The USP7-STAT3-granzyme-Par-1 axis regulates allergic inflammation by promoting differentiation of IL-5-producing Th2 cells.

Uncontrolled type 2 immunity by type 2 helper T (Th2) cells causes intractable allergic diseases; however, whether the interaction of CD4+ T cells shapes the pathophysiology of allergic diseases remains unclear. We identified a subset of Th2 cells that produced the serine proteases granzyme A and B early in differentiation. Granzymes cleave protease-activated receptor (Par)-1 and induce phosphorylation of p38 mitogen-activated protein kinase (MAPK), resulting in the enhanced production of IL-5 and IL-13 in both mouse and human Th2 cells. Ubiquitin-specific protease 7 (USP7) regulates IL-4-induced phosphorylation of STAT3, resulting in granzyme production during Th2 cell differentiation. Genetic deletion of Usp7 or Gzma and pharmacological blockade of granzyme B ameliorated allergic airway inflammation. Furthermore, PAR-1+ and granzyme+ Th2 cells were colocalized in nasal polyps from patients with eosinophilic chronic rhinosinusitis. Thus, the USP7-STAT3-granzymes-Par-1 pathway is a potential therapeutic target for intractable allergic diseases.

Combined Pulmonary Fibrosis and Emphysema: A Narrative Review.

Combined pulmonary fibrosis and emphysema (CPFE) syndrome refers to co-occurrence of two disease processes in the lung that can be difficult to diagnose but is associated with high morbidity and mortality burden. Diagnosis of CPFE is challenging because the two diseases can counterbalance respective impairments resulting in deceivingly normal-appearing chest radiography and spirometry in a dyspneic patient. Although an international committee published the terminology and definitions of CPFE in 2022, consensus on exact diagnostic criteria and optimal management strategy is yet to be determined. Herein, we provide a narrative review summarizing the literature on CPFE from 1990 to 2022, including historical background, epidemiology, pathogenesis, clinical features, imaging and pulmonary function findings, diagnosis, prognosis, complications, and treatment. Although CPFE was initially conceived as a variant presentation of idiopathic pulmonary fibrosis, it has been recognized to occur in patients with a wide variety of interstitial lung diseases, including connective tissue disease-associated interstitial lung diseases, and hypersensitivity pneumonitis. The affected patients have a heightened risk for pulmonary hypertension and lung cancer. Clinicians need to recognize the characteristic presenting features of CPFE along with prognostic implications of this entity.

Histologic factors associated with nintedanib efficacy in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Histopathologic factors predictive of nintedanib efficacy in idiopathic pulmonary fibrosis have not been studied. We aimed to describe the characteristics, focusing on histopathology, of idiopathic pulmonary fibrosis patients who did and did not respond to nintedanib. METHODS: This study retrospectively examined the clinicoradiopathologic features of 40 consecutive patients with surgical lung biopsy-confirmed idiopathic pulmonary fibrosis treated with nintedanib. Additionally, we compared the histopathologic scoring of 21 microscopic features between patients with functional or radiological progression and those with non-progression during 12 months of treatment. RESULTS: The histopathologic evaluation showed edematous changes in the interlobular septum as the only histologic finding observed more frequently in patients with both functional and radiological progression than in those without (58% vs. 14%, P = 0.007 and 50% vs. 0%, P = 0.003, respectively). Regarding per-year change, patients with edematous changes in the interlobular septum showed greater progression in median changes in spared area (-12%, interquartile range: [-25%--5%], vs. -3% [-7%-0%], P = 0.004) and reticular shadow (7% [3%-13%], vs. 0% [0%-5%], P = 0.041) on computed tomography. Functional and radiological progression-free survival were shorter in patients with edematous changes in the interlobular septum than in those without (6.6 months, 95% confidence interval: [5.9-25.3], vs. event <50%, [12.1-Not available], P = 0.0009, and 6.1 months, [5.2-6.6] vs. 14.5 months [7.8-not available], P<0.0001). CONCLUSIONS: Edematous changes in the interlobular septum may indicate poor nintedanib efficacy in idiopathic pulmonary fibrosis. Further studies are needed to validate these findings and address the mechanism behind ECIS.

Prognostic value of chest computed tomography in community-acquired pneumonia patients.

BACKGROUND: Chest computed tomography (CT) is commonly used to diagnose pneumonia in Japan, but its usability in terms of prognostic predictability is not obvious. We modified CURB-65 (confusion, urea >7 mmol·L-1, respiratory rate ≥30 breaths·min-1, blood pressure <90 mmHg (systolic) ≤60 mmHg (diastolic), age ≥65 years) and A-DROP scores with CT information and evaluated their ability to predict mortality in community-acquired pneumonia patients. METHODS: This study was conducted using a prospective registry of the Adult Pneumonia Study Group - Japan. Of the 791 registry patients, 265 hospitalised patients with chest CT were evaluated. Chest CT-modified CURB-65 scores were developed with the first 30 study patients. The 30-day mortality predictability of CT-modified, chest radiography-modified and original CURB-65 scores were validated. RESULTS: In score development, infiltrates over four lobes and pleural effusion on CT added extra points to CURB-65 scores. The area under the curve for CT-modified CURB-65 scores was significantly higher than that of chest radiography-modified or original CURB-65 scores (both p<0.001). The optimal cut-off CT-modified CURB-65 score was ≥4 (positive-predictive value 80.8%; negative-predictive value 78.6%, for 30-day mortality). For sensitivity analyses, chest CT-modified A-DROP scores also demonstrated better prognostic value than did chest radiography-modified and original A-DROP scores. Poor physical status, chronic heart failure and multiple infiltration hampered chest radiography evaluation. CONCLUSION: Chest CT modification of CURB-65 or A-DROP scores improved the prognostic predictability relative to the unmodified scores. In particular, in patients with poor physical status or chronic heart failure, CT findings have a significant advantage. Therefore, CT can be used to enhance prognosis prediction.

Automated computed tomography quantification of fibrosis predicts prognosis in combined pulmonary fibrosis and emphysema in a real-world setting: a single-centre, retrospective study.

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is a heterogeneous clinico-radiological syndrome without a consensus definition. There are limited data on the relation between the amount of parenchymal fibrosis and prognosis. In this study, we assessed the prognostic implications of the extent of fibrosis assessed by an automated quantitative computed tomography (CT) technique and the radiological and functional change over time in patients with a broad spectrum of fibrotic interstitial lung diseases (ILDs) encountered in a real-world setting. METHODS: We conducted a single-centre, retrospective study of 228 consecutive patients with CPFE, encountered from 2007 to 2015 at Kameda Medical Center, Chiba, Japan. We investigated the prognostic value of automated CT fibrosis quantification and the subsequent course of CPFE. RESULTS: Among 228 patients with CPFE, 89 had fibrosis affecting < 5% of their lungs, 54 had 5 to < 10% fibrosis, and 85 had ≥ 10% fibrosis at the time of diagnosis. Lower volume of fibrosis correlated with lower rates of mortality and acute exacerbation (p < 0.001). In particular, among those with < 5% fibrosis, only 4.5% died and none experienced acute exacerbation during follow-up, whereas 57.6% and 29.4% of those with ≥ 10% fibrosis experienced death and acute exacerbation, respectively. Although, the ≥ 10% fibrosis group had the poorest overall survival as well as the highest incidence of acute exacerbation, the incidence of decline in pulmonary function tests, change per year in total lung volume, and progression of fibrosis on chest CT was highest in the 5 to < 10% fibrosis group. The Cox proportional hazard model for CPFE progression (defined by composite criteria of death, acute exacerbation, and decline in forced vital capacity or diffusing capacity) showed fibrosis proportion was a risk factor independent of age, sex, smoking pack-years, the Charlson Comorbidity Index, lung cancer, connective tissue disease, and idiopathic pulmonary fibrosis. CONCLUSIONS: Less severe (< 5%) fibrosis at baseline was associated with disease stability and better prognosis compared to more severe fibrosis in CPFE occurring with fibrotic ILDs. Further studies including a validation cohort will be needed. Trial Registration Retrospectively registered.

Hepatitis B Virus-associated Vasculitis: Multiple Cavitary Masses in the Lung Mimicking Granulomatous Polyangiitis.

Hepatitis B virus (HBV) is one of the main causes of polyarteritis nodosa (PAN). We herein report a rare case of HBV-associated vasculitis presenting with multiple pulmonary nodules, mimicking granulomatous polyangiitis (GPA), with no abnormalities of the ear, nose, or kidney. A surgical lung biopsy revealed geographic necrosis surrounded by palisading granuloma and capillaritis. Because the HBV surface antigen was positive with a serum HBV-DNA level of 2.9 log10 copies/mL, we first treated the patient with entecavir and 2 weeks of prednisone 50 mg/day. The pulmonary nodules resolved, and seroconversion was observed after one month.

Pembrolizumab-induced pneumonitis with a perilymphatic nodular pattern in a lung cancer patient: A radio-pathologic correlation.

A 66-year-old Japanese man with recurrent adenocarcinoma of the lung p-stage IIIA (pT2bN2M0; version 8) on pembrolizumab was present with gradually worsening dyspnea. Although history and physical examination were unremarkable, high-resolution CT showed the perilymphatic distribution of the pembrolizumab-induced pneumonitis. Consistent with the CT result, biopsy revealed the aggregation of the cytotoxic (CD8+) T-lymphocytes around the lymph tracts. Given the clinical, radiological and pathological findings, pembrolizumab-induced pneumonitis was confirmed. The patient was discharged after terminating the pembrolizumab with ameliorated symptoms. This report, in conjunction with existing literature, illustrates the wide variety of the pembrolizumab-induced pneumonitis and bolsters the current understanding of its pathophysiology.

Combined pulmonary fibrosis and emphysema with myeloperoxidase-antineutrophil cytoplasmic antibody positivity that resolved upon smoking cessation.

Myeloperoxidase antineutrophil cytoplasmic autoantibody (MPO-ANCA) is well-known as a serological marker for small-vessel vasculitis. However, when a smoker with interstitial lung disease (ILD) exhibits serum ANCA positivity without systemic vasculitis, diagnosis is a matter of debate; the relationship between smoking and ANCA is unknown. We report a case of combined pulmonary fibrosis and emphysema (CPFE) with elevated MPO-ANCA. Surgical lung biopsy showed emphysema and fibrotic interstitial pneumonia without vasculitis. The MPO-ANCA level decreased after smoking cessation, and no vasculitis or progression was observed during 3 years of follow-up. This suggested that smoking cessation was related to normalization of MPO-ANCA and corresponding disease activity.

Successful treatment with idarucizumab for diffuse alveolar hemorrhage induced by dabigatran etexilate: a case report.

We report the case of an 81-year-old man taking dabigatran etexilate (dabigatran) for chronic atrial fibrillation, who presented with acute-onset hemoptysis and hypoxia. Chest high-resolution computed tomography showed bilateral ground grass opacities. After admission, his respiratory failure progressed rapidly and bronchoalveolar lavage was performed immediately, which showed copious amounts of bloody fluid and hemosiderin-laden macrophages with Prussian blue staining. He was diagnosed as having diffuse alveolar hemorrhage (DAH). We therefore stopped dabigatran and initiated multimodality therapy including idarucizumab, which is a reversal agent for dabigatran. Clinical and radiological improvement was observed and he was discharged without any impairment. There has been no relapse of DAH since then. No abnormalities were detected on further investigation; finally, we concluded that his DAH was caused by dabigatran. This is the first known case of idarucizumab use for severe DAH caused by dabigatran. Our case suggested that dabigatran can cause life-threatening DAH; in such cases, administering idarucizumab could be an effective treatment option.

Immunogenicity of simultaneous versus sequential administration of a 23-valent pneumococcal polysaccharide vaccine and a quadrivalent influenza vaccine in older individuals: A randomized, open-label, non-inferiority trial.

It is unclear whether simultaneous administration of a 23-valent pneumococcal polysaccharide vaccine (PPSV23) and a quadrivalent influenza vaccine (QIV) produces immunogenicity in older individuals. This study tested the hypothesis that the pneumococcal antibody response elicited by simultaneous administration of PPSV23 and QIV in older individuals is not inferior to that elicited by sequential administration of PPSV23 and QIV. We performed a single-center, randomized, open-label, non-inferiority trial comprising 162 adults aged ≥65 years randomly assigned to either the simultaneous (simultaneous injections of PPSV23 and QIV) or sequential (control; PPSV23 injected 2 weeks after QIV vaccination) groups. Pneumococcal immunoglobulin G (IgG) titers of serotypes 23F, 3, 4, 6B, 14, and 19A were assessed. The primary endpoint was the serotype 23F response rate (a ≥2-fold increase in IgG concentrations 4-6 weeks after PPSV23 vaccination). With the non-inferiority margin set at 20% fewer patients, the response rate of serotype 23F in the simultaneous group (77.8%) was not inferior to that of the sequential group (77.6%; difference, 0.1%; 90% confidence interval, -10.8% to 11.1%). None of the pneumococcal IgG serotype titers were significantly different between the groups 4-6 weeks after vaccination. Simultaneous administration did not show a significant decrease in seroprotection odds ratios for H1N1, H3N2, or B/Phuket influenza strains other than B/Texas. Additionally, simultaneous administration did not increase adverse reactions. Hence, simultaneous administration of PPSV23 and QIV shows an acceptable immunogenicity that is comparable to sequential administration without an increase in adverse reactions. (This study was registered with ClinicalTrials.gov [NCT02592486]).

Pharmacological aspects of anticancer drug-induced emesis with emphasis on serotonin release and vagal nerve activity.

Cytotoxic drug-induced nausea and vomiting are the side effects most feared by cancer patients. Emesis is an instinctive defense reaction caused by the somatoautonomic nerve reflex, which is integrated in the medulla oblongata. Emesis caused by cytotoxic drugs such as cisplatin is associated with an increase in the concentration of 5-hydroxytryptamine (5-HT) in the intestine and the brainstem. It is proposed that cytotoxic drugs evoke 5-HT release from the enterochromaffin (EC) cells in the intestinal mucosa and that the released 5-HT stimulates the 5-HT receptors on the adjacent vagal afferent nerves. The depolarization of the vagal afferent nerves stimulates the vomiting center in the brainstem and eventually induces a vomiting reflex. 5-HT released from EC cells seems to mediate the cisplatin-induced emesis sensitive to 5-HT(3) receptor antagonists. The release of 5-HT from the EC cells, however, is regulated by polymodal mechanisms on autoreceptors or heteroreceptors. The precise role of 5-HT on the occurrence of vomiting has not been fully elucidated. The present review aims to describe the role of 5-HT in anticancer drug-induced emesis from the viewpoint of 5-HT release and afferent vagus nerve activity. Various methods for predicting emesis are also evaluated.

[Metabolism of 18F-FDG (2-fluoro-2-deoxy-D-glucose) in tumor cells].

Tumor cell components obtained at 5 min, 1 hr and 3 hr after 18F-FDG injections were analyzed by radio-TLC. Major metabolites were 18F-FDG-phosphate and 18F-FDM-phosphate. 18F-FDM and three unidentified compounds were found as minor metabolites. Time course of the composition of metabolites are as follows; 18F-FDG-phosphate was 88% at 5 min after injection, but decreased to 53% at 3 hr after. 18F-FDM-phosphate was increased to 38% at 3 hr after injection. In conclusion, 18F-FDG is promptly phosphorylated after transportation into cell, and then exists as 18F-FDG-phosphate or 18F-FDM-phosphate. These results support known FDG distribution and metabolism, and it is possible that we use the information accumulated until now employing FDG manufactured by commercial supply system.

[Uptake of FDG (2-fluoro-2-deoxy-D-glucose) as a tumor imaging agent into erythrocytes and accumulation of FDG in tumor cells].

Fluorine-18-2-fluoro-2-deoxy-D-glucose (18F-FDG) injectable was developed as a tumor imaging agent reflecting glucose metabolism. In membrane transportation studies, the uptake of 14C-FDG into erythrocytes decreased with an increase in glucose concentration, and Cytochalasin B, inhibitor of glucose transporter (GLUT), blocked the uptake about 75%. The results means FDG is transported into tumor cells mainly by GLUT as glucose analogues. 18F-FDG is recognized to be phosphorylated to 18F-FDG-6-phosphate with hexokinase. We found that FDG-6-phosphate was further isomerized to 18F-FDM-6-phosphate by phosphoglucose isomerase (PGI) in vitro. About 27% 18F-FDM-6-phosphate was generated at the reaction with 70 U PGI for 90 min. These results show that the 18F-FDG injectable manufactured by the commercial supply system has equivalent properties; membrane transportation characteristic and enzyme affinity, to FDG synthesized at each PET institution.