Dexamethasone-sparing on days 2-4 with combined palonosetron, neurokinin-1 receptor antagonist, and olanzapine in cisplatin: a randomized phase III trial (SPARED Trial).

BACKGROUND: This study evaluated the non-inferiority of dexamethasone (DEX) on day 1, with sparing on days 2-4 in cisplatin-based chemotherapy. METHODS: Patients with malignant solid tumors who were treated with cisplatin (≥50 mg/m²) were randomly assigned (1:1) to receive either DEX on days 1-4 (Arm D4) or DEX on day 1 (Arm D1) plus palonosetron, NK-1 RA, and olanzapine (5 mg). The primary endpoint was complete response (CR) during the delayed (24-120 h) phase. The non-inferiority margin was set at -15%. RESULTS: A total of 281 patients were enrolled, 278 of whom were randomly assigned to Arm D4 (n = 139) or Arm D1 (n = 139). In 274 patients were included in the efficacy analysis, the rates of delayed CR in Arms D4 and D1 were 79.7% and 75.0%, respectively (risk difference -4.1%; 95% CI -14.1%-6.0%, P = 0.023). However, patients in Arm D1 had significantly lower total control rates during the delayed and overall phases, and more frequent nausea and appetite loss. There were no significant between-arm differences in the quality of life. CONCLUSION: DEX-sparing is an alternative option for patients receiving cisplatin; however, this revised administration schedule should be applied on an individual basis after a comprehensive evaluation. CLINICAL TRIALS REGISTRY NUMBER: UMIN000032269.

Myocardial Injury by COVID-19 Infection Assessed by Cardiovascular Magnetic Resonance Imaging　- A Prospective Multicenter Study.

BACKGROUND: This prospective multicenter study assessed the prevalence of myocardial injury in patients with COVID-19 using cardiac magnetic resonance imaging (CMR).Methods and Results: We prospectively screened 505 patients with moderate to severe COVID-19 disease from 7 hospitals in Japan. Of these patients, 31 (mean [±SD] age 63.5±10.4 years, 23 [74%] male) suspected of myocardial injury, based on elevated serum troponin or B-type natriuretic peptide concentrations either upon admission or 3 months after discharge, underwent CMR 3 months after discharge. The primary endpoint was the presence of myocardial injury, defined by any of the following: (1) contrast enhancement in the left or right ventricle myocardium on late gadolinium enhancement CMR; (2) left or right ventricular dysfunction (defined as <50% and <45%, respectively); and (3) pericardial thickening on contrast enhancement. The mean (±SD) duration between diagnosis and CMR was 117±16 days. The primary endpoint was observed in 13 of 31 individuals (42%), with 8 (26%) satisfying the modified Lake Louise Criteria for the diagnosis of acute myocarditis. CONCLUSIONS: This study revealed a high incidence of myocardial injury identified by CMR in patients with moderate to severe COVID-19 and abnormal findings for cardiac biomarkers.

Findings from a discontinued clinical trial of favipiravir in high-risk patients with early-onset COVID-19.

INTRODUCTION: Favipiravir terminates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. Accordingly, early administration of favipiravir to SARS-CoV-2-infected coronavirus disease 2019 (COVID-19) patients may be expected to suppress disease progression. METHODS: A randomized double-blind placebo-controlled trial was conducted to demonstrate efficacy of favipiravir in reducing disease progression in patients with mild COVID-19. The participants were unvaccinated patients with comorbidities and at risk of progression to severe disease. Patients were enrolled within 72 h of disease onset and randomized to receive either favipiravir (1800 mg/dose on Day 1 followed by 800 mg/dose) or matching placebo twice daily for 10 days. The primary endpoint was the proportion of patients requiring oxygen therapy within 28 days of randomization. RESULTS: The trial was discontinued after enrolling 84 patients due to slower than anticipated enrollment caused by rapid uptake of SARS-CoV-2-vaccines and the emergence of the Omicron variant. Results from the 84 patients demonstrated no significant difference in all clinical outcomes. In post-hoc analyses, favipiravir treatment showed higher efficacy in patients within 48 h of onset. No deaths or severe adverse events were documented in the favipiravir group. Plasma concentrations of favipiravir from Day 2 onward were maintained above 40 µg/mL. CONCLUSIONS: Conducting clinical trials for pathogens like SARS-CoV-2 that rapidly accumulate mutations leading to altered disease characteristics carries significant risks unless it can be done in a short period. Therefore, it would be important to prepare the comprehensive clinical trial platform that can appropriately and promptly evaluate drugs even under a pandemic.

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.

Pamrevlumab for Idiopathic Pulmonary Fibrosis: The ZEPHYRUS-1 Randomized Clinical Trial.

Importance: Current treatments for idiopathic pulmonary fibrosis slow the rate of lung function decline, but may be associated with adverse events that affect medication adherence. In phase 2 trials, pamrevlumab (a fully human monoclonal antibody that binds to and inhibits connective tissue growth factor activity) attenuated the progression of idiopathic pulmonary fibrosis without substantial adverse events. Objective: To assess the efficacy and safety of pamrevlumab for patients with idiopathic pulmonary fibrosis. Design, Setting, and Participants: Phase 3 randomized clinical trial including 356 patients aged 40 to 85 years with idiopathic pulmonary fibrosis who were not receiving antifibrotic treatment with nintedanib or pirfenidone at enrollment. Patients were recruited from 117 sites in 9 countries between July 18, 2019, and July 29, 2022; the last follow-up encounter occurred on August 28, 2023. Interventions: Pamrevlumab (30 mg/kg administered intravenously every 3 weeks; n = 181) or placebo (n = 175) for 48 weeks. Main Outcomes and Measures: The primary outcome was absolute change in forced vital capacity (FVC) from baseline to week 48. There were 5 secondary outcomes (including time to disease progression, which was defined as a decline of ≥10% in predicted FVC or death). The exploratory outcomes included patient-reported symptoms. Adverse events were reported. Results: Among 356 patients (mean age, 70.5 years; 258 [72.5%] were men; 221 [62.1%] were White), 277 (77.8%) completed the trial. There was no significant between-group difference for absolute change in FVC from baseline to week 48 (least-squares mean, -260 mL [95% CI, -350 to -170 mL] in the pamrevlumab group vs -330 mL [95% CI, -430 to -230 mL] in the placebo group; mean between-group difference, 70 mL [95% CI, -60 to 190 mL], P = .29). There were no significant between-group differences in any of the secondary outcomes or in the patient-reported outcomes. In the pamrevlumab group, there were 160 patients (88.4%) with treatment-related adverse events and 51 patients (28.2%) with serious adverse events vs 151 (86.3%) and 60 (34.3%), respectively, in the placebo group. During the study, 23 patients died in each group (12.7% in the pamrevlumab group vs 13.1% in the placebo group). Conclusions and Relevance: Among patients with idiopathic pulmonary fibrosis treated with pamrevlumab or placebo, there was no statistically significant between-group difference for the primary outcome of absolute change in FVC from baseline to week 48. Trial Registration: ClinicalTrials.gov Identifier: NCT03955146.

Long-term effect of pulmonary rehabilitation in idiopathic pulmonary fibrosis: a randomised controlled trial.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterised by worsening dyspnoea and exercise intolerance. RESEARCH QUESTION: Does a long-term pulmonary rehabilitation improve exercise tolerance in patients with IPF treated with standard antifibrotic drugs, which are expected to reduce disease progression? METHODS: This open-label randomised controlled trial was performed at 19 institutions. Stable patients receiving nintedanib were randomised into pulmonary rehabilitation and control groups (1:1). The pulmonary rehabilitation group underwent initial rehabilitation which included twice-weekly sessions of monitored exercise training for 12 weeks, followed by an at-home rehabilitation programme for 40 weeks. The control group received usual care only, without pulmonary rehabilitation. Both groups continued to receive nintedanib. The primary and main secondary outcomes were change in 6 min walking distance (6MWD) and change in endurance time (using cycle ergometry) at week 52. RESULTS: Eighty-eight patients were randomised into pulmonary rehabilitation (n=45) and control (n=43) groups. Changes in 6MWD were -33 m (95% CI -65 to -1) and -53 m (95% CI -86 to -21) in the pulmonary rehabilitation and control groups, respectively, with no statistically significant difference (mean difference, 21 m (95% CI -25 to 66), p=0.38). Changes in endurance time were significantly better in the pulmonary rehabilitation (64 s, 95% CI -42.3 to 171)) than in the control (-123 s (95% CI -232 to -13)) group (mean difference, 187 s (95% CI 34 to 153), p=0.019). INTERPRETATION: Although pulmonary rehabilitation in patients taking nintedanib did not improve 6MWD in the long term, it led to prolonged improvement in endurance time. TRIAL REGISTRATION NUMBER: UMIN000026376.

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.

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.

Incidence of acute exacerbation in patients with interstitial lung disease after COVID-19 vaccination.

Acute exacerbations due to COVID-19 vaccination in patients with interstitial lung disease (ILD) have been reported, but their incidence is unknown. We investigated the incidence of exacerbations of ILD and respiratory symptoms due to the mRNA COVID-19 vaccines. A questionnaire survey was conducted on adverse reactions to the mRNA COVID-19 vaccination in 545 patients with ILD attending our hospital and retrospectively examined whether the eligible patients actually developed acute exacerbations of ILD induced by the vaccine. Of the 545 patients, 17 (3.1%) patients were aware of the exacerbation of respiratory symptoms, and four (0.7%) patients developed an acute ILD exacerbation after vaccination. Of the four patients who experienced exacerbations, two had collagen vascular disease-associated ILD, one had nonspecific interstitial pneumonia, another had unclassifiable idiopathic pneumonia, and none had idiopathic pulmonary fibrosis. Four patients were treated using steroid pulse therapy with a steroid taper, and two of the four also received intravenous cyclophosphamide pulse therapy. Tacrolimus was started in one patient with myositis-associated interstitial lung disease. Eventually, all patients exhibited improvement with immunosuppressive treatment and were discharged. COVID-19 vaccination for patients with ILD should be noted for developing acute exacerbations of ILD with low incidence, although manageable with early diagnosis and treatment.

Concordance between transbronchial lung cryobiopsy and surgical lung biopsy for interstitial lung disease in the same patients.

BACKGROUND: The diagnostic accuracy and safety of transbronchial lung cryobiopsy (TBLC) via a flexible bronchoscope under sedation compared with that of surgical lung biopsy (SLB) in the same patients is unknown. METHODS: Retrospectively the data of fifty-two patients with interstitial lung diseases (median age: 63.5 years; 21 auto-antibody positive) who underwent TBLC followed by SLB (median time from TBLC to SLB: 57 days) was collected. The samples from TBLC and SLB were randomly labelled to mask the relationship between the two samples. Diagnosis was made independently by pathologists, radiologists, and pulmonary physicians in a stepwise manner, and a final diagnosis was made at multidisciplinary discussion (MDD). In each diagnostic step the specific diagnosis, the diagnostic confidence level, idiopathic pulmonary fibrosis (IPF) diagnostic guideline criteria, and treatment strategy were recorded. RESULTS: Without clinical and radiological information, the agreement between the histological diagnoses by TBLC and SLB was 42.3% (kappa [κ] = 0.23, 95% confidence interval [CI]: 0.08-0.39). However, the agreement between the TBLC-MDD and SLB-MDD diagnoses and IPF/non-IPF diagnosis using the two biopsy methods was 65.4% (κ = 0.57, 95% CI: 0.42-0.73) and 90.4% (47/52), respectively. Out of 38 (73.1%) cases diagnosed with high or definite confidence at TBLC-MDD, 29 had concordant SLB-MDD diagnoses (agreement: 76.3%, κ = 0.71, 95% CI: 0.55-0.87), and the agreement for IPF/non-IPF diagnoses was 97.4% (37/38). By adding the pathological diagnosis, the inter-observer agreement of clinical diagnosis improved from κ = 0.22 to κ = 0.42 for TBLC and from κ = 0.27 to κ = 0.38 for SLB, and the prevalence of high or definite diagnostic confidence improved from 23.0% to 73.0% and from 17.3% to 73.0%, respectively. Of all 383 TBLC performed during the same period, pneumothorax occurred in 5.0% of cases, and no severe bleeding, acute exacerbation of interstitial lung disease, or fatal event was observed. CONCLUSIONS: TBLC via a flexible bronchoscope under deep sedation is safely performed, and the TBLC-MDD diagnosis with a high or definite confidence level is concordant with the SLB-MDD diagnosis in the same patients.

Frequency of subclinical interstitial lung disease in COVID-19 autopsy cases: potential risk factors of severe pneumonia.

Risk factors of severe coronavirus disease 2019 (COVID-19) have been previously reported; however, histological risk factors have not been defined thus far. The aim of this study was to clarify subclinical hidden interstitial lung disease (ILD) as a risk factor of severe pneumonia associated with COVID-19. We carefully examined autopsied lungs and chest computed tomography scanning (CT) images from patients with COVID-19 for interstitial lesions and then analyzed their relationship with disease severity. Among the autopsy series, subclinical ILD was found in 13/27 cases (48%) in the COVID-19 group, and in contrast, 8/65 (12%) in the control autopsy group (p = 0.0006; Fisher's exact test). We reviewed CT images from the COVID-19 autopsy cases and verified that subclinical ILD was histologically detectable in the CT images. Then, we retrospectively examined CT images from another series of COVID-19 cases in the Yokohama, Japan area between February-August 2020 for interstitial lesions and analyzed the relationship to the severity of COVID-19 pneumonia. Interstitial lesion was more frequently found in the group with the moderate II/severe disease than in the moderate I/mild disease (severity was evaluated according to the COVID-19 severity classification system of the Ministry of Health, Labor, and Welfare [Japan]) (moderate II/severe, 11/15, 73.3% versus moderate I/mild, 108/245, 44.1%; Fisher exact test, p = 0.0333). In conclusion, it was suggested that subclinical ILD could be an important risk factor for severe COVID-19 pneumonia. A benefit of these findings could be the development of a risk assessment system using high resolution CT images for fatal COVID-19 pneumonia.

Atezolizumab for Pretreated Non-Small Cell Lung Cancer with Idiopathic Interstitial Pneumonia: Final Analysis of Phase II AMBITIOUS Study.

BACKGROUND: Interstitial pneumonia (IP) is a poor prognostic comorbidity in patients with non-small cell lung cancer (NSCLC) and is also a risk factor for pneumonitis. The TORG1936/AMBITIOUS trial, the first known phase II study of atezolizumab in patients with NSCLC with comorbid IP, was terminated early because of the high incidence of severe pneumonitis. METHODS: This study included patients with idiopathic chronic fibrotic IP, with a predicted forced vital capacity (%FVC) of >70%, with or without honeycomb lung, who had previously been treated for NSCLC. The patients received atezolizumab every 3 weeks. The primary endpoint was the 1-year survival rate. RESULTS: A total of 17 patients were registered; the median %FVC was 85.4%, and 41.2% had honeycomb lungs. The 1-year survival rate was 53.3% (95% CI, 25.9-74.6). The median overall and progression-free survival times were 15.3 months (95% CI, 3.1-not reached) and 3.2 months (95% CI, 1.2-7.4), respectively. The incidence of pneumonitis was 29.4% for all grades, and 23.5% for grade ≥3. Tumor mutational burden and any of the detected somatic mutations were not associated with efficacy or risk of pneumonitis. CONCLUSION: Atezolizumab may be one of the treatment options for patients with NSCLC with comorbid IP, despite the high risk of developing pneumonitis. This clinical trial was retrospectively registered in the Japan Registry of Clinical Trials on August 26, 2019, (registry number: jRCTs031190084, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190084).

Impact of Body Weight Loss on Survival in Patients with Advanced Gastric Cancer Receiving Second-Line Treatment.

Limited information is available regarding the impact of body weight loss (BWL) in patients with advanced gastric cancer (AGC) who receive second-line chemotherapy. We retrospectively reviewed data for consecutive AGC patients who received second-line treatment with taxane-based chemotherapy at our institution between January 2014 and September 2018. We calculated variables, including percent BWL per month during chemotherapy (%BWL/m), and analyzed the correlations between BWL and other clinicopathological parameters with survival. Forty-four AGC patients were registered (median age, 67.5 years; females, n = 16 [36.3%]; severe ascites, n = 12 [27.3%]). The median overall survival was significantly shorter among patients with a %BWL/m of 1% or more, compared with patients with less weight loss (6.3 mo, vs. 12.3 mo, P = 0.038). The %BWL/m (≥1% vs. <1%) was significantly correlated with survival in a univariate analysis (HR = 2.11, P = 0.04), and the survival period was shorter for patients with severe ascites (HR = 1.92; 95% CI, 0.90-3.90) and if their %BWL/m was 1% or more (HR = 2.01; 95% CI, 0.98-4.10) in a multivariate analysis. In conclusion, BWL during second-line chemotherapy was associated with a poor prognosis among patients with AGC.

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.

Prognostic impact of HNF4α expression in interstitial lung disease.

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

Cardiac involvement in coronavirus disease 2019 assessed by cardiac magnetic resonance imaging: a meta-analysis.

In this systematic review and meta-analysis, we sought to evaluate the prevalence of cardiac involvement in patients with COVID-19 using cardiac magnetic resonance imaging. A literature review was performed to investigate the left ventricular (LV) and right ventricular (RV) ejection fraction (EF), the prevalence of LV late gadolinium enhancement (LGE), pericardial enhancement, abnormality on T1 mapping, and T2 mapping/T2-weighted imaging (T2WI), and myocarditis (defined by modified Lake Louis criteria). Pooled mean differences (MD) between COVID-19 patients and controls for LVEF and RVEF were estimated using random-effects models. We included data from 10.462 patients with COVID-19, comprising 1.010 non-athletes and 9.452 athletes from 29 eligible studies. The meta-analysis showed a significant difference between COVID-19 patients and controls in terms of LVEF [MD = - 2.84, 95% confidence interval (CI) - 5.11 to - 0.56, p < 0.001] and RVEF (MD = - 2.69%, 95% CI - 4.41 to - 1.27, p < 0.001). However, in athletes, no significant difference was identified in LVEF (MD = - 0.74%, 95% CI - 2.41 to - 0.93, p = 0.39) or RVEF (MD = - 1.88%, 95% CI - 5.21 to 1.46, p = 0.27). In non-athletes, the prevalence of LV LGE abnormalities, pericardial enhancement, T1 mapping, T2 mapping/T2WI, myocarditis were 27.5% (95%CI 17.4-37.6%), 11.9% (95%CI 4.1-19.6%), 39.5% (95%CI 16.2-62.8%), 38.1% (95%CI 19.0-57.1%) and 17.6% (95%CI 6.3-28.9%), respectively. In athletes, these values were 10.8% (95%CI 2.3-19.4%), 35.4% (95%CI - 3.2 to 73.9%), 5.7% (95%CI - 2.9 to 14.2%), 1.9% (95%CI 1.1-2.7%), 0.9% (0.3-1.6%), respectively. Both LVEF and RVEF were significantly impaired in COVID-19 patients compared to controls, but not in athletes. In addition, the prevalence of myocardial involvement is not negligible in patients with COVID-19.

Outcome of COVID-19 in interstitial lung disease patients treated with anti-inflammatory drugs and antiviral drugs.

A recent study reported that patients with interstitial lung disease (ILD) are at increased risk of death from coronavirus disease 2019 (COVID-19). However, there are no studies on the outcome of COVID-19 patients with preexisting ILD treated with corticosteroids or antiviral drugs. We extracted 26 patients with preexisting ILD by medical records and HRCT pattern. Of 503 patients with COVID-19, we selected 52 patients as control matched for age and sex. Twenty out of the 26 ILD patients (76.9%) received corticosteroid therapy, and 23 patients (88.5%) also received antiviral treatment with remdesivir or favipiravir. Although no statistical difference was found, the proportion of severe patients in ILD group tended to be higher than in non-ILD group (23.1% vs. 42.3%; p = 0.114). Also, mortality rate in ILD group tended to be higher than in non-ILD patients (11.5% vs. 3.8%; p = 0.326). In univariate analysis to evaluate risk factors for severe condition, diagnosis of idiopathic pulmonary fibrosis, usual interstitial pneumonia pattern, and honeycomb lung were not risk factors of severe disease. Treatment with corticosteroids, antiviral drugs, and immunosuppressive agents may affect the outcome of COVID-19 patients with ILD.

The new useful high-resolution computed tomography finding for diagnosing fibrotic hypersensitivity pneumonitis: "hexagonal pattern": a single-center retrospective study.

BACKGROUND: Centrilobular nodules, ground-glass opacity (GGO), mosaic attenuation, air trapping, and three-density pattern were reported as high-resolution computed tomography (HRCT) findings characteristic of fibrotic hypersensitivity pneumonitis (HP). However, it is often difficult to differentiate fibrotic HP from idiopathic pulmonary fibrosis (IPF). In fibrotic HP, the HRCT sometimes shows tortoiseshell-like interlobular septal thickening that extends from the subpleural lesion to the inner layers. This finding is called "hexagonal pattern," and this study is focused on the possibility that such finding is useful for differentiating fibrotic HP from IPF. METHODS: This study included patients with multidisciplinary discussion (MDD) diagnosis of fibrotic HP or IPF undergoing surgical lung biopsy between January 2015 and December 2017 in Kanagawa Cardiovascular and Respiratory Center. Two radiologists have evaluated the HRCT findings without clinical and pathological information. RESULTS: A total of 23 patients were diagnosed with fibrotic HP by MDD and 48 with IPF. Extensive GGO, centrilobular nodules, and hexagonal pattern were more frequent findings in fibrotic HP than in IPF. No significant difference was observed between the two groups in the presence or absence of mosaic attenuation, air trapping, or three-density pattern. In the multivariate logistic regression, the presence of extensive GGO and hexagonal pattern was associated with increased odds ratio of fibrotic HP. The sensitivity and specificity of the diagnosis of fibrotic HP in the presence of the hexagonal pattern were 69.6% and 87.5%, respectively. CONCLUSION: Hexagonal pattern is a useful finding for differentiating fibrotic HP from IPF.

Usefulness and safety of transbronchial lung cryobiopsy for reassessment of treatment in the clinical course of diffuse parenchymal lung disease.

BACKGROUND: The usefulness and safety of transbronchial lung cryobiopsy (TBLC) for reassessment of diffuse parenchymal lung disease (DPLD) with progression is still unknown. Our purpose was to clarify the usefulness and safety of TBLC for reassessment of DPLD with progression. METHODS: This retrospective study included 31 patients with DPLD diagnosed by surgical lung biopsy who progressed in the clinical course and underwent TBLC for reassessment between January 2017 and September 2019 at Kanagawa Cardiovascular & Respiratory Center. Two pulmonologists independently selected the clinical diagnosis, treatment strategy, and confidence level of the treatment strategy based on clinical and radiological information with and without pathological information from TBLC. A consensus was reached among the pulmonologists regarding the clinical diagnosis, treatment strategy, and confidence level of the treatment strategy. Complications of TBLC were also examined. RESULTS: Seven (22.6%), 5 (16.1%), and 6 (19.4%) of clinical diagnosis was changed after TBLC for Pulmonologist A, for Pulmonologist B, and for consensus, respectively. The treatment strategy was changed in 7 (22.6%), 8 (25.9%), and 6 (19.4%) cases after TBLC for Pulmonologist A, for Pulmonologist B and for consensus, respectively. The definite or high confidence level of the consensus treatment strategy was 54.8% (17/31) without TBLC and 83.9% (26/31) with TBLC. There were 6 cases of moderate bleeding, but no other complications were noted. CONCLUSIONS: Pathological information from TBLC may contribute to decision-making in treatment strategies for the progression of DPLD, and it may be safely performed.

The Conversion of Superoxide to Hydroperoxide on Cobalt(III) Depends on the Structural and Electronic Properties of Azole-Based Chelating Ligands.

Conversion from superoxide (O2-) to hydroperoxide (OOH-) on the metal center of oxygenases and oxidases is recognized to be a key step to generating an active species for substrate oxidation. In this study, reactivity of cobalt(III)-superoxido complexes supported by facially-capping tridentate tris(3,5-dimethyl-4-X-pyrazolyl)hydroborate ([HB(pzMe2,X)3]-; TpMe2,X) and bidentate bis(1-methyl-imidazolyl)methylborate ([B(ImN-Me)2Me(Y)]-; LY) ligands toward H-atom donating reagent (2-hydroxy-2-azaadamantane; AZADOL) has been explored. The oxygenation of the cobalt(II) precursors give the corresponding cobalt(III)-superoxido complexes, and the following reaction with AZADOL yield the hydroperoxido species as has been characterized by spectroscopy (UV-vis, resonance Raman, EPR). The reaction of the cobalt(III)-superoxido species and a reducing reagent ([CoII(C5H5)2]; cobaltocene) with proton (trifluoroacetic acid; TFA) also yields the corresponding cobalt(III)-hydroperoxido species. Kinetic analyses of the formation rates of the cobalt(III)-hydroperoxido complexes reveal that second-order rate constants depend on the structural and electronic properties of the cobalt-supporting chelating ligands. An electron-withdrawing ligand opposite to the superoxide accelerates the hydrogen atom transfer (HAT) reaction from AZADOL due to an increase in the electrophilicity of the superoxide ligand. Shielding the cobalt center by the alkyl group on the boron center of bis(imidazolyl)borate ligands hinders the approaching of AZADOL to the superoxide, although the steric effect is insignificant.