibitors, immune-related pneumonitis is a rare adverse event but may evolve to respiratory failure. Prompt management is required and usually consists of treatment interruption and immunosuppressive drug administration. The aim of this study was to evaluate relationships between immune-related pneumonitis and pre-existing parenchymal status, especially tumour location and history of chest radiotherapy.

Computed tomography (CT) scans of patients with immune-related pneumonitis were retrospectively reviewed. Pattern, distribution and extent of pneumonitis were assessed in six lung regions. In patients who received radiotherapy, the extent of pneumonitis was evaluated according to the radiation field.

Among 253 patients treated with immunotherapy, 15 cases of immune-related pneumonitis were identified. 10 had previous or concomitant chest radiotherapy in addition to immunotherapy. At CT scan, 29 (33%) out of 88 regions encompassed the primary tumour (n=4), a lung metastasis (n=4) and/or radiation fields (n=21). A significantly higher prevalence of parenchymal involvement by immune-related pneumonitis occurred within areas of primary or metastatic malignancy and/or radiation field (97%) as compared to other areas (3%, p=0.009). Lung regions affected by the primary tumour, metastasis or radiotherapy had a higher probability of immune-related pneumonitis than others (OR 10.8, p=0.024). An organising pneumonia (OP) pattern was more frequent after radiotherapy (70% versus 0%, p=0.024), whereas nonspecific interstitial pneumonia features were more commonly seen in radiotherapy-naive patients (100% versus 10%, p=0.002).

In patients with primary or secondary lung tumour treated with immune checkpoint inhibitors, immune-related pneumonitis is preferentially located within lung areas involved by tumour and/or radiation fields.

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<![CDATA[Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis]]> https://www.researchpad.co/article/N88e3e87c-631f-4639-ab94-fe63ab52e8fb

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell–cell adhesion.

Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations.

Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.

Measurements and Main Results: We identified and replicated three new genome-wide significant (P < 5 × 10−8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1, and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility.

Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

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<![CDATA[Skeletal muscle oxygenation and regional blood volume during incremental limb loading in interstitial lung disease]]> https://www.researchpad.co/article/Nbe39e102-5119-4541-b5e9-b874aa55d148

Introduction

Individuals with interstitial lung disease (ILD) exhibit reduced exercise capacity and exertional hypoxaemia. The role of peripheral (muscle) limitation to exercise tolerance in ILD is not well studied to date.

Methods

A prospective cross-sectional study examined skeletal muscle oxygen saturation (SmO2) and regional blood volume of the knee extensors and elbow flexors during incremental limb loading in healthy people and people with varying severity of ILD. Isotonic concentric exercise was performed on an isokinetic dynamometer. SmO2 and regional blood volume were measured by near-infrared spectroscopy over the vastus lateralis and biceps.

Results

Thirteen people who were dependent on oxygen, candidates for lung transplant and with severe ILD (forced vital capacity (FVC) 59±20% predicted), 10 people who were not oxygen dependent with mild ILD (FVC 81±17% predicted) and 13 healthy people (FVC 101±14% predicted) were included. Total haemoglobin, a marker of regional blood volume, was lower at task failure in the knee extensors in participants with severe ILD compared to healthy participants (p=0.05). At task failure for both knee-extensor loading and elbow-flexor loading, SmO2 was decreased to similar levels across all groups, but occurred at lower total workloads in the ILD groups (all p<0.01).

Conclusions

Overall, people with severe ILD had lower levels of total work and experienced less increase in blood volume in the knee extensors after knee-extensor loading compared to healthy people. Peripheral muscle dysfunction in severe ILD may have contributed to muscle deoxygenation at lower workloads.

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<![CDATA[Validation of a new serum granulocyte–macrophage colony-stimulating factor autoantibody testing kit]]> https://www.researchpad.co/article/N2afbccaf-a12c-475f-8986-8a7bd4972fab

Very recently, a modest but significant efficacy of granulocyte–macrophage colony-stimulating factor (GM-CSF) inhalation therapy for the treatment of mild to moderate autoimmune pulmonary alveolar proteinosis (aPAP) has been reported.

As the ability to measure the level of GM-CSF autoantibody (GMAb) in the serum is required to decide the indication for this therapy, we developed a high-performance GMAb testing kit for clinical use.

As the kit succeeded in reducing nonspecific IgG binding to the ELISA plate, the predictive performance shown in the training study to discriminate aPAP patients from healthy subjects was perfect, providing a cut-off value of 1.65 U·mL−1 in 78 patients with aPAP and 90 healthy subjects in an operator-blinded manner using logistic regression analysis. As in the validation study, serum samples from another 213 patients with aPAP were also blinded and evaluated in an operator-blinded manner against external 207 samples from patients with other types of PAP and patients exhibiting various ground-glass opacities on chest high-resolution computed tomography that require discrimination from PAP.

The logistic regression analysis of these validation data sets revealed values of 97.6% and 100% for specificity and sensitivity, respectively. Thus, this new GMAb testing kit is reliable for the diagnosis of aPAP and differential diagnosis of other lung diseases.

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<![CDATA[Efficacy and safety of nintedanib in a Greek multicentre idiopathic pulmonary fibrosis registry: a retrospective, observational, cohort study]]> https://www.researchpad.co/article/N11b8cb90-736b-4915-90f2-e271e7c5d320

Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF). In a retrospective, real-world study across seven Greek hospitals, we evaluated the effectiveness and safety of nintedanib in routine clinical practice. Patients diagnosed with IPF, as per guideline criteria or multidisciplinary diagnosis, received nintedanib between January 2013 and January 2018.

We evaluated 244 patients: mean±sd age 71.8±7.5 years, 79.1% male, 45.1% current smokers and 33.1% ex-smokers at treatment initiation. At baseline, predicted forced vital capacity (FVC) was 73.3±20.7% and predicted diffusing capacity of the lungs for carbon monoxide (DLCO) was 42.6±16.7%. On average, patients spent 23.6±15.0 months on nintedanib. At 3 years, 78 patients had died, equating to a 3-year survival rate of 59.4% (unaffected by treatment discontinuation or dose reduction). FVC% pred and DLCO% pred were largely stable at 3 years, with no significant difference from baseline (FVC 73.3±20.7% pred versus 78±20.1% pred, p=0.074; DLCO 42.6±16.7% pred versus 40.4±18.1% pred, p=0.334). Of the 244 patients, 55.7% reported an adverse event. Gastrointestinal events were the most common (173 (77.2%) out of 224 total events) and 45.0% of patients experienced diarrhoea. Only 32 (13.1%) patients had to permanently discontinue nintedanib due to an adverse event.

This real-world study shows a 3-year survival rate of 59.4% and a low discontinuation rate due to adverse events. Our experience is consistent with previous findings in clinical trials of nintedanib in IPF.

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<![CDATA[Nintedanib and Sildenafil in Patients with Idiopathic Pulmonary Fibrosis and Right Heart Dysfunction. A Prespecified Subgroup Analysis of a Double-Blind Randomized Clinical Trial (INSTAGE)]]> https://www.researchpad.co/article/Nadffc97b-5a58-4429-8e7a-b647fb03c1bb

Rationale: In the INSTAGE trial in patients with idiopathic pulmonary fibrosis (IPF) and severely impaired gas exchange, nintedanib plus sildenafil was associated with numerical benefits on St. George’s Respiratory Questionnaire (SGRQ) total score, brain natriuretic peptide (BNP), and FVC decline versus nintedanib alone. Exploratory analyses of the STEP-IPF (Sildenafil Trial of Exercise Performance in IPF) trial suggested that sildenafil may have a greater effect on SGRQ score in patients with IPF who have right heart dysfunction (RHD).

Objectives: Assess whether RHD influenced the effects of nintedanib plus sildenafil versus nintedanib alone in the INSTAGE trial.

Methods: Subgroup analyses of patients with (n = 117) versus those without (n = 156) echocardiographic signs of RHD at baseline.

Measurements and Main Results: There was no heterogeneity between subgroups by presence of RHD in the effect of nintedanib plus sildenafil versus nintedanib alone on change in SGRQ total score at Week 12 (P = 0.74) or Week 24 (P = 0.90), or change in FVC at Week 12 (P = 0.58) or Week 24 (P = 0.55). In both subgroups, nintedanib plus sildenafil had a numerically greater effect on reducing FVC decline versus nintedanib alone. Between-group differences in change in BNP at Week 24 were −119.9 ng/L (95% confidence interval = −171.3 to −68.5) and −3.6 ng/L (95% confidence interval = −47.2 to 40.0) in patients with and without signs of RHD at baseline, respectively (P < 0.01).

Conclusions: In the INSTAGE trial, there were no significant differences in the effects of nintedanib plus sildenafil versus nintedanib alone on changes in SGRQ and FVC between patients with or without echocardiographic signs of RHD at baseline. The benefit of combination therapy on stabilizing BNP was more pronounced in patients with RHD at baseline.

Clinical trial registered with www.clinicaltrials.gov (NCT02802345).

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<![CDATA[Baseline clinical characteristics, comorbidities and prescribed medication in a real-world population of patients with idiopathic pulmonary fibrosis: the PROOF registry]]> https://www.researchpad.co/article/5c1fdd7bd5eed0c484e9e15d

Introduction

PROOF (a Prospective Observational Registry to Describe the Disease Course and Outcomes of Idiopathic Pulmonary Fibrosis) is an ongoing, observational registry initiated in 2013 with the aim of collecting real-world data from patients with idiopathic pulmonary fibrosis (IPF). Here, we present comprehensive baseline data, which were collected from patients on registry inclusion.

Methods

Patients with IPF were enrolled across eight centres in Belgium and Luxembourg. Baseline data collected included demographics, diagnostic information and clinical characteristics, including lung function and health-related quality of life. Data on comorbidities and prescribed medication were also collected.

Results

A total of 277 patients were enrolled in the PROOF registry. At inclusion, 92.8% and 6.5% of patients had a definite or probable diagnosis of IPF, respectively. Mean per cent predicted forced vital capacity and carbon monoxide diffusing capacity were 80.6% and 46.9%, respectively. Mean St. George’s Respiratory Questionnaire total score was 47.0, and mean Cough-Visual Analogue Scale score was 30.5 mm. The most prevalent comorbidities reported at inclusion were gastrointestinal disorders (50.2%), including gastro-oesophageal reflux disease (47.3%) and metabolism and nutrition disorders (39.7%). At inclusion, 67.2% and 2.2% of patients were prescribed pirfenidone and nintedanib, respectively, with treatment initiated either prior to, or at the time of, inclusion. Medication prescribed concomitantly with pirfenidone included antihypertensives (54.8%), statins (37.1%) and prophylactic antithrombotics/anticoagulants (36.6%).

Conclusion

The PROOF registry provides valuable demographic and clinical data from a real-world population of patients with IPF in Belgium and Luxembourg, demonstrating the high burden of comorbidities and prescribed medication in these patients. Longitudinal data from this patient population will be investigated in future analyses.

Trial registration

PROOF is registered with the relevant authorities in Belgium and Luxembourg, with registration to Comité National d’Éthique et de Recherché (CNER) N201309/03 – 12 September 2013 and a notification to Comité National de Protection des Données (CNDP).

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<![CDATA[Up-Regulation and Profibrotic Role of Osteopontin in Human Idiopathic Pulmonary Fibrosis]]> https://www.researchpad.co/article/5989da08ab0ee8fa60b76ad0

Background

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disorder characterized by fibroproliferation and excessive accumulation of extracellular matrix in the lung.

Methods and Findings

Using oligonucleotide arrays, we identified osteopontin as one of the genes that significantly distinguishes IPF from normal lungs. Osteopontin was localized to alveolar epithelial cells in IPF lungs and was also significantly elevated in bronchoalveolar lavage from IPF patients. To study the fibrosis-relevant effects of osteopontin we stimulated primary human lung fibroblasts and alveolar epithelial cells (A549) with recombinant osteopontin. Osteopontin induced a significant increase of migration and proliferation in both fibroblasts and epithelial cells. Epithelial growth was inhibited by the pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS) and antibody to CD44, while fibroproliferation was inhibited by GRGDS and antibody to αvβ3 integrin. Fibroblast and epithelial cell migration were inhibited by GRGDS, anti-CD44, and anti-αvβ3. In fibroblasts, osteopontin up-regulated tissue inhibitor of metalloprotease-1 and type I collagen, and down-regulated matrix metalloprotease-1 (MMP-1) expression, while in A549 cells it caused up-regulation of MMP-7. In human IPF lungs, osteopontin colocalized with MMP-7 in alveolar epithelial cells, and application of weakest link statistical models to microarray data suggested a significant interaction between osteopontin and MMP-7.

Conclusions

Our results provide a potential mechanism by which osteopontin secreted from the alveolar epithelium may exert a profibrotic effect in IPF lungs and highlight osteopontin as a potential target for therapeutic intervention in this incurable disease.

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<![CDATA[Idiopathic Pulmonary Fibrosis: Aberrant Recapitulation of Developmental Programs?]]> https://www.researchpad.co/article/5989dadcab0ee8fa60bba0c1

The authors discuss evidence suggesting that embryonic signaling pathways involved in epithelium/mesenchymal communication and epithelial cell plasticity may be aberrantly switched on in idiopathic pulmonary fibrosis.

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<![CDATA[Lessons from Our Patients: Development of a Warm Autopsy Program]]> https://www.researchpad.co/article/5989dabaab0ee8fa60bae6f7

Kaminski and colleagues discuss the lessons they have learned in establishing a warm autopsy program to advance research on idiopathic pulmonary fibrosis.

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<![CDATA[A Blood Test for Lung Fibrosis]]> https://www.researchpad.co/article/5989d9eaab0ee8fa60b6c61e

Peter Barnes discusses a new study on the role of two matrix metalloproteinases, MMP1 (collagenase) and MMP7 (matrilysin), as possible biomarkers of idiopathic pulmonary fibrosis.

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<![CDATA[MMP1 and MMP7 as Potential Peripheral Blood Biomarkers in Idiopathic Pulmonary Fibrosis]]> https://www.researchpad.co/article/5989da5aab0ee8fa60b8fc45

Background

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease associated with substantial morbidity and mortality. The objective of this study was to determine whether there is a peripheral blood protein signature in IPF and whether components of this signature may serve as biomarkers for disease presence and progression.

Methods and Findings

We analyzed the concentrations of 49 proteins in the plasma of 74 patients with IPF and in the plasma of 53 control individuals. We identified a combinatorial signature of five proteins—MMP7, MMP1, MMP8, IGFBP1, and TNFRSF1A—that was sufficient to distinguish patients from controls with a sensitivity of 98.6% (95% confidence interval [CI] 92.7%–100%) and specificity of 98.1% (95% CI 89.9%–100%). Increases in MMP1 and MMP7 were also observed in lung tissue and bronchoalveolar lavage fluid obtained from IPF patients. MMP7 and MMP1 plasma concentrations were not increased in patients with chronic obstructive pulmonary disease or sarcoidosis and distinguished IPF compared to subacute/chronic hypersensitivity pneumonitis, a disease that may mimic IPF, with a sensitivity of 96.3% (95% CI 81.0%–100%) and specificity of 87.2% (95% CI 72.6%–95.7%). We verified our results in an independent validation cohort composed of patients with IPF, familial pulmonary fibrosis, subclinical interstitial lung disease (ILD), as well as with control individuals. MMP7 and MMP1 concentrations were significantly higher in IPF patients compared to controls in this cohort. Furthermore, MMP7 concentrations were elevated in patients with subclinical ILD and negatively correlated with percent predicted forced vital capacity (FVC%) and percent predicted carbon monoxide diffusing capacity (DLCO%).

Conclusions

Our experiments provide the first evidence for a peripheral blood protein signature in IPF to our knowledge. The two main components of this signature, MMP7 and MMP1, are overexpressed in the lung microenvironment and distinguish IPF from other chronic lung diseases. Additionally, increased MMP7 concentration may be indicative of asymptomatic ILD and reflect disease progression.

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