Identification of kynurenine and quinolinic acid as promising serum biomarkers for drug-induced interstitial lung diseases.

BACKGROUND: Drug-induced interstitial lung disease (DILD) is a lung injury caused by various types of drugs and is a serious problem in both clinical practice and drug development. Clinical management of the condition would be improved if there were DILD-specific biomarkers available; this study aimed to meet that need. METHODS: Biomarker candidates were identified by non-targeted metabolomics focusing on hydrophilic molecules, and further validated by targeted approaches using the serum of acute DILD patients, DILD recovery patients, DILD-tolerant patients, patients with other related lung diseases, and healthy controls. RESULTS: Serum levels of kynurenine and quinolinic acid (and kynurenine/tryptophan ratio) were elevated significantly and specifically in acute DILD patients. The diagnostic potentials of these biomarkers were superior to those of conventional lung injury biomarkers, Krebs von den Lungen-6 and surfactant protein-D, in discriminating between acute DILD patients and patients with other lung diseases, including idiopathic interstitial pneumonia and lung diseases associated with connective tissue diseases. In addition to identifying and evaluating the biomarkers, our data showed that kynurenine/tryptophan ratios (an indicator of kynurenine pathway activation) were positively correlated with serum C-reactive protein concentrations in patients with DILD, suggesting the potential association between the generation of these biomarkers and inflammation. Our in vitro experiments demonstrated that macrophage differentiation and inflammatory stimulations typified by interferon gamma could activate the kynurenine pathway, resulting in enhanced kynurenine levels in the extracellular space in macrophage-like cell lines or lung endothelial cells. Extracellular quinolinic acid levels were elevated only in macrophage-like cells but not endothelial cells owing to the lower expression levels of metabolic enzymes converting kynurenine to quinolinic acid. These findings provide clues about the molecular mechanisms behind their specific elevation in the serum of acute DILD patients. CONCLUSIONS: The serum concentrations of kynurenine and quinolinic acid as well as kynurenine/tryptophan ratios are promising and specific biomarkers for detecting and monitoring DILD and its recovery, which could facilitate accurate decisions for appropriate clinical management of patients with DILD.

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.

A multicenter, double-blind, randomized, parallel-group, placebo-controlled study to evaluate the efficacy and safety of camostat mesilate in patients with COVID-19 (CANDLE study).

BACKGROUND: In vitro drug screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19). METHODS: This was a multicenter, double-blind, randomized, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were enrolled, randomized, and allocated to each group using an interactive web response system. Randomization was performed using a minimization method with the factors medical institution, age, and underlying diseases (chronic respiratory disease, chronic kidney disease, diabetes mellitus, hypertension, cardiovascular diseases, and obesity). The patients, investigators/subinvestigators, study coordinators, and other study personnel were blinded throughout the study. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. RESULTS: One-hundred fifty-five patients were randomized to receive camostat mesilate (n = 78) or placebo (n = 77). The median time to the first test was 11.0 days (95% confidence interval [CI]: 9.0-12.0) in the camostat mesilate group and 11.0 days (95% CI: 10.0-13.0) in the placebo group. Conversion to negative viral status by day 14 was observed in 45 of 74 patients (60.8%) in the camostat mesilate group and 47 of 74 patients (63.5%) in the placebo group. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified. CONCLUSIONS: Camostat mesilate did not substantially reduce the time to viral clearance, based on upper airway viral loads, compared with placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04657497. Japan Registry for Clinical Trials, jRCT2031200198.

Preliminary study regarding the predicted body weight-based dexamethasone therapy in patients with COVID-19 pneumonia.

BACKGROUND: The RECOVERY clinical trial reported that 6 mg of dexamethasone once daily for up to 10 days reduces the 28-day mortality in patients with coronavirus disease 2019 (COVID-19) receiving respiratory support. In our clinical setting, a fixed dose of dexamethasone has prompted the question of whether inflammatory modulation effects sufficiently reduce lung injury. Therefore, preliminary verification on the possibility of predicted body weight (PBW)-based dexamethasone therapy was conducted in patients with COVID-19 pneumonia. METHODS: This single-center retrospective study was conducted in a Japanese University Hospital to compare the treatment strategies/management in different periods. Consecutive patients (n = 90) with COVID-19 pneumonia requiring oxygen therapy and were treated with dexamethasone between June 2020 and May 2021 were analyzed. Initially, 60 patients administered a fixed dexamethasone dose of 6.6 mg/day were defined as the conventional group, and then, 30 patients were changed to PBW-based therapy. The 30-day discharged alive rate and duration of oxygen therapy were analyzed using the Kaplan-Meier method and compared using the log-rank test. The multivariable Cox regression was used to evaluate the effects of PBW-based dexamethasone therapy on high-flow nasal cannula (HFNC), noninvasive ventilation (NIV), or mechanical ventilation (MV). RESULTS: In the PBW-based group, 9, 13, and 8 patients were administered 6.6, 9.9, and 13.2 mg/day of dexamethasone, respectively. Additional respiratory support including HFNC, NIV, or MV was significantly less frequently used in the PBW-based group (P = 0.0046), with significantly greater cumulative incidence of being discharged alive and shorter oxygen demand within 30 days (92 vs. 89%, log-rank P = 0.0094, 90 vs. 92%, log-rank P = 0.0002, respectively). Patients treated with PBW-based therapy significantly decreased the use of additional respiratory support after adjusting for baseline imbalances (adjusted odds ratio, 0.224; 95% confidence interval, 0.062-0.813, P = 0.023). Infection occurred in 13 (21%) and 2 (7%) patients in the conventional and PBW-based groups, respectively (P = 0.082). CONCLUSIONS: In patients with COVID-19 pneumonia requiring oxygen therapy, PBW-based dexamethasone therapy may potentially shorten the length of hospital stay and duration of oxygen therapy and risk of using HFNC, NPPV, or MV without increasing serious adverse events or 30-day mortality.

Thrombomodulin Alfa for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. A Randomized, Double-Blind Placebo-controlled Trial.

Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombomodulin alfa, a recombinant human soluble thrombomodulin, has anticoagulant and antiinflammatory effects. Several clinical studies have shown that thrombomodulin alfa may improve survival of acute exacerbation.Objectives: To determine the efficacy and safety of thrombomodulin alfa compared with placebo in acute exacerbation of idiopathic pulmonary fibrosis.Methods: This randomized, double-blind placebo-controlled phase 3 study conducted at 27 sites in Japan involved patients with an acute exacerbation of idiopathic pulmonary fibrosis. Subjects were randomized 1:1 to receive placebo or thrombomodulin alfa (380 U/kg/d for 14 d by intravenous drip infusion). All subjects were treated with high-dose corticosteroid therapy. The primary endpoint was the survival proportion on Day 90.Measurements and Main Results: Of the 82 randomized subjects, 77 completed the study and were included in the full analysis set (thrombomodulin alfa, n = 40; placebo, n = 37). The survival proportions on Day 90 were 72.5% (29 of 40) in the thrombomodulin alfa group and 89.2% (33 of 37) in the placebo group, a difference of -16.7 percentage points (95% confidence interval, -33.8 to 0.4%; P = 0.0863). In the safety population (n = 80), bleeding adverse events occurred in the thrombomodulin alfa group (10 of 42; 23.8%) and the placebo group (4 of 38; 10.5%).Conclusions: Thrombomodulin alfa did not improve the 90-day survival proportion. The present results suggest that the use of thrombomodulin alfa for the treatment of acute exacerbation of idiopathic pulmonary fibrosis not be recommended.Clinical trial registered with www.clinicaltrials.gov (NCT02739165).

Tolerability of nintedanib-related diarrhea in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Nintedanib is an important drug for the treatment of idiopathic pulmonary fibrosis (IPF). However, the drug is discontinued in some patients who present with diarrhea. In this study, we aimed to assess the drug continuation rate in patients who developed diarrhea during nintedanib therapy and to evaluate if antidiarrheal drugs or nintedanib dose reductions improved clinical tolerability and efficacy. METHODS: Eighty-six patients with IPF were treated in our institution between December 2015 and March 2018. Among them, 50 patients who experienced nintedanib-related diarrhea were analyzed regarding tolerability and persistence rate. RESULTS: In 50 patients who experienced nintedanib-related diarrhea, 26 (n = 11, without reduction and n = 15, with reduction) continuously received nintedanib. Meanwhile, the drug was discontinued in 24 patients (n = 13, without reduction and n = 11, with reduction). In 9 of 24 patients, the drug was discontinued due to diarrhea. The annual rate of decline in forced vital capacity and the duration of nintedanib administration were not significantly different between groups with and without dosage reduction. Moreover, 23, 13, 8, and 2 patients received 1, 2, 3, and 4 agents, respectively. Clostridium butyricum is a probiotic bacterium most commonly used as an antidiarrheal agent. In this study, it was used in 28 of 46 patients. The total durations of nintedanib administration differed significantly according to the number of antidiarrheal drugs taken: 853 ± 221 days, more than three agents; 424 ± 365 days, without an agent (p = 0.043); and 460 ± 142, one agent (p = 0.0003). CONCLUSIONS: When diarrhea occurs within a year after using nintedanib, the dose reduction may be acceptable without affecting pulmonary function. Moreover, treatment with multiple antidiarrheals may be a practical option to maintain the use of nintedanib therapy compared with monotherapy and no therapy.

Whole-lung pathology of pleuroparenchymal fibroelastosis (PPFE) in an explanted lung: Significance of elastic fiber-rich, non-specific interstitial pneumonia-like change in chemotherapy-related PPFE.

Pleuroparenchymal fibroelastosis (PPFE) is characterized by upper lobe-predominant subpleural fibroelastosis. Despite its characteristic uneven distribution, detailed whole-lung pathological features of PPFE have rarely been studied. We investigated PPFE in the explanted lungs from a 19-year-old male patient with a history of chemotherapy. Grossly, the explanted lungs showed upper lobe-predominant shrinkage with subpleural and central consolidation. Histologically, fibroelastosis was prominent in the perilobular areas and along the bronchovascular bundles. The other areas of the lung showed diffuse, non-specific interstitial pneumonia (NSIP)-like change with a characteristic increase of septal elastic fibers. In the digital image analysis, the ratio of elastic fibers to whole fibrosis (EF score) was lower in the subpleural areas than in the NSIP-like lesions, but the EF scores of the latter showed no significant difference between upper and middle/lower lobes. In the present case, the diffusely distributed elastic fiber-rich NSIP-like change, probably caused by the earlier chemotherapy, may have been conducive to the development of PPFE. This suggests that some unknown vulnerability of the upper lobe may exist, various primary lesions converging to the upper lobe predominance of PPFE.

Transbronchial evaluation of peripheral pulmonary lesions using ultrasonic spectrum analysis in lung cancer patients.

BACKGROUND AND OBJECTIVE: Analysis of the endobronchial ultrasound (EBUS) radiofrequency spectrum has been used for convex-probe EBUS technology. Quantitative imaging analysis is also warranted for guided bronchoscopy using radial-probe EBUS (RP-EBUS) targeting peripheral pulmonary lesions (PPL). This study aimed to determine the feasibility of radiofrequency spectrum analysis for distinguishing malignant and benign PPL during diagnostic bronchoscopy. METHODS: Raw RP-EBUS images with radiofrequency data, including backscatter signals, were prospectively recorded. The ultrasonic spectral parameters, such as intercept, midband-fit and slope within the region of interest, were retrospectively computed by linear regression analysis and compared with the final diagnosis. RESULTS: A total of 71 PPL, including 45 malignant and 26 benign lesions, were analysed. Malignant PPL showed a significantly lower intercept (P < 0.0001), lower midband-fit (P < 0.0001) and higher slope (P = 0.014) than benign PPL. Analyses of the area under the curve of receiver operating characteristic plots demonstrated that the intercept showed the best diagnostic performance among three parameters (0.87, 0.77 and 0.69 for intercept, midband-fit and slope, respectively). The sensitivity, specificity, accuracy, positive likelihood and negative likelihood were 75.6%, 96.2%, 83.1%, 19.6 and 0.25 for the intercept; 88.9%, 57.7%, 77.5%, 2.1 and 0.19 for the midband-fit; and 68.9%, 73.1%, 70.4%, 2.6 and 0.43 for the slope. CONCLUSION: Spectrum analysis of EBUS radiofrequency can be used as a novel non-invasive predictor of malignant or benign PPL. Analysis of the 'intercept' of the targeted lesion may provide useful supporting data for real-time sampling from PPL during diagnostic bronchoscopy.

Efficacy of End-Tidal Capnography Monitoring during Flexible Bronchoscopy in Nonintubated Patients under Sedation: A Randomized Controlled Study.

BACKGROUND: Although appropriate sedation is recommended during flexible bronchoscopy (FB), patients are at risk for hypoventilation due to inadvertent oversedation. End-tidal capnography is expected as an additional useful monitor for these patients during FB. OBJECTIVES: The aim of this study was to evaluate the benefit of additional end-tidal capnography monitoring in reducing the incidence of hypoxemia during FB in patients under sedation. METHODS: Patients undergoing FB under moderate sedation without tracheal intubation were randomly assigned to receive standard monitoring including pulse oximetry or additional capnography monitoring. Bronchoscopy examiners for the only capnography group were informed of apnea events by alarms and display of the capnography monitor. RESULTS: A total of 185 patients were enrolled. Patient characteristics were well balanced between the two groups. Hypoxemia (at least one episode of pulse oximeter oxygen saturation [SpO2] < 90%) was observed in 27 out of 94 patients in the capnography group (29%) and in 42 out of 91 patients in the control group (46%; p = 0.014), resulting in an absolute risk difference of -17.4% (95% confidence interval, -31.1 to -3.7). In the capnography group, hypoxemia duration was shorter (20.4 vs. 41.7 s, p = 0.029), severe hypoxemic events (SpO2 < 85%) were observed less frequently (16 [17%] vs. 29 [32%], p = 0.019), and the mean lowest SpO2 value was higher (90.5 vs. 87.6%, p = 0.002). CONCLUSION: End-tidal capnography monitoring can reduce the incidence and duration of hypoxemia during FB in nonintubated patients under sedation.

End-tidal capnographic monitoring to detect apnea episodes during flexible bronchoscopy under sedation.

BACKGROUND: Apnea developing as a result of oversedation is a potential clinical problem in patients undergoing flexible bronchoscopy (FB) under sedation. However, there are no reports of evaluation using a standardized method of the frequency of occurrence of apnea episodes during FB under sedation. The aim of this study was to investigate the frequency of apnea episodes during FB under sedation in the clinical setting by end-tidal capnography. METHODS: This study was a single-institution retrospective review of a prospectively maintained database and medical records, including capnographic data, from April 2015 to March 2016. We enrolled patients who were sedated with midazolam and underwent diagnostic FB under end-tidal capnographic monitoring. Apnea was defined as cessation of airflow for more than 10 s. RESULTS: Data from a total of 121 eligible patients were analyzed. A total of 131 apnea episodes (median duration 33 s) were recorded in 59 patients (48.8%). Prolonged apnea episodes lasting for more than 30 s occurred in 24 patients (19.8%). Furthermore, 55 apnea episodes (42.0%) were followed by a decline of the SpO2 by ≥4% from the baseline. CONCLUSIONS: In this study, end-tidal capnography revealed the occurrence of apnea episodes at a high frequency in patients undergoing FB under sedation in the clinical setting.

Moyamoya disease and artery tortuosity as rare phenotypes in a patient with an elastin mutation.

Sporadic and familial elastin mutations can occur in large vessel stenosis such as supravalvular aortic stenosis and narrowing of the descending aorta. However, there are very few reports regarding the arteriopathy of cerebral, pulmonary or abdominal arteries in elastin mutations. We herein report the case of a Japanese female patient presenting with multiple arteriopathy including moyamoya disease, a tortuosity of abdominal arteries and pulmonary hypertension due to peripheral pulmonary artery stenosis. This case suggests the possible progression of cerebral arteriopathy including moyamoya disease in patients with elastin mutations. © 2016 Wiley Periodicals, Inc.

Immunological priming requires regulatory T cells and IL-10-producing macrophages to accelerate resolution from severe lung inflammation.

Overwhelming lung inflammation frequently occurs following exposure to both direct infectious and noninfectious agents and is a leading cause of mortality worldwide. In that context, immunomodulatory strategies may be used to limit severity of impending organ damage. We sought to determine whether priming the lung by activating the immune system, or immunological priming, could accelerate resolution of severe lung inflammation. We assessed the importance of alveolar macrophages, regulatory T cells, and their potential interaction during immunological priming. We demonstrate that oropharyngeal delivery of low-dose LPS can immunologically prime the lung to augment alveolar macrophage production of IL-10 and enhance resolution of lung inflammation induced by a lethal dose of LPS or by Pseudomonas bacterial pneumonia. IL-10-deficient mice did not achieve priming and were unable to accelerate lung injury resolution. Depletion of lung macrophages or regulatory T cells during the priming response completely abrogated the positive effect of immunological priming on resolution of lung inflammation and significantly reduced alveolar macrophage IL-10 production. Finally, we demonstrated that oropharyngeal delivery of synthetic CpG-oligonucleotides elicited minimal lung inflammation compared with low-dose LPS but nonetheless primed the lung to accelerate resolution of lung injury following subsequent lethal LPS exposure. Immunological priming is a viable immunomodulatory strategy used to enhance resolution in an experimental acute lung injury model with the potential for therapeutic benefit against a wide array of injurious exposures.

Bronchoscopy-Guided Cooled Radiofrequency Ablation as a Novel Intervention Therapy for Peripheral Lung Cancer.

BACKGROUND: Our previous animal and preliminary human studies indicated that bronchoscopy-guided cooled radiofrequency ablation (RFA) for the lung is a safe and feasible procedure without major complications. OBJECTIVES: The present study was performed to evaluate the safety, effectiveness and feasibility of computed tomography (CT)-guided bronchoscopy cooled RFA in patients with medically inoperable non-small-cell lung cancer (NSCLC). METHODS: Patients with pathologically diagnosed NSCLC, who had no lymph node involvement or distant metastases (T1-2aN0M0) but were not surgical candidates because of comorbidities (e.g., synchronous multiple nodules, advanced age, cardiovascular disease, poor pulmonary function, etc.) were enrolled in the present study. The diagnosis and location between the nearest bronchus and target tumor were made by CT-guided bronchoscopy before the treatment. A total of 28 bronchoscopy-guided cooled RFA procedures were performed in 20 patients. After treatment, serial CT imaging was performed as follow-up. RESULTS: Eleven lesions showed significant reductions in tumor size and 8 lesions showed stability, resulting in a local control rate of 82.6%. The median progression-free survival was 35 months (95% confidence interval: 22-45 months), and the 5-year overall survival was 61.5% (95% confidence interval: 36-87%). Three patients developed an acute ablation-related reaction (fever, chest pain) and required hospitalization but improved with conservative treatment. There were no other adverse events in the present study. CONCLUSIONS: CT-guided bronchoscopy cooled RFA is applicable for only highly selected subjects; however, our trial may be an alternative strategy, especially for disease local control in medically inoperable patients with stage I NSCLC.

Thrombomodulin for acute exacerbations of idiopathic pulmonary fibrosis: a proof of concept study.

INTRODUCTION: The mortality of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is high. Anticoagulation therapy (recombinant human soluble thrombomodulin (rhTM)) is recognized as a potential new strategy for treating disseminated intravascular coagulation in Japan. This preliminary study was to evaluate whether the coagulation factors increase or decrease in AE-IPF-patients, and whether the additional administration of rhTM for AE-IPF-patients has any beneficial effects on inflammatory mediators and activated coagulation. METHODS: We retrospectively compared the clinical data of AE-IPF-patients, idiopathic pulmonary fibrosis (IPF) with pneumonia-patients and slowly progressive IPF-patients. As a subsequent study, AE-IPF-patients were prospectively treated with a bolus of rhTM intravenously for six days under mechanical ventilation. We historically investigated the improvement of the serial clinical data in both oxygenation and intravascular coagulation disturbance between treated AE-IPF-patients and untreated AE-IPF-patients. RESULTS: Eleven AE-IPF, 21 IPF with pneumonia and 16 slowly progressive IPF-patients were enrolled, and the coagulatory levels of the AE-IPF-patients were found to be significantly higher than in the other patients. In 20 treated AE-IPF-patients, the 28-day mortality and in-hospital mortality were 35% and 45%, respectively. The levels of oxygenation rapidly increased on day 1 and continued to improve until day 7 in the survival AE-IPF-patients. The thrombin-antithrombin complex levels and inflammatory cytokine levels in the survivors on day 7 were significantly different from those observed in the nonsurvivors. CONCLUSION: AE-IPF-patients were found to have significantly higher levels of coagulation. The rhTM administration in the surviving AE-IPF-patients led to significant differences in the oxygenation and intravascular coagulation disturbance.

Resolution of experimental lung injury by monocyte-derived inducible nitric oxide synthase.

Although early events in the pathogenesis of acute lung injury (ALI) have been defined, little is known about the mechanisms mediating resolution. To search for determinants of resolution, we exposed wild type (WT) mice to intratracheal LPS and assessed the response at intervals to day 10, when injury had resolved. Inducible NO synthase (iNOS) was significantly upregulated in the lung at day 4 after LPS. When iNOS-/- mice were exposed to intratracheal LPS, early lung injury was attenuated; however, recovery was markedly impaired compared with WT mice. iNOS-/- mice had increased mortality and sustained increases in markers of lung injury. Adoptive transfer of WT (iNOS+/+) bone marrow-derived monocytes or direct adenoviral gene delivery of iNOS into injured iNOS-/- mice restored resolution of ALI. Irradiated bone marrow chimeras confirmed the protective effects of myeloid-derived iNOS but not of epithelial iNOS. Alveolar macrophages exhibited sustained expression of cosignaling molecule CD86 in iNOS-/- mice compared with WT mice. Ab-mediated blockade of CD86 in iNOS-/- mice improved survival and enhanced resolution of lung inflammation. Our findings show that monocyte-derived iNOS plays a pivotal role in mediating resolution of ALI by modulating lung immune responses, thus facilitating clearance of alveolar inflammation and promoting lung repair.

Usefulness of Combined Measurement of Surfactant Protein D, Thrombin-Antithrombin III Complex, D-Dimer, and Plasmin-α2 Plasmin Inhibitor Complex in Acute Exacerbation of Interstitial Lung Disease: A Retrospective Cohort Study.

Background/Objectives: The coagulation cascade due to tissue damage is considered to be one of the causes of poor prognostic outcomes in patients with acute exacerbations of interstitial lung disease (AE-ILD). This study aimed to confirm coagulopathy in AE-ILD by evaluating the differences in the clinical characteristics of coagulation/fibrinolysis markers between stable ILD and AE-ILD. Methods: Overall, 81 patients were enrolled in this retrospective study and categorized into the following two groups: a chronic ILD group comprising 63 outpatients and an acute ILD group comprising 18 inpatients diagnosed with AE-ILD. Serum markers, including thrombin-antithrombin III complex (TAT), D-dimer, plasmin-α2 plasmin inhibitor complex (PIC), and surfactant protein D (SP-D), were compared between the groups. Results: Among the 18 patients with acute ILD, 17 did not meet the International Society of Thrombosis and Hemostasis scoring system for disseminated intravascular coagulation. In acute ILD, the SP-D levels were statistically significantly positively correlated with TAT, D-dimer, and PIC levels, while the Krebs von den Lungen 6 (KL-6) levels showed no correlation with any of these coagulation/fibrinolytic markers. A positive correlation was observed between SP-D levels and TAT, D-dimer, and PIC levels in acute ILD. Serum TAT, D-dimer, and PIC all showed good area under the receiver operating characteristic (ROC) curve (AUC) values in ROC analysis for the diagnosis of acute ILD. Conclusions: In the clinical setting of AE-ILD, it may be important to focus not only on alveolar damage markers such as SP-D but also on coagulation/fibrinolytic markers including TAT, D-dimer, and PIC.

Relationship between Anti-SARS-CoV-2 S Abs and IFN-λ3 Levels in the Administration of Oxygen following COVID-19 Vaccination.

Although the effectiveness of vaccination at preventing hospitalization and severe coronavirus disease (COVID-19) has been reported in numerous studies, the detailed mechanism of innate immunity occurring in host cells by breakthrough infection is unclear. One hundred forty-six patients were included in this study. To determine the effects of vaccination and past infection on innate immunity following SARS-CoV-2 infection, we analyzed the relationship between anti-SARS-CoV-2 S Abs and biomarkers associated with the deterioration of COVID-19 (IFN-λ3, C-reactive protein, lactate dehydrogenase, ferritin, procalcitonin, and D-dimer). Anti-S Abs were classified into two groups according to titer: high titer (≥250 U/ml) and low titer (<250 U/ml). A negative correlation was observed between anti-SARS-CoV-2 S Abs and IFN-λ3 levels (r = -0.437, p < 0.001). A low titer of anti-SARS-CoV-2 S Abs showed a significant association with oxygen demand in patients, excluding aspiration pneumonia. Finally, in a multivariate analysis, a low titer of anti-SARS-CoV-2 S Abs was an independent risk factor for oxygen demand, even after adjusting for age, sex, body mass index, aspiration pneumonia, and IFN-λ3 levels. In summary, measuring anti-SARS-CoV-2 S Abs and IFN-λ3 may have clinical significance for patients with COVID-19. To predict the oxygen demand of patients with COVID-19 after hospitalization, it is important to evaluate the computed tomography findings to determine whether the pneumonia is the result of COVID-19 or aspiration pneumonia.

A case of bunashimeji mushroom-induced hypersensitivity pneumonitis diagnosed by inhalational provocation test in a hospital room.

A 66-year-old woman was admitted to our hospital with a 2-month history of dry cough and exertional dyspnea. She had worked as a mushroom farmer and had been exposed to mushroom for more than 40 years. The patient showed elevated levels of KL-6 (2966 U/mL) and surfactant protein D (410 ng/mL), and computed tomography of the chest revealed ground-glass opacities and fine nodular shadows in both lungs, suggesting mushroom-induced hypersensitivity pneumonitis. Pulmonary function testing revealed decreases in forced vital capacity (78% of predicted) and carbon monoxide diffusing capacity (67% of predicted). The inhalational provocation test was positive for bunashimeji mushrooms. Precipitating antibody was only identified for spores or bodies of bunashimeji mushrooms, and lymphocyte stimulation testing with spores or bodies of bunashimeji mushrooms also yielded positive results. Bunashimeji mushroom-induced hypersensitivity pneumonitis was therefore diagnosed. Radiological findings and pulmonary function were improved by corticosteroid therapy and the patient has since remained healthy with allergen avoidance.