BACKGROUND:Acute exacerbation (AE) is a critical prognostic event in interstitial lung diseases (ILDs), initially recognized in idiopathic pulmonary fibrosis (IPF). Current AE diagnostic criteria do not account for oxygenation deterioration, and evidence of new computed tomography (CT) findings alone is insufficient to diagnose AE-ILD. We investigated a CT-based criterion for distinguishing AE from acute deterioration (AD)-ILD and assessed the prognostic significance of oxygenation deterioration in AE-ILD. METHODS:Patients with AD-ILD, defined by worsening shortness of breath and new lung abnormalities within 1 month, were prospectively enrolled. AD-ILD included both AE-ILD and other acute conditions, non-AE-AD-ILD. Oxygenation deterioration was assessed using modified Blancal criteria. CT-based AE criteria were developed through receiver operating characteristic (ROC) curve and multivariate logistic regression analyses based on CT findings suggestive of AE. RESULTS:Overall, 394 patients were analyzed, including 303 diagnosed with AE and 91 with non-AE-AD-ILD. The underlying ILDs included IPF (n = 177) and non-IPF ILDs (n = 217). The presence of at least two of three CT-based parameters, including bilateral shadows, ground-glass opacity predominance, and diffuse pattern, was identified as predictive of AE diagnosis in AD-ILDs using logistic and ROC analyses. Ninety-day survival was significantly lower in patients with AE-ILD with oxygenation deterioration than in those without deterioration and in patients with non-AE-AD-ILDs. Oxygenation deterioration independently predicted poor survival in multivariate Cox proportional hazard regression analysis. CONCLUSIONS:The developed CT-based AE criteria effectively predicted AE and oxygenation deterioration in AD-ILD. Additionally, oxygenation deterioration predicted worse survival in AE-ILD. This study was registered with the University Hospital Medical Information Network (UMIN000027844; registered 1 July 2017).

Background:Idiopathic pulmonary fibrosis (IPF) and non-IPF interstitial lung diseases (ILDs) with progressive pulmonary fibrosis (PPF) are associated with poor prognosis. Nintedanib slows the decline in forced vital capacity (FVC) and improves survival; however, diarrhea is the most common adverse event and often leads to treatment discontinuation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has protective effects on intestinal epithelial integrity, whereas anti-GM-CSF autoantibodies (GMAb) have been associated with disease activity in inflammatory bowel diseases (IBDs). This study aimed to evaluate the utility of serum GMAb levels as a predictor of nintedanib-induced diarrhea. Methods:Forty-one patients with ILDs treated with nintedanib were included. Diarrhea within 3 months of treatment initiation was retrospectively assessed using structured interviews. Predictive factors were analyzed using univariate and multivariate logistic regression models, including relevant clinical variables. Results:The cohort included 30 male patients with underlying diagnoses of IPF (n=26) and non-IPF ILDs meeting PPF criteria (n=15). Diarrhea within 3 months occurred in 26 patients. Male sex was significantly associated with diarrhea (P=0.036), whereas IPF showed a trend toward association (P=0.096). Serum GMAb levels >0.77 µg/mL were independently associated with diarrhea after adjustment for ILD type, sex, and nintedanib dose normalized by body surface area (BSA, multivariate logistic regression). Conclusions:Elevated serum GMAb levels might serve as a predictor of nintedanib-induced diarrhea. GM-CSF/GMAb-related pathways might be associated with the pathogenesis of nintedanib-induced diarrhea. However, validation with a large-scale study is needed to show the clinical and pathophysiological role of GMAb in the future.

RATIONALE:Common and rare variants that are associated with the risk of developing idiopathic pulmonary fibrosis (IPF) have been identified predominantly in European ancestry populations. OBJECTIVES:To better understand the genetic variants that contribute to IPF in individuals with Asian ancestry, we conducted a genome-wide association study of IPF in East Asian populations. METHODS:We included 1026 patients with IPF and compared them to 1723 unaffected controls of Japanese and Korean ancestry. Genome-wide association analysis was conducted in the Japanese and Korean ancestry cohorts separately and combined using meta-analysis. Restricted maximum likelihood was used to estimate the SNP-based heritability and local ancestry of chromosome 11 was inferred for each subject. MEASUREMENTS AND MAIN RESULTS:We identified loci on chromosomes 4 (FAM13A; rs7690839), 5 (TERT; rs7734992), 6 (DSP; rs2076295), and 11 (MUC5B; rs35705950) that were significantly associated with risk of IPF. Importantly, the sentinel variants in each of these loci are the same as, or in strong linkage disequilibrium with, the risk variants that have been observed in studies of European ancestry populations. In aggregate, common variants (not including the MUC5B promoter variant) account for approximately 25% of the risk of developing IPF in these East Asian ancestry cohorts. Moreover, local ancestry analysis indicates that the presence of MUC5B promoter variant in the East Asian population is not a result of admixture with European ancestry populations. CONCLUSIONS:We conclude that the IPF risk loci in East Asian populations are shared with those of European ancestry populations, although their risk allele frequencies and effect sizes differ. These findings indicate shared genetic risk factors of IPF across ancestries.

Lymphangioleiomyomatosis (LAM) is a cystic lung disease characterized by rounded, thin-walled cysts uniformly distributed within normal lung parenchyma on high-resolution chest computed tomography. We report a case of diffuse cystic lung disease with multiple alveolar opacities. Transbronchial lung biopsy showed organizing pneumonia, but LAM cells were not observed. She was diagnosed with cryptogenic organizing pneumonia (COP) and treated with corticosteroid therapy. LAM was definitively diagnosed by transbronchial lung cryobiopsy about two years after completing corticosteroid therapy for COP. We reported the first case of LAM with concomitant COP.

BACKGROUND:Interstitial lung disease (ILD) is a heterogeneous group of more than 200 diseases that cause fibrosis or inflammation of the pulmonary parenchyma. ILD is a leading cause of death, yet data on its precise incidence and prevalence are limited due to the complexity of diagnostic criteria. To address this gap, we developed and validated claims-based algorithms to identify selected ILD (restricted to idiopathic interstitial pneumonias and drug-induced ILD) in Japan. METHODS:We identified potential ILD cases from 2010 to 2020 from electronic medical record databases at two large healthcare institutions using a primary claims-based algorithm for high positive predictive value (PPV) and a relaxed algorithm for improved sensitivity. We calculated sensitivity and assessed the validity of the algorithms by comparing them to two gold standard definitions: (1) physician's diagnosis on the medical record, and (2) adjudication by a team of ILD experts based on abstracted medical record data including chest computed tomography images. RESULTS:Among 7638 potential ILD cases, we sampled 460 patients. The estimated PPV was 87.0% (95% CI 83.2-90.8%) for the primary algorithm and 71.4% (64.0-78.7%) for the relaxed algorithm, based on confirmed ILD responses in the expert adjudication as the gold standard. Estimated sensitivity was 30.4% (27.4-33.8%) and 59.4% (54.1-65.1%) for the primary and relaxed algorithms respectively. CONCLUSIONS:The algorithms developed in this study may be useful for identifying selected ILD from administrative data in post-marketing database studies and other clinical and epidemiologic research. The appropriate algorithm may be selected based on the specific research objective.

BACKGROUND:Asbestos bodies (ABs) in bronchoalveolar lavage fluid (BALF) are valuable markers for assessing past asbestos exposure. However, the clinical significance of detecting ABs at ≥1 AB/mL in patients with diffuse lung disease remains unclear. Herein, we investigated the clinical utility of detecting ABs at this threshold, focusing on its association with asbestos exposure history, bronchoalveolar lavage (BAL) cellular analysis, imaging findings, and the rate of respiratory function decline in patients with diffuse lung disease. METHODS:This retrospective single-center study included patients who underwent BAL and asbestos body (AB) quantification for respiratory disease evaluation. The relationship between the AB number (cutoff: 1 AB/mL) and clinical parameters was analyzed. Pulmonary function decline was assessed in patients with ≥1 year of follow-up. RESULTS:This study involved 304 patients. An AB number of ≥1 AB/mL was significantly associated with asbestos exposure history (p < 0.001) and the presence of pleural plaques on computerized tomography (CT) imaging (p < 0.001). However, no significant differences were found in BAL cellular patterns or respiratory function decline between patients with an AB number of ≥1 AB/mL and those with <1 AB/mL. CONCLUSION:The presence of ≥1 AB/mL in the BALF reflects substantial asbestos exposure and is associated with pleural plaques on CT imaging but not with BAL cellular patterns or the rate of decline in respiratory function. These findings suggest that AB detection in BALF has limited predictive value for respiratory function decline but could be valuable for identifying unrecognized asbestos exposure in patients with diffuse lung disease.

Abstract Background Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare interstitial lung disease characterized by restricted ventilation and upper-lobe fibroelastosis. Historically, ankylosing spondylitis has been implicated in upper-lobe fibrosis and ventilatory impairment due to chest wall restriction, and impaired thoracic motion has recently been appreciated in IPPFE. We hypothesized that thoracic joint abnormalities (costovertebral, manubriosternal, and sternocostal joints) contribute to the impaired thoracic motion in patients with IPPFE. Methods Seventeen patients with IPPFE and 15 non-PPFE interstitial lung disease were retrospectively investigated. Thoracic joint abnormalities were assessed as abnormal calcifications on inspiratory CT images. Thoracic motion was evaluated by the average moving distance of four anterior thoracic landmarks between inspiratory and expiratory CT images. Thoracic motion ratio (TMR) was defined as the ratio of the measured average moving distance to the cube root of the predicted vital capacity. The ratio of the lung volume change (LVCR) was calculated from inspiratory and expiratory CT images. Associations between TMR, LVCR, and pulmonary function test parameters (PFT) parameters were assessed. Results Thoracic joint abnormalities were observed in 14 of 17 IPPFE patients, mainly at sternocostal joints. Impaired thoracic motion, defined by the thoracic motion ratio less than half of the normal value, was observed in 9 of 17 IPPFE patients, but in only 1 of 15 non-PPFE patients. All 9 IPPFE patients with impaired thoracic motion exhibited joint abnormalities. The correlation between TMR and LVCR was stronger in the IPPFE group than in the non-PPFE group. Conclusion Thoracic joint abnormalities associated with impaired motion are frequently observed in IPPFE patients. These abnormalities may restrict thoracic movement and lead to the development of IPPFE.

BACKGROUND:Delirium is common among patients with advanced illness. The prevention of delirium and management of its symptoms are important to the palliative care of patients with interstitial lung diseases (ILDs). We investigated the incidence of delirium among patients with terminally ill ILDs and risk factors for its development. METHODS:This retrospective observational study included patients with ILDs who were admitted to the National Hospital Organization (NHO) Kinki Chuo Chest Medical Center between April 2020 and September 2022 and died during hospitalization. The primary and secondary outcomes were the percentage of patients with delirium and risk factors associated with delirium. RESULTS:A total of 85 patients were included in this study. Delirium was present in 38 of these 85 patients (44.7%). Patients with dementia had a significantly higher risk of delirium compared to those without dementia [risk ratio, 2.38; 95% confidence interval (CI): 1.84-3.08], and patients who were physically restrained also had a higher risk of delirium compared to those without restraint (risk ratio, 2.32; 95% CI: 1.53-3.52). CONCLUSIONS:Delirium is prevalent in terminally ill patients with ILDs. Dementia and physical restraint may be risk factors for delirium. Physicians should recognize the risk factors for delirium and prepare for its development in terminally ill patients with ILDs.

Low agreements among experts for differentiating usual interstitial pneumonia (UIP) from nonspecific interstitial pneumonia (NSIP) motivate the use of automated imaging diagnosis. Volume histogram analysis (VHA) of the lung parenchyma using computer-aided diagnostic software is more straightforward to perform and interpret than radiomics. To assess whether a predictive model generated by VHA (VHA model), using voxel data of each lung lobe obtained via whole-lung CT, can differentiate radiological UIP from NSIP, and to explore the relationship between VHA model outcomes and patient prognosis. This study included 74 patients from one university hospital (cohort A: 47 patients with idiopathic pulmonary fibrosis [IPF]/UIP and 27 with idiopathic NSIP [iNSIP] and connective tissue disease-associated NSIP [CTD-NSIP]) and 146 patients from another hospital (cohort B: 111 with IPF/UIP and 35 with iNSIP/CTD-NSIP), with diagnoses confirmed through multidisciplinary discussion. Using the VHA values obtained from each lung lobe in cohort A, a formula-based VHA model was developed. The regularization parameters were optimized using five-fold cross-validation to maximize the area under the receiver operating characteristic curve (AUC). This VHA model was externally validated in cohort B. The correlation between various parameters and prognosis was analyzed using Cox proportional hazards multivariate analysis. The mean AUC of the best VHA model that differentiated UIP patterns in cohort A was 0.91 (95

Rationale: Interstitial lung disease (ILD) is a heterogeneous group of more than 200 diseases that causes inflammation or fibrosis of the pulmonary parenchyma. ILD is a leading cause of death in Japan; however, data on its precise incidence and prevalence are limited due to the complexity of diagnostic criteria. Large databases have become recently available in Japan, and the validity and applicability of claims-based algorithms for ILD are unknown. Thus, we developed and validated claims-based algorithms to identify ILD. Methods: We identified potential ILD cases in electronic medical record (EMR) databases at two large institutions between 2010 and 2020. ILD cases were identified using a primary claims-based algorithm. These algorithms are aimed at identifying Idiopathic Interstitial Pneumonias (IIPs) and drug-induced ILD excluding ILD of other causes. We assessed the validity of these algorithms by comparing them to two gold standard definitions: (1) physician's diagnosis on the medical record and (2) adjudication by a team of ILD experts. We calculated the PPV and estimated-sensitivity with 95% confidence interval in the overall study sample and separately for each institution. Results: Among 7,638 potential ILD cases, we sampled 460 patients. The expert team reviewed abstracted medical record data and chest computed tomography images for all sampled cases. Serum biomarkers, KL-6 (Krebs von den Lungen-6) and surfactant protein D (SP-D) were measured in 99.7% and 82.0% of cases identified by the primary algorithm. Both the primary and revised algorithms included biomarker measurements as part of their definition, given their significant role in diagnosing ILD in Japan. The primary algorithm had a PPV of 91%(95% CI (confidence interval): 88-94%) while the revised algorithm's PPV was 79% (95% CI: 72-86%) based on the ‘confirmed’ and ‘unsure’ ILD responses in the expert adjudication as the gold standard. The estimated-sensitivity was 29% (26-32%) and 60% (55-65%) for the primary and revised algorithms, respectively. Conclusions: In this multi-institutional validation study of 460 claims-based ILD cases with a detailed review by ILD experts, the primary algorithm demonstrated a PPV exceeding 90% but with low estimated-sensitivity. The revised algorithm had an improved estimated sensitivity but at the cost of reduced PPV. Therefore, the utility and choice of different algorithms should be guided by the specific research objective of each clinical study.

BACKGROUND:Prognostic factors in patients with newly diagnosed idiopathic interstitial pneumonia (IIP) have rarely been analyzed using prospective data. This study investigated prognostic factors in patients with IIP. METHODS:Central interstitial lung disease (ILD) experts established the diagnoses for fibrotic ILD. Prognostic factors using baseline data, including the pathological confidence level of usual interstitial pneumonia (UIP) assessed on a 0%-100% linear analog scale by high-resolution CT (HRCT), pulmonary function tests, and patient-reported outcomes were investigated. RESULTS:Overall, 866 eligible patients were registered. Patients with unclassifiable idiopathic interstitial pneumonia (n = 272) survived longer than those with idiopathic pulmonary fibrosis (IPF) (n = 469) (hazard ratio [HR] = 0.67; [95% confidence interval [CI]: 0.47-0.95]; P = 0.022); however, IPF as IIPs classification was not a significant prognostic factor at diagnosis (P = 0.577). UIP pattern on HRCT, age, body mass index, forced vital capacity, diffusing capacity of the lungs for carbon monoxide, and St. George's Respiratory Questionnaire were risk factors for survival (P < 0.05). Patients with proposed progressive pulmonary fibrosis (PPF) had poorer prognoses than those without proposed PPF (HR = 5.63; [95% CI: 3.17-10.00]; P < 0.001). Patients with progressive fibrosing ILD (PF-ILD) had poorer prognoses than those without PF-ILD (HR = 7.85; [95% CI: 3.38-18.3]; P < 0.001). CONCLUSIONS:A prospective registry of patients with newly diagnosed IIP provided evidence that the UIP pattern on HRCT by analog scale was a prognostic predictor. Proposed PPF and PF-ILD were valuable for discriminating prognosis. (JIPS Registry, ClinTrials.gov, NCT03041623).

Background: The prognosis of patients with coronavirus disease 2019 (COVID-19) was poor although its survival rate has been improved after the occurrence of the Omicron strain. Autoimmune pulmonary alveolar proteinosis (APAP), a lung disease caused by macrophage dysfunction induced by anti-granulocyte-macrophage colony-stimulating factor (GM-CSF)-neutralizing autoantibodies, is characterized by the deposition of proteinaceous material in the alveolar spaces. The clinical course of COVID-19 in patients with APAP remains unclear and this study aimed to clarify it. Methods: The data of 23 patients with APAP, who were diagnosed with COVID-19 between January 2020 and May 2023 and collected through a nationwide questionnaire surveillance system, were retrospectively reviewed. Results: Based on the epidemiological frequency at disease onset, suspected strains of severe acute respiratory syndrome coronavirus 2 were Omicron (n = 18) and non-Omicron (n = 5). Fifteen patients were vaccinated. Six and three patients received anti-viral drugs and corticosteroids, respectively. One patient in the third trimester of pregnancy died despite treatment in the intensive care unit. Six patients were complicated by pneumonia and/or required supplemental oxygen. These patients were suspected to have non-Omicron strains (p = 0.087). Vaccination status showed a significant association with suspected Omicron strains. The radiological findings in four patients and shortness of breath improved in two of the four patients after COVID-19. Conclusions: The severity and prognosis of the patients were not worse than those predicted based on the results of a previous study. The transition from a non-Omicron strain to an Omicron strain and the vaccination status may have affected these results.

Background:Idiopathic pulmonary fibrosis (IPF) is an idiopathic fibrotic interstitial lung disease with poor prognosis. Recently, the prognostic value of serum platelet-derived growth factor (PDGF) levels in patients with IPF has been clarified. Monocyte counts in the peripheral blood have also been reported to be an important predictor of survival in IPF. This study aimed to clarify the prognostic value of serum immunoglobulin (Ig) A levels in patients with IPF to predict survival and occurrence of acute exacerbations (AE). Methods:This retrospective study included 71 patients diagnosed with IPF based on the 2022 guidelines. Serum PDGF and interleukin (IL)-10 levels were measured using the Bio-Plex method. IgA levels were measured by a clinical testing company. Results:Of the enrolled patients, 59 were male, and the median age of the sample was 67 [interquartile range (IQR): 61-72] years. The median serum IgA level was 307 (IQR: 232-408) mg/dL and 18 patients had serum IgA levels of >400 mg/dL. Univariate Cox proportional hazard regression analysis revealed that high IgA levels (>400 mg/dL) were a significant predictor of poor prognosis; however, monocyte counts were not. A high IgA level was a significant prognostic factor after adjusting for the percent predicted value of forced vital capacity, age, gender, and body mass index. Serum PDGF levels tended to be higher in patients with high IgA levels than in those with low IgA levels. IL-10 was not significantly correlated with IgA levels; however, IgA levels tended to be negatively correlated with monocyte counts. High IgA levels did not significantly predict AE. High monocyte counts (>600/µL) significantly predicted the early incidence of AE by univariate Cox analysis but was not confirmed by multivariate analysis. However, monocyte counts, and a monocyte count of >600/µL were significant predictors of AE occurrence for patients with low IgA ≤400 mg/dL. Conclusions:The serum IgA level is an independent prognostic predictor of survival in patients with IPF. Serum IgA levels might suggest serum fibrogenic cytokine levels. Serum IgA levels might be associated with prognosis differently from peripheral monocyte counts. The pathophysiological role of IgA needs to be elucidated in future studies.

We report a rare case of a patient experiencing persistent exertional dyspnoea due to a subacute, adhesive and immobile airway blood clot following haemoptysis. Cryoextraction with short freezing times, which fragmented the clot into small pieces, proved effective, despite previous reports on acute airway blood clots recommending longer freezing times.

Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases. Analysis of the blood DNA virome in patients with COVID-19 and autoimmune disease associates endogenous HHV-6 (eHHV-6) and high anellovirus load with increased disease risk, most notably for systemic lupus erythematosus. eHHV-6 carriers show a distinct immune response.