Compatible with fibrotic hypersensitivity pneumonitis on high-resolution computed tomography: from the ATS/JRS/ALAT 2020 hypersensitivity pneumonitis guidelines.

Background: In compatible with fibrotic hypersensitivity pneumonitis (HP) of the computed tomography (CT) classification using the American Thoracic Society (ATS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) HP guidelines, the lung fibrosis pattern was classified as either a usual interstitial pneumonia (UIP) pattern or a diffuse ground-glass opacity (GGO) pattern with subtle fibrosis. We investigated whether patients with the same imaging classification had different disease progression. We also attempted to reclassify these patients using the CHEST HP guidelines. Methods: Patients with fibrotic HP who had compatible CT pattern in the ATS/JRS/ALAT classification were investigated retrospectively. Results: With 62 patients in the UIP pattern group and 25 patients in the diffuse GGO pattern group, 87 patients with fibrotic HP had compatible pattern on CT. Annual forced vital capacity changes in the UIP pattern group and diffuse GGO pattern group were -2.7% and +3.3% (P=0.004), respectively. The 5-year survival rates in the UIP pattern group and diffuse GGO pattern group were 86% and 100% (P=0.02). In UIP pattern group in the ATS/JRS/ALAT classification, 27% patients were classified as typical fibrotic HP pattern in the CHEST guidelines. In the diffuse GGO pattern group, 52% patients were classified as typical pattern of fibrotic HP. In the CHEST guidelines, more patients in the GGO pattern were classified as typical pattern compared with those in the UIP pattern (P=0.02). Conclusions: The two patterns in compatible with fibrotic HP of CT classification using the ATS/JRS/ALAT HP guidelines had different disease progression. Typical patterns were more frequent in the CHEST guidelines than the ATS/JRS/ALAT guidelines.

Longitudinal changes in serum immunoglobulin G testing in patients with fibrotic avian hypersensitivity pneumonitis.

BACKGROUND: Evaluation of the antigen responsible for fibrotic hypersensitivity pneumonitis (HP) is challenging. Serum immunoglobulin (Ig) G testing against HP-associated antigens is performed. Although single-serum IgG testing has been investigated, multiple-serum IgG testing has not yet been studied. METHODS: This study included patients who underwent histopathological examination and positive inhalation challenge test as well as those with moderate or high HP guideline confidence level. Serum IgG testing against pigeon serum was conducted twice using two methods: enzyme linked-immunosorbent assay (ELISA) and ImmunoCAP. The association between changes in serum IgG antibody titers and changes in forced vital capacity (FVC) and other parameters was investigated. RESULTS: In this study, 28 patients (mean age, 64.5 years; mean FVC, 85.3%) with fibrotic avian HP were selected, of whom 20 and 8 underwent surgical lung biopsy and transbronchial lung cryobiopsy, respectively. Of the 28 patients, 19 had been keeping birds for more than 6 months. A correlation was observed between the annual changes in serum IgG antibody titers by ELISA and changes in relative FVC (r = - 0.6221, p < 0.001). Furthermore, there was a correlation between the annual changes in serum IgG antibody titers by ImmunoCAP and changes in relative FVC (r = - 0.4302, p = 0.022). Multiple regression analysis revealed that the change in serum IgG antibody titers by both ELISA and ImmunoCAP also influenced the relative FVC change (p = 0.012 and p = 0.015, respectively). Moreover, 13 patients were given additional treatments between the first and second blood test; however, the additional treatment group was not significantly different in relative FVC change compared to the group with no additional treatment (p = 0.982). CONCLUSIONS: In patients with fibrotic avian HP, the annual changes in serum IgG testing were correlated with FVC changes, highlighting the importance of serum IgG testing over time.

Hypersensitivity pneumonitis with Paecilomyces as suspected inciting antigen.

A 73-year-old man visited our hospital for persistent cough. Chest high-resolution CT (HRCT) showed infiltration shadows in lower lobes and diffuse ground glass opacities in the upper lobes. Blood tests showed elevated white blood cell, C-reactive protein, surfactant protein D, and Krebs von den Lungen-6 levels. After an antigen avoidance test, his HRCT and blood test findings improved; we diagnosed him with hypersensitivity pneumonitis (HP). A culture of the rotting interior walls within his home revealed Paecilomyces, which we believe caused his HP. Given the few patients with Paecilomyces-induced HP, systematic approach was important to identify the inciting antigen.

High prevalence of upper lung field pulmonary fibrosis radiologically consistent with pleuroparenchymal fibroelastosis in patients with round atelectasis.

BACKGROUND: Upper-lung field pulmonary fibrosis (upper-PF), radiologically consistent with pleuroparenchymal fibroelastosis (PPFE), was reported to develop in patients with a history of asbestos exposure and tuberculous pleurisy, indicating that chronic pleuritis is correlated with upper-PF development. Round atelectasis reportedly emerges after chronic pleuritis. This study aimed to clarify the association between round atelectasis and upper-PF. METHODS: We examined the radiological reports of all consecutive patients with round atelectasis between 2006 and 2018 and investigated the incidence of upper-PF development. RESULTS: Among 85 patients with round atelectasis, 21 patients (24.7%) were confirmed to finally develop upper-PF lesions. Upper-PF was diagnosed after round atelectasis recognition in more than half of the patients (13/21, 61.9%), whereas upper-PF and round atelectasis were simultaneously detected in the remaining 8 patients. At the time of round atelectasis detection, almost all patients (19/21, 90.5%) had diffuse pleural thickening and round atelectasis was commonly observed in non-upper lobes of 19 patients (90.5%). Fourteen patients had round atelectasis in unilateral lung, and the remaining 7 patients had round atelectasis in bilateral lungs. Among all 14 patients with unilateral round atelectasis, upper-PF developed on the same (n = 11) or both sides (n = 3). Thus, upper-PF emerged on the same side where round atelectasis was present (14/14, 100%). The autopsy of one patient revealed a thickened parietal-visceral pleura suggestive of chronic pleuritis. Subpleural fibroelastosis was also observed. CONCLUSIONS: Upper-PF occasionally develops on the same side of round atelectasis. Upper-PF may develop as a sequela of chronic pleuritis.

Acute Exacerbation and Proposed Criteria for Progressive Pulmonary Fibrosis in Patients with Fibrotic Hypersensitivity Pneumonitis and Idiopathic Pulmonary Fibrosis.

BACKGROUND: Acute exacerbation (AE) occasionally develops in the course of fibrotic hypersensitivity pneumonitis (HP). OBJECTIVE: The aim of the study was to compare AE of fibrotic HP with that of idiopathic pulmonary fibrosis (IPF). METHODS: Consecutive patients with pathologically confirmed fibrotic HP and IPF diagnosed based on a multidisciplinary discussion were included in the analysis. AE in patients with fibrotic HP and IPF was evaluated retrospectively. RESULTS: This study included 309 and 160 patients with fibrotic HP and IPF, respectively. Their 50% survival times were 96.1 and 78.0 months, respectively (hazard ratio [HR]: 0.54 [95% confidence interval, CI: 0.36-0.77], log-rank test; p < 0.001). Notably, the cumulative AE rates of fibrotic HP were 3% at 1 year and 10% at 3 years. Moreover, the corresponding rates of IPF were 8% at 1 year and 20% at 3 years (HR: 0.66 [95% CI: 0.45-0.93], log-rank test; p = 0.034). The 90-day survival rates from the AE onset of fibrotic HP and IPF were 75% and 64%, respectively (HR: 0.51 [95% CI: 0.31-0.83], log-rank test; p = 0.006). The respiratory function test on the physiological criteria of progressive pulmonary fibrosis (PPF) was a predictor of AE in fibrotic HP. However, the high-resolution CT (HRCT) changes in the criteria of PPF were not. Nevertheless, both the physiological and radiological criteria of PPF were a predictor of AE of IPF. CONCLUSION: AE of fibrotic HP has a lesser prognostic effect than that of IPF. HRCT criteria for PPF were not a risk factor for AE in patients with fibrotic HP.

Safety and Efficacy of Combination Therapy of Remdesivir, Baricitinib, and High-dose Steroids in Patients Hospitalized with Moderate to Severe COVID-19.

Objective Dexamethasone, remdesivir (REM), and baricitinib (BAR) are commonly used to treat coronavirus disease 2019 (COVID-19). High-dose steroids have also been reported to be well tolerated, even when used in combination with multiple drugs. In this retrospective study, we assessed the safety and therapeutic efficacy of a three-drug combination of high-dose steroids, REM, and BAR in hospitalized COVID-19 patients. Methods We retrospectively evaluated the safety and efficacy of three-drug combination therapy. Patients We evaluated 107 patients hospitalized with moderate or severe COVID-19 who underwent 3-drug combination therapy with high-dose steroids (80 mg of methylprednisolone or more, REM, and BAR) in our institution from December 2020 to June 2021. The mean age was 62.1±13.7 years old, and 71.2% were men. The severity of the study patients was as follows: 18 (16.8%) with an 8-category ordinal score of 4, 84 (78.5%) with a score of 5, and 5 (4.7%) with a score of 6. Results The frequency of high-grade adverse events was low, except for hyperglycemia (n=59, 45.8%). The median duration from symptom onset to the start of three-drug combination therapy was eight days. All but one of the patients treated with the combination therapy improved. The median time to improvement by 1 category of the eight-category ordinal score was 6 days, and the 28-day mortality was 0.9%. Conclusion This study showed the safety profile of three-drug combination therapy of high-dose steroids, REM, and BAR in moderate to severe COVID-19 patients. The three-drug combination therapy is well tolerated and has the potential to prevent exacerbation of severity.

Multidisciplinary Discussion for Fibrotic Hypersensitivity Pneumonitis with a Positive Antigen Avoidance.

Background: In the two fibrotic hypersensitivity pneumonitis (fHP) diagnostic guidelines, the multidisciplinary discussion (MDD) is required to be performed in diagnosis of fHP, as in idiopathic pulmonary fibrosis (IPF) diagnostic guideline. Although some patients with fHP can improve disease condition during antigen avoidance, which can facilitate the diagnosis of fHP, it is unclear if MDD is necessary in all patients with suspected fHP who improved an antigen avoidance. Objective: To investigate the diagnosis of fHP via MDD with positive antigen avoidance tests (AATs) and the clinical diagnosis with positive AATs. Methods: A single-center, retrospective study was conducted. Between 2012 and 2019, patients with fHP were enrolled in the study. Patients in the MDD diagnostic group consisted of patients diagnosed with MDD, including histopathology findings and positive ATTs, and patients in the clinical diagnostic group were diagnosed by two respiratory physicians and had positive ATTs. Results: AAT was performed on 72 of 219 patients, and 58 had positive AATs. The study included 37 patients in the MDD diagnosis group and 21 patients in the clinical diagnosis group. No significant differences in overall survival (OS) were detected between the two groups (HR: 1.99 [95% CI: 0.82‒4.83], p = 0.127). The conducting MDD was not a risk factor for OS; only <79% forced vital capacity was a risk factor in the multivariate Cox hazard regression analysis. No significant difference in annual changes of forced vital capacity, diffusion of the lung for carbon monoxide and Krebs von den Lungen-6 between the MDD diagnostic and the clinical diagnostic groups were observed (p = 0.41, 0.79, and 0.81, respectively). Conclusion: In patients with positive AATs, the disease progression of the MDD diagnostic and the clinical diagnostic groups were similar. Therefore, MDD could not be necessary in all patients with suspected fHP who had positive AATs.

Serum Immunoglobulin G Testing against Pigeon Egg in Stable Fibrotic Hypersensitivity Pneumonitis.

INTRODUCTION: The accuracy of serum immunoglobulin (Ig) G testing for diagnosis of stable bird-related fibrotic hypersensitivity pneumonitis (HP) is controversial. Furthermore, avian serum, extracts, or feathers were employed as antigens in bird-related HP; however, the usage of egg whites has not been reported. We investigated the utility of IgG testing against pigeon egg whites in patients with stable bird-related fibrotic HP. METHODS: Patients having a positive inhalation test for pigeon antigen and a histological investigation with diagnostic confidence of fibrotic HP greater than moderate confidence were included. The control group consisted of patients with interstitial lung diseases (ILDs) other than HP. To select patients in the stable phase, patients with fibrotic HP were excluded if they were clinically considered to be in the acute exacerbation or acute phase. The IgG testing against pigeon egg whites by enzyme-linked immunosorbent assay and the commercialized anti-pigeon IgG testing by fluorescence enzyme immunoassay were investigated. RESULTS: In this study, 37 patients with stable bird-related fibrotic HP and 32 patients with ILDs other than HP participated. Serum IgG testing for pigeon egg whites revealed that the control group's optical density was 0.147 and the group with bird-related fibrotic HP had a mean value of 0.207 (p = 0.011). IgG testing in bronchial alveolar lavage fluid was not significantly higher in the bird-related fibrotic HP group than in controls (p = 0.42). No significant difference in area under the curve between an IgG testing against pigeon egg whites and a commercialized anti-pigeon IgG testing was observed (p = 0.24). Test accuracy for stable bird-related fibrotic HP ranged from 62% to 76% sensitivity and 59-66% specificity. CONCLUSION: IgG testing to identify the inciting antigen in patients with stable bird-related fibrotic HP had relatively low accuracy.

Design and rationale of the Japanese Idiopathic Interstitial Pneumonias (JIPS) Registry.

BACKGROUND: Numerous studies investigated patients with IPF; however, only a few examined patients with idiopathic interstitial pneumonias (IIPs). METHODS: The Japanese Idiopathic Interstitial Pneumonias (JIPS) Registry, which was initiated in December 2016, is a multicenter prospective observational study of patients newly diagnosed with IIPs from 86 facilities treating ILDs. The plan is to enroll more than 600 new patients during the 2-year enrolment period and to follow their progress for 3 years after the last case enrolment. If additional consent is obtained, the study will continue for another 2 years. Research questions mainly focus on identifying the frequency by IIP classification, patient background, and diagnostic methods during enrolment, survival, acute exacerbation rate, changes in high-resolution CT imaging, forced vital capacity, and interstitial pneumonia markers over time. Other research questions, including those regarding disease behavior in patients with progressive fibrosing-ILD and new biomarkers associated with genetic predispositions, will be investigated. DISCUSSION: The JIPS Registry will provide a comprehensive description of the disease progression, prognosis, treatment status, new biomarkers, and validity of guidelines and central multidisciplinary decisions for IPF and similar diseases that can be differentiated from IPF among IIPs. ETHICS AND DISSEMINATION: Ethical approval was obtained from the institutional review board of Kanagawa Cardiovascular and Respiratory Center (KCRC-16-0005), and that of Jichi Medical University approved the biobank part (I18-005). Results will be published in peer-reviewed journals and will be presented at national and international conferences. TRIAL REGISTRATION: ClinTrials.gov Registry (NCT03041623, first posted on February 3, 2017).

Establishment of experimental salivary gland cancer models using organoid culture and patient-derived xenografting.

PURPOSE: Depending on its histological subtype, salivary gland carcinoma (SGC) may have a poor prognosis. Due to the scarcity of preclinical experimental models, its molecular biology has so far remained largely unknown, hampering the development of new treatment modalities for patients with these malignancies. The aim of this study was to generate experimental human SGC models of multiple histological subtypes using patient-derived xenograft (PDX) and organoid culture techniques. METHODS: Tumor specimens from surgically resected SGCs were processed for the preparation of PDXs and patient-derived organoids (PDOs). Specimens from SGC PDXs were also processed for PDX-derived organoid (PDXO) generation. In vivo tumorigenicity was assessed using orthotopic transplantation of SGC organoids. The pathological characteristics of each model were compared to those of the original tumors using immunohistochemistry. RNA-seq was used to analyze the genetic traits of our models. RESULTS: Three series of PDOs, PDXs and PDXOs of salivary duct carcinomas, one series of PDOs, PDXs and PDXOs of mucoepidermoid carcinomas and PDXs of myoepithelial carcinomas were successfully generated. We found that PDXs and orthotopic transplants from PDOs/PDXOs showed similar histological features as the original tumors. Our models also retained their genetic traits, i.e., transcription profiles, genomic variants and fusion genes of the corresponding histological subtypes. CONCLUSION: We report the generation of SGC PDOs, PDXs and PDXOs of multiple histological subtypes, recapitulating the histological and genetical characteristics of the original tumors. These experimental SGC models may serve as a useful resource for the development of novel therapeutic strategies and for investigating the molecular mechanisms underlying the development of these malignancies.

A Retrospective Study of the Clinical, Radiological, and Pathological Characteristics of Patients with Interstitial Pneumonia Preceding Rheumatoid Arthritis.

Objective Interstitial lung disease (ILD) is the most critical manifestation in patients with rheumatoid arthritis (RA). In some cases, ILD may appear before the RA onset. Some patients with an initial diagnosis of idiopathic interstitial pneumonia (IIPs) develop RA; however, few studies have reported on its features, and the details remain unknown. In the present study, the clinical, radiological, and pathological features were evaluated in patients with ILD preceding RA. Methods The clinical, radiological, and pathological features of patients with ILD preceding RA were retrospectively reviewed using the medical records. Patients Ten patients with ILD preceding RA out of 883 IIP patients who underwent a surgical lung biopsy at our hospital from 2004 to 2018 were retrospectively examined. Results The median patient age was 59 (range 50-76) years old, and 7 of the patients were women. The median time from the ILD diagnosis to the RA onset was 50 (range 33-65) months. Regarding the high-resolution computed tomography pattern, the "indeterminate for UIP" pattern was the most popular, and cysts were seen in all cases. Attenuation around the cyst was prominent. Pathological findings showed plasma cell infiltration, bronchus-associated lymphoid tissue (BALT), and bronchiolitis in the lobules. Cellular and destructive bronchiolitis was noticeable in many patients with ILD preceding RA and contributed to the destruction and dilation of the bronchiole. Conclusion In ILD patients with IIP, radiological and pathological findings with increased attenuation around the cysts, prominent inflammatory cell infiltration (especially in plasma cells), an increase in the BALT number, and cellular and destructive bronchiolitis might serve as helpful RA development indicators.

Impact of antigen avoidance test for fibrotic hypersensitivity pneumonitis in stable phase.

BACKGROUND: The antigen avoidance has been used in the diagnosis and treatment of hypersensitivity pneumonitis (HP); however, its usefulness in stable fibrotic HP is controversial. OBJECTIVE: To investigate the usefulness of the antigen avoidance test in patients with fibrotic HP in stable phase. METHODS: The antigen avoidance test was conducted during a 2-week hospitalization comparing clinical parameters at admission and before discharge. A retrospective review of patients who underwent surgical lung biopsy or transbronchial lung cryobiopsy, who were diagnosed with fibrotic HP by multi-disciplinary discussion, and whose disease progression was stable for more than two months before the antigen avoidance test was done. RESULTS: Between 2016 and 2021, 40 patients met the criteria, and 17 (43%) patients had a positive antigen avoidance test. The patients with positive in the antigen avoidance test had significantly greater annual forced vital capacity (FVC) decline than those with negative before the test (- 6.5% vs. - 0.3%, p = 0.045). The patients with positive antigen avoidance test had less annual FVC decline than those with negative in the year following the test (0.8% vs. - 5.0%, p = 0.048). The differences in annual improvement were found for serum Krebs von den Lungen-6 between the positive and negative patients in the year following the test (- 27% vs. - 5%, p = 0.049). In multivariate Cox hazard regression analysis, a negative result of the antigen avoidance test was a risk factor for death or acute exacerbation of fibrotic HP (HR = 0.26 [95% CI: 0.07-0.90], p = 0.034). CONCLUSIONS: In fibrotic HP patients in stable phase, the antigen avoidance test under a 2-week hospitalization was valuable in predicting prognosis.

Validation of inhalation challenge test and serum immunoglobulin G test for bird-related fibrotic hypersensitivity pneumonitis.

BACKGROUND: The inhalation challenge test is considered to be the item for diagnosis of hypersensitivity pneumonitis (HP) and identifying the causative antigen in patients with fibrotic HP. However, the inhalation challenge test is not widely used. OBJECTIVE: To evaluate the values of the inhalation challenge test by comparing with serum immunoglobulin (Ig)G test. METHODS: This was a single-center, retrospective study. The patients with fibrotic HP were diagnosed pathologically by surgical lung biopsy or transbronchial lung cryobiopsy and were assumed to have bird-related fibrotic HP if they had a history of obvious avian exposure. RESULTS: On the basis of pathologic findings and history of avian exposure, 43 of 86 patients were diagnosed with having bird-related fibrotic HP. In 43 patients with bird-related fibrotic HP, 15 (35%) were positive for anti-bird IgG antibody and 36 (84%) were positive for the inhalation challenge test; in addition, the specificity of the inhalation challenge test was 67%. Patients with both positive results from inhalation challenge test and anti-bird IgG antibodies had a 2.7% decline in annual forced vital capacity (FVC) before the inhalation (P = .02). In patients with positive result from inhalation challenge test and negative result from anti-bird IgG antibodies, the annual FVC decreased by 5.8% (P = .03). FVC was not consistent in patients with positive result from the anti-bird IgG antibodies. CONCLUSION: The inhalation challenge test for bird-related fibrotic HP was more sensitive than the anti-bird IgG antibodies. Furthermore, the inhalation challenge test could select patients with similar disease progression.

Disease activity of lung cancer at the time of acute exacerbation of interstitial lung disease during cytotoxic chemotherapy.

BACKGROUND: The prognosis of lung cancer patients with interstitial lung disease (ILD) is poor, and acute exacerbation (AE) of ILD can occur during chemotherapy as a fatal adverse event. Although AE-ILD development is correlated with various factors, no reports are investigating the disease activity of lung cancer at the time of AE-ILD development. METHODS: All consecutive lung cancer patients with ILD who developed chemotherapy-related AE-ILD within 28 days after the last administration of cytotoxic chemotherapy between 2011 and 2020 were retrospectively reviewed. RESULTS: Among 206 lung cancer patients with ILD who were treated with cytotoxic chemotherapy, 30 patients were included. The median age was 72 years and all patients were men with smoking history. Usual interstitial pneumonia (UIP) and non-UIP patterns of ILD was observed in 17 and 13 patients. Most of AE-ILD occurred during second- or later-line (22/30, 73.3%) and developed within first or second courses during chemotherapy (19/30, 63.3%). Regarding tumor response to chemotherapy at AE-ILD development, majority of patients (18 patients, 60.0%) experienced progressive disease and only one patient (3.3%) experienced a partial response. Notably, 27 patients (90.0%) did not exhibit any tumor shrinkage of the thoracic lesions. CONCLUSION: Lung cancer was uncontrolled with cytotoxic chemotherapy at the time of AE-ILD development. Although AE-ILD during chemotherapy has been generally discussed in terms of drug-specific adverse effects, uncontrolled lung cancer may be also correlated with AE-ILD development.

Randomized phase II study of nintedanib with or without pirfenidone in patients with idiopathic pulmonary fibrosis who experienced disease progression during prior pirfenidone administration.

INTRODUCTION: A subgroup analysis of the CAPACITY and ASCEND trials showed that pirfenidone use beyond disease progression reduced the risk of subsequent forced vital capacity (FVC) decline and death. Our study aimed to compare the efficacy and safety of nintedanib with or without pirfenidone for patients with idiopathic pulmonary fibrosis (IPF) who experienced disease progression during previous pirfenidone therapy. METHODS: In this randomized, open-label, selection design phase II trial, patients with IPF and a ≥5% relative decline in FVC within 6 months of the pirfenidone administration period were randomly assigned to nintedanib (switch group) or nintedanib plus pirfenidone (combination group). The primary endpoint was the incidence of a ≥5% relative decline in FVC or death during the first 6 months. RESULTS: Only 7 patients were enrolled (4 in the switch group and 3 in the combination group). Although the switch group continued with nintedanib for 1 year or more, 2 patients (66.7%) in the combination group discontinued nintedanib within 6 months due to severe adverse events. Given the slow case registration and safety concerns in the combination group, the trial was terminated without extending the registration. The incidence of a ≥5% relative decline in FVC during the first 6 months was 50.0% in the switch group and 66.7% in the combination group. There were no deaths during the observation period. CONCLUSIONS: Clinical trials verifying the use of pirfenidone after disease progression in IPF may be difficult to enroll patients. Definitive conclusions on both safety and efficacy cannot be drawn from the results of this study alone. TRIAL REGISTRATION: UMIN Clinical Trial Registry; registration number, UMIN000019436; date of first registration, 21/10/2015; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000022471.

Asbestos exposure and tuberculous pleurisy as developmental causes of progressive unilateral upper-lung field pulmonary fibrosis radiologically consistent with pleuroparenchymal fibroelastosis.

BACKGROUND: Unilateral upper-lung field pulmonary fibrosis (upper-PF), which is radiologically consistent with pleuroparenchymal fibroelastosis, develops after thoracic surgery. In most patients with unilateral upper-PF, aberrant intra-/extra thoracic air commonly emerges and an autopsy shows chronic pleuritis, which indicates that pleural involvement is associated with upper-PF development. If so, there may be patients with unilateral upper-PF who have a history of pleural involvement, including tuberculous pleurisy (TP) or asbestos exposure (AE). This study aimed to examine this supposition. METHODS: We examined the radiological reports of all consecutive patients from 2012 to 2018 to investigate whether there were patients having unilateral upper-PF and a history of TP or AE. RESULTS: Eight patients were included in the study. Five patients had a history of TP, and the remaining three had that of AE. All patients were men and had respiratory symptoms, and seven patients presented with restrictive ventilatory impairment. The interval between TP or last AE and upper-PF development was long, with a median of over 20 years. The upper-PF lesion was commonly located in the right lung, and aberrant intrathoracic air was observed in five patients during their clinical course. Additionally, the upper-PF lesion transformed into a cystic lesion in six patients, which resulted in Aspergillus infection in two patients. The prognosis was poor, with a median overall survival of 38 months. CONCLUSIONS: Unilateral upper-PF developed even in patients with a history of pleural involvement. Our results indicate that pleural involvement plays an important role in the development of unilateral upper-PF.

Serum Krebs von den Lungen-6 levels are associated with mortality and severity in patients with coronavirus disease 2019.

BACKGROUND: The serum Krebs von den Lungen-6 (KL-6) level is a predictive factor for acute respiratory distress syndrome (ARDS). The development of ARDS has been reported in patients with coronavirus disease 2019 (COVID-19). This study aimed to determine whether serum KL-6 levels are associated with mortality and severity in patients with COVID-19. METHODS: Among 361 Japanese patients with COVID-19 who were hospitalized at Kanagawa Cardiovascular and Respiratory Center between February 2020 and December 2020, 356 patients with data on serum KL-6 levels were enrolled and their medical records were retrospectively analyzed. RESULTS: A negative correlation was observed between KL-6 levels and the ratio of the arterial partial pressure of oxygen to the fraction of inspired oxygen on admission. The KL-6 levels on admission and the maximal KL-6 levels were higher in patients with severe disease (n = 60) than in those with nonsevere disease (n = 296). Furthermore, the maximal KL-6 levels were higher in nonsurvivors (n = 6) than in survivors (n = 350). In nonsurvivors, the KL-6 levels increased as the disease progressed. The optimal cutoff value of the maximal KL-6 level for discriminating between survivors and nonsurvivors was 684 U/mL, with a sensitivity of 83.3%, a specificity of 90.5%, and an area under the curve of 0.89. CONCLUSIONS: The serum KL-6 level was associated with disease severity. Patients with KL-6 levels ≥684 U/mL had a significantly poorer outcome than those with KL-6 levels <684 U/mL.

A case of exogenous lipoid pneumonia diagnosed by transbronchial lung cryobiopsy.

A 57-year-old man visited a referral physician due to abnormal chest shadows. Transbronchial lung biopsy (TBLB) failed to diagnose his condition. As antibiotics and systemic steroids did not improve the condition, he was referred to our hospital. A second TBLB in our hospital also failed to diagnose the disease. Transbronchial lung cryobiopsy (TBLC) was performed using radial endobronchial ultrasound with guide sheath (EBUS-GS), and the patient was diagnosed with lipoid pneumonia. Right upper lobe resection was performed, and lipoid pneumonia was confirmed from the surgical specimen. We report a case of lipoid pneumonia diagnosed by EBUS-GS TBLC.

Clinical characteristics of Japanese patients with moderate to severe COVID-19.

INTRODUCTION: Although several reports on the risk factors for severe disease of COVID-19 already exist, reports on effective early indicators are still limited, especially from Japan. This study was conducted to clarify the patient's characteristics whose disease progressed to severe status. METHODS: The medical records of all consecutive 300 Japanese patients hospitalized at our institution between February and November 2020 were retrospectively reviewed. The clinical characteristics were evaluated to compare between mild (no oxygen needed), moderate (oxygen needs of 1-4 L/min), and severe diseases (oxygen needs of 5 L/min or more). RESULTS: The median age was 68 years old, with 123 (41.0%) males and 177 (59.0%) females. Of these, 199 patients (66.3%), 55 patients (18.3%), 46 patients (15.3%) patients were in the mild disease, moderate disease, severe disease groups, respectively. Patients with severe disease were more likely to be older, have more comorbidities, and tended to have higher body mass index. In laboratory data, lymphocyte count, levels of C-reactive protein (CRP), LDH, and AST on admission were significantly associated with the severity. In multivariate analysis, age and CRP were the independent risk factors for severe disease (OR = 1.050, 1.130, respectively). The optimal cut-off value for age was 74 years old and that for CRP was 3.15 mg/dL. CONCLUSIONS: Age and CRP were independently associated with disease severity of COVID-19 in multivariate analysis. Additionally, the numbers of underlying disease, lymphocyte count, and inflammatory markers such as LDH and D-dimer may also be related to disease severity.

Predictive factors for the long-term use of pirfenidone in patients with fibrosing interstitial lung disease.

BACKGROUND: Pirfenidone is an anti-fibrotic agent approved for idiopathic pulmonary fibrosis (IPF), and long-term treatment data and the effect of continuation after disease progression have been reported. The efficacy and safety of pirfenidone in fibrosing interstitial lung disease (ILD) patients without IPF have been recently reported in clinical trials; therefore, the benefits of long-term treatment are also expected. This study aims to analyze the long-term treatment data of pirfenidone and clarify the predictive factors for long-term use of pirfenidone in non-IPF patients. METHODS: We retrospectively reviewed the records of consecutive fibrosing ILD patients who started using pirfenidone between 2008 and 2014. RESULTS: Of the 266 fibrosing ILD patients, 167 patients had IPF, and 99 had non-IPF. Despite the non-significant differences in body size and pulmonary function between IPF and non-IPF patients, the non-IPF patients had better overall survival than the IPF patients (median 4.06 years vs. 2.09 years, p < 0.0001). In addition, the non-IPF patients had a significantly longer time to treatment discontinuation than the IPF patients (median 2.20 years vs. 1.20 years, p = 0.002). Multivariate logistic regression analysis for ≥2 years of use of pirfenidone showed that the percent predicted forced vital capacity (%FVC) and age were predictive factors common to both IPF and non-IPF patients. CONCLUSIONS: Our results indicate that non-IPF patients can continue using pirfenidone for longer durations than IPF patients. Initiation of pirfenidone for fibrosing ILD patients with higher %FVC and younger age would lead to long-term use of pirfenidone.