Validation of a computed tomography diagnostic model for differentiating fibrotic hypersensitivity pneumonitis from idiopathic pulmonary fibrosis.

BACKGROUND: The diagnosis of fibrotic hypersensitivity pneumonitis (fHP) from other interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF), is often difficult. This study aimed to examine computed tomography (CT) findings that were useful for differentiating between fHP and IPF and to develop and validate a radiological diagnostic model. METHODS: In this study, 246 patients (fHP, n = 104; IPF, n = 142) from two institutions were included and randomly divided into the test (n = 164) and validation (n = 82) groups (at a 2:1 ratio). Three radiologists evaluated CT findings, such as pulmonary fibrosis, small airway disease, and predominant distribution, and compared them between fHP and IPF using binomial logistic regression and multivariate analysis. A prognostic model was developed from the test group and validated with the validation group. RESULTS: Ground-glass opacity (GGO) with traction bronchiectasis (TB), honeycombing, hypoattenuation area, three-density pattern, diffuse craniocaudal distribution, peribronchovascular opacities in the upper lung, and random distribution were more common in fHP than in IPF. In multivariate analysis, GGO with TB, peribronchovascular opacities in the upper lung, and random distribution were significant features. The area under the curve of the fHP diagnostic model with the three aforementioned CT features was 0.733 (95% confidence interval [CI], 0.655-0.811, p < 0.001) in the test group and 0.630 (95% CI, 0.504-0.755, p < 0.047) in the validation group. CONCLUSION: GGO with TB, peribronchovascular opacities in the upper lung, and random distribution were important CT features for differentiating fHP from IPF.

Identification and management of interstitial lung disease associated with systemic sclerosis (SSc-ILD), rheumatoid arthritis (RA-ILD), and polymyositis/dermatomyositis (PM/DM-ILD): development of expert consensus-based clinical algorithms.

BACKGROUND: Clinical guidance on the identification and management of connective tissue disease-associated interstitial lung disease (CTD-ILD) is needed for optimal clinical practice. We aimed to develop clinical algorithms for identifying and managing three common CTD-ILDs: those associated with systemic sclerosis (SSc-ILD), rheumatoid arthritis (RA-ILD), and polymyositis/dermatomyositis (PM/DM-ILD). RESEARCH DESIGN AND METHODS: Meetings were held October-November 2023 to create consensus-based algorithms for identifying and managing SSc-ILD, RA-ILD, and PM/DM-ILD in clinical practice, based on expert consensus statements for identification and management of CTD-ILD previously derived from a Delphi process. RESULTS: We developed clinical algorithms for SSc-ILD, RA-ILD, and PM/DM-ILD that highlight both commonalities and differences in the identification and management of these CTD-ILDs. Importantly, ILD should be suspected in patients with SSc, RA, or PM/DM who have respiratory symptoms. Chest high-resolution computed tomography has utility for screening, diagnosis and assessment of severity. Furthermore, regular follow-up and multidisciplinary management are important. Disease-specific considerations include unique risk factors such as anti-topoisomerase I antibodies in SSc-ILD, high-titer cyclic citrullinated peptide antibodies in RA, anti-aminoacyl tRNA synthetase antibodies in PM/DM, and anti-melanoma differentiation-associated gene 5 antibody in DM. CONCLUSIONS: These algorithms may help physicians to identify and manage patients with SSc-ILD, RA-ILD, or PM/DM-ILD.

Pulmonary Hypertension With Interstitial Pneumonia: Initial Treatment Effectiveness and Severity in a Japan Registry.

Background: Recent guidelines discourage the use of pulmonary arterial hypertension (PAH)-targeted therapies in patients with pulmonary hypertension (PH) associated with respiratory diseases. Therefore, stratifications of the effectiveness of PAH-targeted therapies are important for this group. Objectives: The authors aimed to identify phenotypes that might benefit from initial PAH-targeted therapies in patients with PH associated with interstitial pneumonia and combined pulmonary fibrosis and emphysema. Methods: We categorized 270 patients with precapillary PH (192 interstitial pneumonia, 78 combined pulmonary fibrosis and emphysema) into severe and mild PH using a pulmonary vascular resistance of 5 WU. We investigated the prognostic factors and compared the prognoses of initial (within 2 months after diagnosis) and noninitial treatment groups, as well as responders (improvements in World Health Organization functional class, pulmonary vascular resistance, and 6-minute walk distance) and nonresponders. Results: Among 239 treatment-naive patients, 46.0% had severe PH, 51.8% had mild ventilatory impairment (VI), and 40.6% received initial treatment. In the severe PH with mild VI subgroup, the initial treatment group had a favorable prognosis compared with the noninitial treatment group. The response rate in this group was significantly higher than the others (48.2% vs 21.8%, ratio 2.21 [95% CI: 1.17-4.16]). In multivariate analysis, initial treatment was a better prognostic factor for severe PH but not for mild PH. Within the severe PH subgroup, responders had a favorable prognosis. Conclusions: This study demonstrated an increased number of responders to initial PAH-targeted therapy, with a favorable prognosis in severe PH cases with mild VI. A survival benefit was not observed in mild PH cases. (Multi-institutional Prospective Registry in Pulmonary Hypertension associated with Respiratory Disease; UMIN000011541).

Squamous metaplasia is an indicator of acute exacerbation in patients with usual interstitial pneumonia / idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation (AE) is a potentially lethal event in patients with usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF). However, to date, no pathological predictors of AE have been identified. This retrospective study aimed to elucidate the pathological features that could predict AE in patients with UIP. METHODS: We reviewed the pathological findings of 91 patients with UIP/IPF and correlated these findings with AE events. Thirteen histological variables related to acute lung injury were evaluated by three independent observers and classified as positive or negative. The patients' clinical data during follow-up were collected and reviewed for AE. A recursive partition using the Gini index for the prediction of AE was performed, with each pathological finding as a candidate for branching. RESULTS: Twenty patients (22%) developed AE during the median follow-up duration of 40 months. Thirty-eight patients died (15 due to AE and 23 for other reasons). The median time interval from surgical lung biopsy to AE onset was 497 (interquartile range: 901-1657) days. Histologically, squamous metaplasia was positively associated with AE (odds ratio: 4.7, P = 0.015) and worse event-free survival in patients with UIP (P = 0.04). Leaf scoring based on the Gini index for recursive partition, including five positive findings (squamous metaplasia, neutrophilic infiltration, septal widening, Kuhn's hyaline, and fibrin), showed a sensitivity of 90% with a specificity of 74.7% (area under curve: 0.89). CONCLUSIONS: We found that squamous metaplasia is an important histopathological finding that predicts AE events and tends to unfavorable outcome in patients with UIP/IPF.

Progressive pulmonary fibrosis (PPF): Estimation of incidence and treatment rates in Japan using a claims database.

BACKGROUND: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders, a subset of which develop progressive pulmonary fibrosis (PPF). There is little information on the epidemiology and treatment of PPFs in Japan. This retrospective cohort study estimated the incidence probability of progression to PPFs in patients with fibrosing ILDs other than idiopathic pulmonary fibrosis in a real-world Japanese setting. Management procedures and treatment patterns were also quantified. METHODS: Data were extracted from the Medical Data Vision database from 01-Jan-2012 to 28-May-2020, comprising a 6.91-year patient identification period, 1-year pre-index period, and post-index period. The primary outcome was the cumulative incidence probability of progression to PPF up to 24 months. Subgroup analyses were performed by the presence/absence of connective tissue disease-ILD and by pre-specified ILD clinical diagnosis. RESULTS: Of the 34,960 eligible patients (mean age: 71.1 years, males: 52.5%), 14,580 (41.7%) progressed to PPF. The 24-month incidence probability of progression to PPF was 39.5%. A relatively comparable percentage of patients progressed across all ILD subtypes. Oral corticosteroids and tacrolimus were the most common therapies during the pre- and post-index periods. Treatment rates were very low in the post-index period. CONCLUSIONS: This is the first claims database study to estimate the incidence probability of progression to PPF in Japan. Progression appeared common in patients with chronic fibrosing ILDs, with comparable percentages of patients across all subtypes developing PPF at 2 years. Future studies should assess the impact of regular monitoring and early intervention on treating fibrotic ILDs and preventing progression.

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a single cohort study.

BACKGROUND: Extracellular mitochondrial DNA (mtDNA) is released from damaged cells and increases in the serum and bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. While increased levels of serum mtDNA have been reported to be linked to disease progression and the future development of acute exacerbation (AE) of IPF (AE-IPF), the clinical significance of mtDNA in BALF (BALF-mtDNA) remains unclear. We investigated the relationships between BALF-mtDNA levels and other clinical variables and prognosis in IPF. METHODS: Extracellular mtDNA levels in BALF samples collected from IPF patients were determined using droplet-digital PCR. Levels of extracellular nucleolar DNA in BALF (BALF-nucDNA) were also determined as a marker for simple cell collapse. Patient characteristics and survival information were retrospectively reviewed. RESULTS: mtDNA levels in serum and BALF did not correlate with each other. In 27 patients with paired BALF samples obtained in a stable state and at the time of AE diagnosis, BALF-mtDNA levels were significantly increased at the time of AE. Elevated BALF-mtDNA levels were associated with inflammation or disordered pulmonary function in a stable state (n = 90), while being associated with age and BALF-neutrophils at the time of AE (n = 38). BALF-mtDNA ≥ 4234.3 copies/µL in a stable state (median survival time (MST): 42.4 vs. 79.6 months, p < 0.001) and ≥ 11,194.3 copies/µL at the time of AE (MST: 2.6 vs. 20.0 months, p = 0.03) were associated with shorter survival after BALF collection, even after adjusting for other known prognostic factors. On the other hand, BALF-nucDNA showed different trends in correlation with other clinical variables and did not show any significant association with survival time. CONCLUSIONS: Elevated BALF-mtDNA was associated with a poor prognosis in both IPF and AE-IPF. Of note, at the time of AE, it sharply distinguished survivors from non-survivors. Given the trends shown by analyses for BALF-nucDNA, the elevation of BALF-mtDNA might not simply reflect the impact of cell collapse. Further studies are required to explore the underlying mechanisms and clinical applications of BALF-mtDNA in IPF.

Presence of focal usual interstitial pneumonia is a key prognostic factor in progressive pulmonary fibrosis.

AIMS: Progressive pulmonary fibrosis (PPF) is a newly recognised clinical phenotype of interstitial lung diseases in the 2022 interstitial pulmonary fibrosis (IPF) guidelines. This category is based entirely on clinical and radiological factors, and the background histopathology is unknown. Our objective was to investigate the histopathological characteristics of PPF and to examine the correlation between usual interstitial pneumonia (UIP) and prognosis in this new disease type. We hypothesised that the presence of UIP-like fibrosis predicts patients' survival in PPF cases. METHODS AND RESULTS: We selected 201 cases fulfilling the clinical criteria of PPF from case archives. Cases diagnosed as IPF by a multidisciplinary team were excluded. Whole slide images were evaluated by three pathologists who were blinded to clinical and radiological data. We measured areas of UIP-like fibrosis and calculated what percentage of the total lesion area they occupied. The presence of focal UIP-like fibrosis amounting to 10% or more of the lesion area was seen in 148 (73.6%), 168 (83.6%) and 165 (82.1%) cases for each pathologist, respectively. Agreement of the recognition of UIP-like fibrosis in PPF cases was above κ = 0.6 between all pairs. Survival analysis showed that the presence of focal UIP-like fibrosis correlated with worsened survival under all parameters tested (P < 0.001). CONCLUSIONS: The presence of UIP-like fibrosis is a core pathological feature of clinical PPF, and its presence within diseased areas is associated with poorer prognosis. This study highlights the importance of considering the presence of focal UIP-like fibrosis in the evaluation and management of PPF.

Pulmonary function and chest CT abnormalities 3 months after discharge from COVID-19, 2020-2021: A nation-wide multicenter prospective cohort study from the Japanese respiratory society.

BACKGROUND: No comprehensive analysis of the pulmonary sequelae of coronavirus disease 2019 (COVID-19) in Japan based on respiratory function tests and chest computed tomography (CT) has been reported. We evaluated post-COVID-19 conditions, especially focusing on pulmonary sequelae assessed by pulmonary function tests and chest CT. METHODS: For this prospective cohort study, we enrolled 1069 patients who presented pneumonia at the time of admission in 55 hospitals from February 2020 to September 2021. Disease severity was classified as moderateⅠ, moderate II, and severe, defined primarily according to the degree of respiratory failure. The data on post-COVID-19 conditions over 12 months, pulmonary function, and chest CT findings at 3 months were evaluated in this study. Additionally, the impact of COVID-19 severity on pulmonary sequelae, such as impaired diffusion capacity, restrictive pattern, and CT abnormalities, was also evaluated. RESULTS: The most frequently reported post-COVID-19 conditions at 3 months after COVID-19 were muscle weakness, dyspnea, and fatigue (48.4%, 29.0%, and 24.7%, respectively). The frequency of symptoms gradually decreased over subsequent months. In pulmonary function tests at 3 months, the incidence of impaired diffusion capacity and restrictive pattern increased depending on disease severity. There also were differences in the presence of chest CT abnormalities at the 3 months, which was markedly correlated with the severity. CONCLUSION: We reported a comprehensive analysis of post-COVID-19 condition, pulmonary function, and chest CT abnormalities in Japanese patients with COVID-19. The findings of this study will serve as valuable reference data for future post-COVID-19 condition research in Japan.

Japanese guidelines for the treatment of idiopathic pulmonary fibrosis 2023:Revised edition.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with a poor prognosis and an unknown cause that generally progresses to pulmonary fibrosis and leads to irreversible tissue alteration. The "Guidelines for the treatment of idiopathic pulmonary fibrosis 2017," specializing in the treatment of IPF for the first time in Japan and presenting evidence-based standard treatment methods suited to the state of affairs in Japan, was published in 2017, in line with the 2014 version of "Formulation procedure for Minds Clinical Practice Guidelines." Because new evidence had accumulated, we formulated the "Guidelines for the treatment of Idiopathic Pulmonary Fibrosis 2023 (revised 2nd edition)." While keeping the revision consistent with the ATS/ERS/JRS/ALAT IPF treatment guidelines, new clinical questions (CQs) on pulmonary hypertension were added to the chronic stage, in addition to acute exacerbation and comorbid lung cancer, which greatly affect the prognosis but are not described in the ATS/ERS/JRS/ALAT IPF guidelines. Regarding the advanced stages, we additionally created expert consensus-based advice for palliative care and lung transplantation. The number of CQs increased from 17 in the first edition to 24. It is important that these guidelines be used not only by respiratory specialists but also by general practitioners, patients, and their families; therefore, we plan to revise them appropriately in line with ever-advancing medical progress.

Role of microbiota-derived corisin in coagulation activation during SARS-CoV-2 infection.

BACKGROUND: Coagulopathy is a major cause of morbidity and mortality in COVID-19 patients. Hypercoagulability in COVID-19 results in deep vein thrombosis, thromboembolic complications, and diffuse intravascular coagulation. Microbiome dysbiosis influences the clinical course of COVID-19. However, the role of dysbiosis in COVID-19-associated coagulopathy is not fully understood. OBJECTIVES: The present study tested the hypothesis that the microbiota-derived proapoptotic corisin is involved in the coagulation system activation during SARS-CoV-2 infection. METHODS: This cross-sectional study included 47 consecutive patients who consulted for symptoms of COVID-19. A mouse acute lung injury model was used to recapitulate the clinical findings. A549 alveolar epithelial, THP-1, and human umbilical vein endothelial cells were used to evaluate procoagulant and anticoagulant activity of corisin. RESULTS: COVID-19 patients showed significantly high circulating levels of corisin, thrombin-antithrombin complex, D-dimer, tumor necrosis factor-α, and monocyte-chemoattractant protein-1 with reduced levels of free protein S compared with healthy subjects. The levels of thrombin-antithrombin complex, D-dimer, and corisin were significantly correlated. A monoclonal anticorisin-neutralizing antibody significantly inhibited the inflammatory response and coagulation system activation in a SARS-CoV-2 spike protein-associated acute lung injury mouse model, and the levels of corisin and thrombin-antithrombin complex were significantly correlated. In an in vitro experiment, corisin increased the tissue factor activity and decreased the anticoagulant activity of thrombomodulin in epithelial, endothelial, and monocytic cells. CONCLUSION: The microbiota-derived corisin is significantly increased and correlated with activation of the coagulation system during SARS-CoV-2 infection, and corisin may directly increase the procoagulant activity in epithelial, endothelial, and monocytic cells.

Mild elevation of pulmonary vascular resistance predicts mortality regardless of mean pulmonary artery pressure in mild interstitial lung disease.

BACKGROUND: Pulmonary hypertension (PH) is defined by elevated mean pulmonary arterial pressure (MPAP), and elevated pulmonary vascular resistance (PVR) reflects pulmonary vascular abnormalities. The clinical significance of non-severe PH in patients with various interstitial lung diseases (ILDs) has not been fully elucidated. We aimed to investigate the clinical significance of MPAP and PVR for mortality in patients with newly diagnosed ILD. METHODS: We retrospectively analysed consecutive patients with ILD at initial evaluations that included right heart catheterisation from 2007 to 2018. These patients were classified by MPAP and PVR using the 2022 the European Society of Cardiology (ESC)/the European Respiratory Society (ERS) guidelines for PH. The clinical significance of MPAP and PVR for mortality was analysed. RESULTS: Among 854 patients, 167 (19.6%) had MPAP>20 mm Hg. The proportion of patients with PVR>2 Wood units (WU) among those with MPAP≤20 mm Hg, 202 WU was associated with a higher mortality rate (HR 1.61, 95% CI 1.28 to 2.02, p<0.0001) even in a group with MPAP≤20 mm Hg. CONCLUSIONS: Mild elevation of PVR was associated with a higher mortality rate in patients with newly diagnosed ILD, even in those with MPAP≤20 mm Hg.

Prognostic Role of Interferon-λ3 in Anti-Melanoma Differentiation-Associated Gene 5-Positive Dermatomyositis-Associated Interstitial Lung Disease.

OBJECTIVE: Interferon-λ3 (IFNλ3) is a cytokine with antiviral functions on barrier surfaces, and it is associated with disease activity in autoimmune diseases. This study assessed the clinical significance of serum IFNλ3 levels in polymyositis/dermatomyositis (PM/DM)-associated interstitial lung disease (ILD). METHODS: We measured serum IFNλ3 levels in 221 patients with PM/DM-ILD (155 in the derivation cohort, 66 in the validation cohort) and 38 controls. We evaluated factors associated with mortality risk among 79 patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM-ILD. RESULTS: Serum IFNλ3 levels at diagnosis were significantly higher in patients with PM/DM-ILD than in healthy controls. Remarkably, serum IFNλ3 levels were specifically increased in patients with anti-MDA5 antibody-positive DM-ILD in both the derivation and validation cohorts. In anti-MDA5 antibody-positive DM-ILD, patients with high IFNλ3 levels (>120 pg/mL) had significantly lower survival rates than those with low IFNλ3 levels (≤120 pg/mL). A multivariate analysis revealed that high IFNλ3 levels, as well as old age and low Pao2, were significantly associated with poor prognoses in patients with anti-MDA5 antibody-positive DM-ILD. In a classification analysis of patients with anti-MDA5 antibody-positive DM-ILD based on age, IFNλ3 level, and Pao2, patients with old age (>53 years), high IFNλ3 levels (>120 pg/mL), and low Pao2 (<75 mm Hg) had the worst survival. In lung pathologic analyses, IFNλ3-positive staining was observed in macrophages, airway epithelial cells, the pleural region, and intrapulmonary veins in patients with anti-MDA5 antibody-positive DM-ILD. CONCLUSION: Serum IFNλ3 is a promising biomarker for identifying patients at high risk of poor outcomes in anti-MDA5 antibody-positive DM-ILD.

Physical activity in idiopathic pulmonary fibrosis: Longitudinal change and minimal clinically important difference.

BACKGROUND AND OBJECTIVE: Reference values of physical activity to interpret longitudinal changes are not available in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to define the minimal clinical important difference (MCID) of longitudinal changes in physical activity in patients with IPF. METHODS: Using accelerometry, physical activity (steps per day) was measured and compared at baseline and 6-months follow-up in patients with IPF. We calculated MCID of daily step count using multiple anchor-based and distribution-based methods. Forced vital capacity and 6-minute walk distance were applied as anchors in anchor-based methods. Effect size and standard error of measurement were used to calculate MCID in distribution-based methods. RESULTS: One-hundred and five patients were enrolled in the study (mean age: 68.5 ± 7.5 years). Step count significantly decreased from baseline to 6-months follow-up (-461 ± 2402, p = .031). MCID calculated by anchor-based and distribution-based methods ranged from 570-1358 steps. CONCLUSION: Daily step count significantly declined over 6-months in patients with IPF. MCID calculated by multiple anchor-based and distribution-based methods was 570 to 1358 steps/day. These findings contribute to interpretation of the longitudinal changes of physical activity that will assist its use as a clinical and research outcome in patients with IPF.

A prospective cohort study of periostin as a serum biomarker in patients with idiopathic pulmonary fibrosis treated with nintedanib.

This study investigated the utility of periostin, a matricellular protein, as a prognostic biomarker in patients with idiopathic pulmonary fibrosis (IPF) who received nintedanib. Monomeric and total periostin levels were measured by enzyme-linked immunosorbent assay in 87 eligible patients who participated in a multicenter prospective study. Forty-three antifibrotic drug-naive patients with IPF described in previous studies were set as historical controls. Monomeric and total periostin levels were not significantly associated with the change in forced vital capacity (FVC) or diffusing capacity of the lungs for carbon monoxide (DLCO) during any follow-up period. Higher monomeric and total periostin levels were independent risk factors for overall survival in the Cox proportional hazard model. In the analysis of nintedanib effectiveness, higher binarized monomeric periostin levels were associated with more favorable suppressive effects on decreased vital capacity (VC) and DLCO in the treatment group compared with historical controls. Higher binarized levels of total periostin were associated with more favorable suppressive effects on decreased DLCO but not VC. In conclusion, higher periostin levels were independently associated with survival and better therapeutic effectiveness in patients with IPF treated with nintedanib. Periostin assessments may contribute to determining therapeutic strategies for patients with IPF.