鈴木 拓児

BACKGROUND Although sotrovimab reduces the risk of hospitalization or death due to COVID-19, there have been few reports of its use in clinical practice. Particularly, information on the effectiveness of sotrovimab against the omicron variant of the virus is limited. We present 10 cases of COVID-19 treated with sotrovimab at our unit between December 2021 and February 2022. CASE REPORT The age of the patients ranged from 32 to 81 years (median: 40 years). The comorbidities included lung cancer, cardiovascular disease, chronic kidney disease requiring hemodialysis, and AIDS. Two of the patients were also organ recipients. Oxygen saturation (SpO2) was above 97% in all patients. None of the patients presented with pneumonia on admission. However, blood test results showed that all patients had risk factors for severe COVID-19 outcomes. The interval from symptom onset to sotrovimab administration and resolution ranged from 2 to 5 days (median: 2 days) and 2 to 15 days (median: 5 days), respectively. Only 1 patient developed pneumonia and was treated with remdesivir after sotrovimab administration. However, this patient did not require oxygen therapy. Although no moderate to severe adverse events were observed, a mild adverse event was observed in 1 patient. CONCLUSIONS Sotrovimab could be safe and effective in preventing progression of COVID-19 in patients with a variety of underlying diseases and who are at high risk of severe disease outcomes.

We herein report a case of pulmonary veno-occlusive disease (PVOD) induced by allo-hematopoietic stem cell transplantation (HSCT) in a 48-year-old man who was diagnosed with acute myeloid leukemia. Five months after transplantation, he developed dyspnea and was diagnosed with pulmonary hypertension based on right heart catheterization. Although he received treatment with pulmonary vasodilators, diuretics, and corticosteroids, his pulmonary artery pressure did not decrease, and his pulmonary edema worsened. Based on the clinical course, hypoxemia, diffusion impairment, and computed tomography findings, the patient was diagnosed with HSCT-related PVOD. Critical attention should be paid to dyspnea after HSCT for the early diagnosis of PVOD.

BACKGROUND: Coronavirus disease (COVID-19) has induced an urgent need to train medical students not only in infection prevention control but also in the treatment of infectious diseases, including COVID-19. This study evaluates the impact of simulated clinical practice with peer role-plays and a lecture on clinical education for COVID-19. METHODS: The sample for the study included 82 fourth- and fifth-year medical students undergoing clinical clerkship in respiratory medicine. They answered questionnaires and participated in semi-structured focus group interviews (FGIs) regarding the advantages of simulated clinical practice with peer role-plays and lectures on clinical education for COVID-19. RESULTS: A total of 75 students participated in the COVID-19 education program between January and November 2021. The responses to the questionnaire revealed that the satisfaction level of students with COVID-19 education was high. No significant change was found among students concerning fear of COVID-19 before and after the program. The degree of burden of handling information on COVID-19 reduced significantly, while the degree with respect to the use of personal protective equipment (PPE), including appropriate wearing and removing of PPE, and care of patients with confirmed COVID-19 while taking steps to prevent infection, exhibited a decreasing trend. Nine FGIs were conducted (n = 74). The advantages of simulated clinical practice were segregated into five categories (infection prevention control, educational methods, burden on healthcare providers, self-reflection, and fear of COVID-19); and that of the lecture were segregated into four categories (information literacy, knowledge of COVID-19, educational methods, and self-reflection). CONCLUSIONS: Simulated clinical practice with peer role-plays and the lecture pertaining to COVID-19 can prove to be efficient and safe methods for learning about COVID-19 infection and prevention control for medical students. They can reduce the burden of COVID-19 patients' care. Moreover, they can also provide an opportunity for self-reflection, realize the burden of medical care, and acquire relevant information.

BACKGROUND COVID-19 is treated using antiviral and immunosuppressive drugs. Therefore, patients treated for COVID-19 may have an increased risk of secondary infection and a masked inflammatory response. We present a case of a deep neck abscess caused by pyogenic sternoclavicular arthritis during treatment for COVID-19. CASE REPORT A 55-year-old man with COVID-19 was admitted to the hospital with hypoxemia. He was then treated with remdesivir, tocilizumab, and dexamethasone and was placed in the prone position. When his condition stabilized, pain in the left shoulder appeared. There was no fever or elevation in inflammation markers, and he was administered analgesics. However, the pain worsened and redness of the left neck appeared. Plain computed tomography (CT) showed swelling of the left neck muscles. Because cellulitis was suspected, he was treated with antibiotics, but his symptoms did not improve. Three days after the plain CT, contrast-enhanced CT showed sternoclavicular arthritis, deep neck abscess, and mediastinal abscess. Therefore, an emergency incisional drainage was performed under general anesthesia. Wound cleaning and drainage were continued after surgery, and after drainage tubes were removed, the patient was discharged on postoperative day 17. CONCLUSIONS Cervical infections after COVID-19 treatment have been reported in a few cases. Particularly, deep neck abscesses require more attention since they could be fatal if not treated immediately. If a secondary infection is suspected in a patient treated with immunosuppressive drugs for COVID-19, a thorough physical examination should be performed to avoid misdiagnosis.

71歳女性。2年以上持続し6ヵ月前より増悪傾向の湿性咳嗽あり、胸部単純X線で左下肺野浸潤影を指摘された。同時に血清CA19-9高値が判明したが、精査で明らかな消化器悪性腫瘍は認められなかった。慢性気管支炎に対して、14員環マクロライド系薬剤の抗炎症・免疫調整作用を念頭にエリスロマイシン(erythromycin:EM)内服治療が開始された。その結果、自覚症状および胸部画像所見の改善とともに血清CA19-9値が低下した。血清CA19-9値は、消化器悪性腫瘍マーカーとしての役割のみならず、気道炎症の程度を反映する炎症指標にもなりうることが示唆された。(著者抄録)

In pulmonary arterial hypertension (PAH), right ventricular failure is accompanied by metabolic alterations in cardiomyocytes, which may be due to mitochondrial dysfunction and decreased energy production. Chrysin (CH) is a phytochemical with pharmacological activity that is involved in the regulation of mitochondrial biogenesis. The present study investigated the role of CH in the right ventricle (RV) by analyzing the cardiac transcriptome and metabolome of a SU5416(a vascular endothelial growth factor receptor blocker, /hypoxia (Su/Hx) rat model of PAH. RNA‑sequencing of the RV transcriptome between Su/Hx, Su/Hx with CH (Su/Hx + CH) and control groups, extracellular matrix (ECM) organization and ECM‑receptor interaction‑associated genes were upregulated in the RV of Su/Hx but not Su/Hx + CH rats. Furthermore, expression of mitochondrial function‑, energy production‑, oxidative phosphorylation‑ and tricarboxylic acid (TCA) cycle‑associated genes was decreased in the RV of Su/Hx rats; this was reverse by CH. Metabolomic profiling analysis of Su/Hx and Su/Hx + CH rats showed no significant changes in glycolysis, TCA cycle, glutathione, NADH or NADPH. By contrast, in the RV of Su/Hx rats, decreased adenylate energy charge was partially reversed by CH administration, suggesting that CH was involved in the improvement of mitochondrial biogenesis. Reverse transcription‑quantitative PCR analysis revealed that expression of peroxisome proliferator‑activated receptor γ, a master regulator of fatty acid metabolism and mitochondrial biogenesis, was increased in the RV of Su/Hx + CH rats. CH ameliorated cardiac abnormality, including cardiac fibrosis, RV hypertrophy and PH. The present study suggested that CH altered patterns of gene expression and levels of mitochondrial metabolites in cardiomyocytes, thus improving RV dysfunction in a Su/Hx PAH rat model.

RATIONALE AND OBJECTIVES: Pulmonary endarterectomy (PEA) is one of the most effective treatments for chronic thromboembolic pulmonary hypertension (CTEPH). Right heart catheterization (RHC) is the gold standard assessment for pulmonary circulatory dynamics. However, computed tomography (CT) is less invasive than RHC and can elucidate some of the morphological changes caused by thromboembolism. We hypothesized that CT could facilitate the evaluation of heterogeneous pulmonary perfusion. This study investigated whether CT imaging features reflect the disease severity and changes in pulmonary circulatory dynamics in patients with CTEPH before and after PEA. MATERIALS AND METHODS: This retrospective study included 58 patients with CTEPH who underwent PEA. Pre-PEA and post-PEA CT images were assessed for heterogeneity using CT texture analysis (CTTA). The CT parameters were compared with the results of the RHC and other clinical indices and analyzed with receiver operating characteristic curves analysis for patients with and without residual pulmonary hypertension (PH) (post-PEA mean pulmonary artery pressure ≥ 25 mmHg). RESULTS: CT measurements reflecting heterogeneity were significantly correlated with mean pulmonary artery pressure. Kurtosis, skewness, and uniformity were significantly lower, and entropy was significantly higher in patients with residual PH than patients without residual PH. Area under the curve values of pre-PEA and post-PEA entropy between patients with and without residual PH were 0.71 (95% confidence interval 0.57-0.84) and 0.75 (0.63-0.88), respectively. CONCLUSION: Heterogeneity of lung density might reflect pulmonary circulatory dynamics, and CTTA for heterogeneity could be a less invasive technique for evaluation of changes in pulmonary circulatory dynamics in patients with CTEPH undergoing PEA.

BACKGROUND AND OBJECTIVE: Osimertinib as first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor (EGFR) mutations remains controversial. Sequential EGFR-tyrosine kinase inhibitor (TKI) might be superior to the first line osimertinib in patients at risk of developing acquired T790M mutations. METHODS: We enrolled consecutive patients with EGFR-mutated (deletion 19 or L858R) advanced NSCLC treated with first-line drugs and evaluated predictive markers using classification and regression tree (CART) for the detection of T790M mutations based on patient backgrounds prior to initial treatment. RESULTS: Patients without acquired T790M mutations had worse outcomes than those with T790M mutations (median OS: 798 days vs. not reached; HR: 2.70; P < 0.001). CART identified three distinct groups based on variables associated with acquired T790M mutations (age, CYF, WBC, liver metastasis, and LDH; AUROC: 0.77). Based on certain variables, CART identified three distinct groups in deletion 19 (albumin, LDH, bone metastasis, pleural effusion, and WBC; AUROC: 0.81) and two distinct groups in L858R (age, CEA, and ALP; AUROC: 0.80). The T790M detection frequencies after TKI resistance of afatinib and first-generation EGFR-TKIs were similar (35.3% vs. 37.4%, P = 0.933). Afatinib demonstrated longer PFS (398 vs. 279 days; HR: 0.67; P = 0.004) and OS (1053 vs. 956 days; HR: 0.68; P = 0.051) than first-generation EGFR-TKIs. CONCLUSION: Identification of patients at risk of acquiring T790M mutations after EGFR-TKI failure may aid in choice of first-line EGFR-TKI. Furthermore, afatinib may be the more effective 1st-line EGFR-TKI treatment for patients at risk of developing T790M as initial EGFR-TKI resistance.

Hereditary pulmonary alveolar proteinosis (hPAP) is a rare disorder caused by recessive mutations in GM-CSF receptor subunit a/b genes (CSF2RA/CSF2RB, respectively) characterized by impaired GM-CSF dependent surfactant clearance by alveolar macrophages (AMs) resulting in alveolar surfactant accumulation and hypoxemic respiratory failure. Because hPAP is caused by CSF2RA mutations in most patients, we created an animal model of hPAP caused by Csf2ra gene disruption (Csf2ra-/- mice) and evaluated the effects on AMs and lungs. Macrophages from Csf2ra-/- mice were unable to bind and clear GM-CSF, did not exhibit GM-CSF signaling, and had functional defects in phagocytosis, cholesterol clearance, and surfactant clearance. Csf2ra-/- mice developed a time-dependent, progressive lung disease similar to hPAP in children caused by CSF2RA mutations with respect to the clinical, physiological, histopathological, biochemical abnormalities, biomarkers of PAP lung disease, and clinical course. In contrast, Csf2ra+/- mice had functionally normal AMs and no lung disease. Pulmonary macrophage transplantation (PMT) without myeloablation resulted in long-term engraftment, restoration of GM-CSF responsiveness to AMs, and a safe and durable treatment effect that lasted for the duration of the experiment (6 months). Results show that homozygous (but not heterozygous) Csf2ra gene ablation caused hPAP identical to that in children with CSF2RA mutations, identified AMs as the cellular site of hPAP pathogenesis in Csf2ra-/- mice, and have implications for preclinical studies supporting the translation of PMT as therapy of hPAP in humans.

千葉大学医学部附属病院呼吸器内科での医師臨床研修における取り組みの効果を検証した。2020年度より指導者間で研修医面談によるニーズ評価と日々の研修内容の情報共有を行い、研修の調整を行った。研修満足度や研修内容に関してアンケートで2019年度と比較した。2019年度と比較し研修満足度が有意に高くなり、経験できた項目や疾患が増加した。呼吸器内科への興味も有意に高かった。指導者間の学習者ニーズ評価、研修内容の情報共有は研修医の満足度を向上させ、研修の充実につながる。(著者抄録)

Pneumocystis pneumonia (PCP) typically occurs in immunocompromised individuals and rarely presents in immunocompetent individuals. A 55-year-old man was referred to our hospital with cough and anorexia that persisted for 2 months. Chest computed tomography revealed bilateral central consolidation. He was diagnosed with PCP via bronchoscopy. His symptoms and imaging findings improved with the administration of only trimethoprim and sulfamethoxazole. Although he had non-alcoholic fatty liver disease, there were no other complications that could potentially cause immunodeficiency. It should be noted that PCP in immunocompetent individuals can have a subacute disease course presenting with bilateral central consolidation.

千葉大学医学部附属病院呼吸器内科での医師臨床研修における取り組みの効果を検証した。2020年度より指導者間で研修医面談によるニーズ評価と日々の研修内容の情報共有を行い、研修の調整を行った。研修満足度や研修内容に関してアンケートで2019年度と比較した。2019年度と比較し研修満足度が有意に高くなり、経験できた項目や疾患が増加した。呼吸器内科への興味も有意に高かった。指導者間の学習者ニーズ評価、研修内容の情報共有は研修医の満足度を向上させ、研修の充実につながる。(著者抄録)

Primary racemose hemangioma of the bronchial artery (RHBA) is one of the causes of massive hemoptysis. A 72-year-old woman was admitted to our hospital with recurrent hemoptysis. Bronchoscopy showed an endobronchial lesion, and the angiography of the right bronchial arteries indicated RHBA. Bronchial arterial embolization (BAE) was performed to prevent hemoptysis. Although the endobronchial lesion shrank after the first BAE, the lesion re-increased and caused massive hemoptysis. A thoracoscopic right upper lobectomy was performed, and hemoptysis did not recur. Therefore, in cases of RHBA where there is recurrent hemoptysis and the endobronchial lesions that remain after BAE, additional treatments should be considered.

We report the case of a 29-year-old man who underwent umbilical cord blood transplantation for chronic myelogenous leukemia 14 years previously. He was diagnosed with secondary pleuroparenchymal fibroelastosis (sPPFE) following treatment for hematologic malignancies (sPPFE after HM-Tx) 2.5 years ago. On computed tomography, pleural thickening in the upper lobe, lung volume loss, and recurrent bilateral pneumothorax were detected. Although he waited for cadaveric lung transplantation (LTx) for 1.5 years, his respiratory failure worsened, and he died. Pathological autopsy and clinical course indicated sPPFE. After diagnosing sPPFE after HM-Tx, the timing for deciding LTx is critical, especially when pneumothorax recurs.

Background/Aim: Nab-paclitaxel (Nab-PTX) has been widely used to treat several advanced cancers. Nab-PTX can cause drug-induced lung injury (DILI); however, its clinical and radiographic features have not been clarified. We aimed to assess the clinical characteristics of Nab-PTX-induced lung injury and identify its associated risk factors. Patients and Methods: We retrospectively investigated 304 patients who received Nab-PTX at Chiba University Hospital between November 2010 and November 2017. We obtained information regarding the clinical course, laboratory findings, and chest computed tomography findings from their medical records. Results: Forty-one patients (13%) developed DILI. Grade 1 lung injury occurred in 27 patients (8.8%), grade 2, 8 patients (2.6%); grade 3, 3 patients (0.9%); grade 4, 1 (0.3%); and grade 5, 2 (0.6%). Multivariate analysis revealed that age >56 years (odds ratio [OR]: 3.0), pre-existing interstitial lung changes (OR: 3.2), and combined drugs with gemcitabine (OR: 2.7) were independent risk factors for DILI owing to Nab-PTX administration. Conclusion: Nab-PTX-induced lung injury is not rare; however, most cases are asymptomatic (grade 1). Older age, pre-existing interstitial lung changes, and combined drugs with gemcitabine could increase the incidence of Nab-PTX-induced lung injury; such patients should be treated with greater care.

Background: Sarcoidosis is a granulomatous systemic disease of unknown etiology. Mononuclear cells such as macrophages or lymphocytes in lung tissue and hilar or mediastinal lymph nodes have been recognized to play an essential role in granuloma formation in pulmonary sarcoidosis. Peripheral blood mononuclear cells (PBMCs) consist of several immunocompetent cells and have been shown to play a mechanistic role in the pathogenesis of sarcoidosis. However, the genetic modifications that occur in bulk PBMCs of sarcoidosis remain to be elucidated. Purpose: This study aimed to explore the pathobiological markers of sarcoidosis in PBMCs by comparing the transcriptional signature of PBMCs from patients with pulmonary sarcoidosis with those of healthy controls by RNA sequencing. Methods: PBMC samples were collected from subjects with pulmonary sarcoidosis with no steroid/immunosuppressant drugs (n = 8) and healthy controls (n = 11) from August 2020 to April 2021, and RNA sequencing was performed with the PBMC samples. Results: Principal component analysis using RNA sequencing datasets comparing pulmonary sarcoidosis with healthy controls revealed that the two groups appeared to be differentiated, in which 270 differentially expressed genes were found in PBMCs between sarcoidosis and healthy controls. Enrichment analysis for gene ontology suggested that some biological processes related to the pathobiology of sarcoidosis, such as cellular response to interleukin (IL)-1 and IFN-γ, regulation of IL-6 production, IL-8 secretion, regulation of mononuclear cell migration, and response to lipopolysaccharide, were involved. Enrichment analysis of the KEGG pathway indicated the involvement of tumor necrosis factor (TNF), toll-like receptor signaling, IL-17 signaling pathways, phagosomes, and ribosomes. Most of the genes involved in TNF and IL-17 signaling pathways and phagosomes were upregulated, while most of the ribosome-related genes were downregulated. Conclusion: The present study demonstrated that bulk gene expression patterns in PBMCs were different between patients with pulmonary sarcoidosis and healthy controls. The changes in the gene expression pattern of PBMCs could reflect the existence of sarcoidosis lesions and influence granuloma formation in sarcoidosis. These new findings are important to strengthen our understanding of the etiology and pathobiology of sarcoidosis and indicate a potential therapeutic target for sarcoidosis.

Excessive inflammation in the lung is a primary cause of acute respiratory distress syndrome (ARDS). CD26/dipeptidyl peptidase-4 (DPP4) is a transmembrane protein that is expressed in various cell types and exerts multiple pleiotropic effects. We recently reported that pharmacological CD26/DPP4 inhibition ameliorated lipopolysaccharide (LPS)-induced lung injury in mice and exerted anti-inflammatory effects on human lung microvascular endothelial cells (HLMVECs), in vitro. However, the mechanistic roles of CD26/DPP4 in lung injury and its effects on HLMVECs remain unclear. In this study, transcriptome analysis, followed by various confirmation experiments using siRNA in cultured HLMVECs, are performed to evaluate the role of CD26/DPP4 in response to the pro-inflammatory involved in inflammation, barrier function, and regenerative processes in HLMVECs after pro-inflammatory stimulation. These are all functions that are closely related to the pathophysiology and repair process of lung injury. Confirmatory experiments using flow cytometry; enzyme-linked immunosorbent assay; quantitative polymerase chain reaction; dextran permeability assay; WST-8 assay; wound healing assay; and tube formation assay, reveal that the reduction of CD26/DPP4 via siRNA is associated with altered parameters of inflammation, barrier function, and the regenerative processes in HLMVECs. Thus, CD26/DPP4 can play a pathological role in mediating injury in pulmonary endothelial cells. CD26/DPP4 inhibition can be a new therapeutic strategy for inflammatory lung diseases, involving pulmonary vascular damage.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension caused by persistent thromboembolism of the pulmonary arteries. In clinical practice, CTEPH patients often show obstructive ventilatory impairment, even in the absence of a smoking history. Recent reports imply a tendency for CTEPH patients to have a lower FEV1.0; however, the mechanism underlying obstructive impairment remains unknown. METHODS: We retrospectively analyzed CTEPH patients who underwent a pulmonary function test and respiratory impedance test to evaluate their exertional dyspnea during admission for right heart catheterization from January 2000 to December 2019. We excluded patients with a smoking history to rule out the effect of smoking on obstructive impairment. RESULTS: A total of 135 CTEPH patients were analyzed. The median FEV1.0/FVC was 76.0%, %FEV 1.0 had a negative correlation with the mean pulmonary artery pressure and pulmonary vascular resistance and the CT Angiogram (CTA) obstruction score. A multivariate regression analysis revealed that the CTA obstruction score was an independent factor of a lower %FEV1.0. In the 54 patients who underwent pulmonary endarterectomy, %FEV1.0 was improved in some cases and was not in some. Mean PAP largely decreased after PEA in the better %FEV1.0 improved cases, suggesting that vascular involvement in CTEPH could be associated with spirometry obstructive impairment. CONCLUSION: %FEV1.0 had a significant correlation with the CTA obstruction score. Obstructive impairment might have an etiological relationship with vascular involvement. Further investigations could shed new light on the etiology of CTEPH.

BACKGROUND: Bronchoscopy is a minimally invasive procedure for establishing the diagnosis of lung cancer. It sometimes fails to obtain tissue samples but readily collects cytological samples. METHODS: We developed PNA-LNA dual-PCR (PLDP), which amplified mutant sequences by a high-fidelity DNA polymerase in the presence of a peptide nucleic acid (PNA) oligomer having a wild-type sequence. Mutations are detected either by locked nucleic acid (LNA) probes for quick detection of a limited number of mutations, which are EGFR, KRAS, and BRAF mutations in the current study, or by direct sequencing for a comprehensive screening. In a total of 233 lung cancer samples, the results for cytological samples by PLDP were compared with those for tissue samples by cobas® EGFR mutation test (cobas) or by the PNA-LNA PCR clamp method (P-LPC). Moreover, the performance of PLDP using cell-free DNA (cfDNA) was investigated. RESULTS: Peptide nucleic acid-LNA dual-PCR was able to detect each synthesized mutant sequence with high sensitivity. PLDP detected EGFR mutations in 80 out of 149 clinical samples, while the cobas or the P-LPC detected in 66 matched. The correctness of PLDP was confirmed both by clinical response and by the results of sequencing using a next-generation sequencer. PLDP detected mutations from cfDNA in approximately 70% of patients who harbors mutations in the tumor. CONCLUSIONS: Peptide nucleic acid-LNA dual-PCR exhibited an excellent performance, even using cytological samples. PLDP is applicable for the investigation of cfDNA. The combination of bronchoscopy and PLDP is attractive and will expand the utility of bronchoscopy in clinical practice.

BACKGROUND Although bronchial arteries are the most common cause of hemoptysis, other systemic arteries can cause hemoptysis and are potential pitfalls for successful embolization. CASE REPORT We present 6 cases of hemoptysis showing vascularization from systemic arteries other than bronchial arteries that presented to our department between 2013 and 2020. Chronic inflammatory diseases such as tuberculosis and pulmonary aspergillosis were the underlying diseases in 4 of the 6 cases. In all 6 cases, the lesions were close to the pleura. The abnormal non-bronchial systemic arteries were the internal thoracic artery in 4 cases, intercostal artery in 2 cases, lateral thoracic artery in 2 cases, and the subclavian, thyrocervical, and inferior phrenic arteries in 1 case each, all of which formed a shunt with the pulmonary artery. Additionally, depending on the location of the lesion, the non-bronchial systemic arteries near the lesion proliferated into the lung parenchyma through the adherent pleura. CONCLUSIONS When lesions are in contact with the pleura, various non-bronchial systemic arteries near the lesion can develop in the pulmonary parenchyma via the adherent pleura, which can cause hemoptysis. In patients with hemoptysis, it may be useful to evaluate chest contrast-enhanced computed tomography and angiography, while always accounting for the potential involvement of non-bronchial systemic arteries to ensure a safer and more reliable treatment.

Pulmonary hypertension (PH) is a life-threatening disorder, which originates from various aetiologies. Ventilation-perfusion (V/Q) scanning is commonly used to evaluate the differential diagnosis of PH. Meanwhile, previous studies have shown that single-photon emission computed tomography (SPECT)/CT imaging can provide a more detailed analysis for the assessment of pulmonary blood flow. However, there is insufficient evidence supporting the merits of V/Q SPECT/CT image data in detecting pulmonary vascular disease. Here, we report a case of pulmonary arterial hypertension with localized accumulation and peculiar distribution just below the pleura on V/Q SPECT/CT. Our finding is unique, and it suggests that V/Q SPECT/CT image data might be useful to detect blood flow not only in cases of pulmonary embolism, but also in the more commonly encountered PH.

We herein report the long-term changes in chest computed tomography (CT) findings from early sarcoidosis lesions to pleuroparenchymal fibroelastosis (PPFE)-like lesions in a 30-year-old man with granulomas on a transbronchial lung biopsy. Multiple bilateral micronodular and nodular opacities around the bronchovascular bundle in the upper lobes detected by chest CT in 2004 disappeared, but paradoxically, peripheral consolidations continued to grow at the periphery of the original lesions. Chest CT in 2017 confirmed the progression of bilateral shrinkage of the upper lobe, spread of peripheral consolidations and wedge-shaped opacities below the first rib, and bronchiectatic air bronchograms, confirming PPFE-like lesions.

Objective: Pulmonary mycobacterium avium complex (MAC) disease is increasing significantly worldwide. Several studies have investigated the clinical features of pulmonary MAC disease in the setting of cancer. Here, we aimed to clarify the clinical characteristics of patients with cancer with recent onset of pulmonary MAC disease and the effect of cancer on the onset of this disease. Patients and Methods: Of the 323 consecutive Japanese patients newly diagnosed with pulmonary MAC disease at Jichi Medical University Hospital between and 2006-2017, we retrospectively reviewed 79 consecutive patients with cancer. Results: Seventeen patients had lung cancer (21.0%), while 62 had non-lung cancer. Of the 17 patients with lung cancer, 16 had adenocarcinoma of which 10 had stage I to III disease; 8 of the 10 patients had not received chemotherapy. Sixteen patients with lung cancer had a MAC infection in the ipsilateral lung. Notably, 9 of the 11 lung cancer patients who did not undergo surgery had a MAC infection in the affected lobe. Of the 39 patients with the most common types of non-lung cancer (14 had gastric cancer, 13 had colorectal cancer, and 12 had breast cancer), 22 had stage I to III disease, and 18 of these 22 had not received chemotherapy. Conclusion: Lung cancer may act as a local factor contributing to the onset of pulmonary MAC disease in the ipsilateral lung. However, the underlying mechanism by which a history of cancer might affect the onset of pulmonary MAC disease remains unclear. Further investigation into this mechanism is needed.

Objective: Histological verification of epithelioid cell granuloma is important in diagnosing sarcoidosis; tissue sampling is a worldwide requirement. In 2006, to reduce medical expenses and avoid invasive procedures, diagnostic criteria without histological verification were permitted by the Japanese government. In 2015, new diagnostic criteria, allowed clinical diagnoses based on only respiratory, ocular, and cardiac systems with at least a two-system involvement, increasing the need to sample tissue from clinically unevaluable organs in suspected sarcoidosis. This study aimed to compare the characteristics of patients who were diagnosed with sarcoidosis according to the 2006 and 2015 criteria. Materials and Methods: Using the 2015 version, we re-evaluated the characteristics of 264 patients with diagnosed or suspected sarcoidosis according to the 2006 criteria, at Jichi Medical University Hospital between 2004 and 2012 (clinical diagnosis, 84; histological diagnosis, 117; suspected sarcoidosis 63). Results: Thirty-nine patients were diagnosed with suspected sarcoidosis due to the absence of at least a two-system involvement; two patients had insufficient laboratory data suggestive of sarcoidosis. Six patients moved from suspected sarcoidosis to a histological diagnosis because of a greater leniency in the criteria for supportive findings. The 2015 diagnostic criteria excluded patients with organ involvement without a requirement for systemic steroids from the clinical diagnosis group. A case of schwannoma, erroneously placed in the clinical diagnosis group by the 2006 criteria, was reclassified according to the 2015 criteria. Conclusion: The 2015 version is preferable for clinically diagnosing sarcoidosis, even without histological specimens, and provides guidance for indications for systemic treatment.

A 46-year-old woman with uveitis was referred to our respiratory diseases department in July 2018. Her medical history included transient bilateral hilar mediastinal lymphadenopathy (BHL) and multiple pulmonary nodules in May 2013 during pegylated interferon-alpha and ribavirin treatment for chronic hepatitis C infection. Five years post-treatment, chest X-ray revealed BHL and nodular recurrence. A biopsy of the subcutaneous buttock nodules revealed scattered non-caseating epithelioid granulomas with positive PAB immunohistochemical staining. This seem to be the first report of Propionibacterium acnes-associated sarcoidosis possibly initially triggered by interferon-alpha therapy. Understanding the mechanisms underlying interferon-triggered P. acnes-associated sarcoidosis may clarify the sarcoidosis immunopathogenesis.

Herein, we present the case of a 63-year-old man with autoimmune pulmonary alveolar proteinosis (APAP) complicated by Mycobacterium avium complex (MAC) infection. APAP was diagnosed based on serum anti-granulocyte-macrophage colony-stimulating factor antibody, bronchoalveolar lavage fluid (BALF) findings, and transbronchial lung biopsy. Nodular shadows with cavities were visible on chest CT images, and Mycobacterium intracellulare was identified by BALF culture. Rifampicin, ethambutol, and clarithromycin were administered, and 4 months later, the nodular shadows of MAC had disappeared, and APAP was remarkably improved. Thus, in cases of APAP exacerbation complicated with infections, such as MAC, control of the infections may improve APAP.

INTRODUCTION: Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. Although most patients with COVID-19 develop asymptomatic or mild disease, some patients develop severe disease. The effectiveness of various therapeutic agents, including antiviral drugs, steroids, and anti-inflammatories for COVID-19, have been being confirmed. The effect of administering steroids in early disease is unclear. This study therefore aimed to evaluate the effectiveness and risk of exacerbation of steroids administered preceding antiviral drugs in patients with COVID-19 pneumonia. METHODS: This retrospective, single-center, observational study included consecutive patients with COVID-19 between March 2020 and March 2021. Patients were divided into a steroids-first group and antiviral-drugs-first group. Mortality, duration of hospitalization, incidence rate and duration of intensive care unit (ICU) admission, intubation, and extracorporeal membrane oxygenation (ECMO) induction of the two groups were compared. RESULTS: A total of 258 patients were admitted during the study period. After excluding patients who received symptomatic treatment only, who were taking immunosuppressive drugs, or who were administered antiviral drugs only, 68 patients were included in the analysis, 16 in the steroids-first group and 52 in the antiviral-drugs-first group. The rate of intubation, ICU admission and ECMO induction were significantly higher in the steroids-first group than in the antiviral-drugs-first group (81.3% vs. 33.3, p<0.001, 75.0% vs. 29.4%, p = 0.001, and 31.3% vs. 7.8%, p = 0.017, respectively). Furthermore, patients who received steroids within ten days after starting antiviral drugs had significantly lower rates of ICU admission, intubation, and ECMO induction. (81.3% vs. 42.9% p = 0.011, 75.0% vs. 37.1% p = 0.012, and 31.3% vs. 8.6% p = 0.039, respectively). CONCLUSIONS: Administering steroids prior to antiviral drugs soon after symptom onset can aggravate disease severity. When administration of steroids is considered soon after symptom onset, it may be safer to initiate antiviral drugs first.

Intestinal ischemia/reperfusion (I/R) injury is a life-threatening complication that leads to inflammation and remote organ damage. The NLRP3 inflammasome regulates the caspase-1-dependent release of IL-1β, an early mediator of inflammation after I/R injury. In this study, we investigated the role of the NLRP3 inflammasome in mice with intestinal I/R injury. Deficiency of NLRP3, ASC, caspase-1/11, or IL-1β prolonged survival after intestinal I/R injury, but neither NLRP3 nor caspase-1/11 deficiency affected intestinal inflammation. Intestinal I/R injury caused acute lung injury (ALI) characterized by inflammation, reactive oxygen species generation, and vascular permeability, which was markedly improved by NLRP3 deficiency. Bone marrow chimeric experiments showed that NLRP3 in non-bone marrow-derived cells was the main contributor to development of intestinal I/R-induced ALI. The NLRP3 inflammasome in lung vascular endothelial cells is thought to be important to lung vascular permeability. Using mass spectrometry, we identified intestinal I/R-derived lipid mediators that enhanced NLRP3 inflammasome activation in lung vascular endothelial cells. Finally, we confirmed that serum levels of these lipid mediators were elevated in patients with intestinal ischemia. To our knowledge, these findings provide new insights into the mechanism underlying intestinal I/R-induced ALI and suggest that endothelial NLRP3 inflammasome-driven IL-1β is a novel potential target for treating and preventing this disorder.

Hereditary pulmonary alveolar proteinosis due to GM-CSF receptor deficiency (herPAP) constitutes a life-threatening lung disease characterized by alveolar deposition of surfactant protein secondary to defective alveolar macrophage function. As current therapeutic options are primarily symptomatic, we have explored the potential of hematopoietic stem cell-based gene therapy. Using Csf2rb-/- mice, a model closely reflecting the human herPAP disease phenotype, we here demonstrate robust pulmonary engraftment of an alveolar macrophage population following intravenous transplantation of lentivirally corrected hematopoietic stem and progenitor cells. Engraftment was associated with marked improvement of critical herPAP disease parameters, including bronchoalveolar fluid protein, cholesterol and cytokine levels, pulmonary density on computed tomography scans, pulmonary deposition of Periodic Acid-Schiff+ material as well as respiratory mechanics. These effects were stable for at least nine months. With respect to engraftment and alveolar macrophage differentiation kinetics, we demonstrate the rapid development of CD11c+/SiglecF+ cells in the lungs from a CD11c-/SiglecF+ progenitor population within four weeks after transplantation. Based on these data, we suggest hematopoietic stem cell-based gene therapy as an effective and cause-directed treatment approach for herPAP.

BACKGROUND: The presence of histologically evident epithelioid granuloma is required for the diagnosis of sarcoidosis worldwide. The Japan Society of Sarcoidosis and Other Granulomatous Disorders 2015 diagnostic criteria (JSSOG 2015 criteria) includes "clinically proven diagnosis" (involvement of at least 2 of 3 systems confirmed solely by clinical assessment) because of the frequency of sarcoidosis with ocular, cardiac, and respiratory involvement in Japan and the difficulty of obtaining specimens. Here, we describe in detail the clinical presentation of clinically diagnosed sarcoidosis. METHODS: We enrolled 68 consecutive patients with clinically diagnosed sarcoidosis (12 men, 56 women) based on the JSSOG 2015 criteria who were treated at Jichi Medical University between December 2018 and January 2000. We analyzed age at diagnosis, organ involvement, and laboratory findings. RESULTS: Age at diagnosis was unimodal in women. Ocular, splenic, cardiac, and skin involvement, and hypercalcemia were observed in 95.6%, 8.8%, 7.4%, 5.9%, and 35.0% of patients, respectively. High serum lysozyme and soluble interleukin-2 receptor (sIL-2R) levels, bilateral hilar lymphadenopathy on chest radiography, high-grade atrioventricular block or fatal ventricular arrhythmia, and bundle branch block were found in 18.8%, 48.3%, 95.6%, 5.0%, and 10.0% of patients, respectively. CONCLUSIONS: The age-specific distribution of clinically diagnosed sarcoidosis was similar to histologically diagnosed sarcoidosis in women, as previously reported. Rates of elevated serum lysozyme and sIL-2R levels were lower in this study than previously reported in histologically diagnosed patients in Japan.

Background and Aims: Cancer cells can be isolated from malignant pleural effusion (MPE). They may provide an experimental system to explore the cell biology of lung cancer. Anti-VEGF antibody has been reported to efficiently control MPE, which contains a high concentration of VEGF this suggests the important role of VEGF acting on MPE. We aimed to develop a method for culturing cancer cells from MPE and investigate the role of VEGF in MPE. Methods: Cancer cells in MPE were obtained from six patients and cultured using three different types of media, includ-ing (1) supernatant of MPE, (2) 1:1 mixture of supernatant and common culture medium, and (3) common culture medium only. We further co-cultured cancer cells with γ-irradiated mouse 3T3-J2 embryonic fibroblasts. Using co-cultured cells, we investigated the effect of VEGF on cancer cells and measured the amount of VEGF secreted from them. Results: Cancer cells were poorly maintained in three types of media, while well proliferated when co-cultured with 3T3-J2 feeder cells. VEGF didn’t affect cell proliferation. VEGF secreted from cancer cells didn’t reach to a concentration that may show an apparent biological effect. Conclusion: Proliferation of cancer cells in MPE requires a specific factor(s) in addition to those residing in the supernatant of MPE or conventional culture medium. Co-cultured cancer cells suggested a lack of proliferative effect of VEGF. The concentration of VEGF produced by cancer cells was not sufficient to exert a biological effect. Co-cultured cancer cells may provide a valuable experimental system for further cancer studies.

Desquamative interstitial pneumonia (DIP) is a rare, smoking-related, diffuse parenchymal lung disease characterized by marked accumulation of alveolar macrophages (AMs) and emphysema, without extensive fibrosis or neutrophilic inflammation. Because smoking increases expression of pulmonary GM-CSF (granulocyte/macrophage-colony stimulating factor) and GM-CSF stimulates proliferation and activation of AMs, we hypothesized that chronic exposure of mice to increased pulmonary GM-CSF may recapitulate DIP. Wild-type (WT) mice were subjected to inhaled cigarette smoke exposure for 16 months, and AM numbers and pulmonary GM-CSF mRNA levels were measured. After demonstrating that smoke inhalation increased pulmonary GM-CSF in WT mice, transgenic mice overexpressing pulmonary GM-CSF (SPC-GM-CSF+/+) were used to determine the effects of chronic exposure to increased pulmonary GM-CSF (without smoke inhalation) on accumulation and activation of AMs, pulmonary matrix metalloproteinase (MMP) expression and activity, lung histopathology, development of polycythemia, and survival. In WT mice, smoke exposure markedly increased pulmonary GM-CSF and AM accumulation. In unexposed SPC-GM-CSF+/+ mice, AMs were spontaneously activated as shown by phosphorylation of STAT5 (signal inducer and activator of transcription 5) and accumulated progressively with involvement of 84% (interquartile range, 55-90%) of the lung parenchyma by 10 months of age. Histopathologic features also included scattered multinucleated giant cells, alveolar epithelial cell hyperplasia, and mild alveolar wall thickening. SPC-GM-CSF+/+ mice had increased pulmonary MMP-9 and MMP-12 levels, spontaneously developed emphysema and secondary polycythemia, and had increased mortality compared with WT mice. Results show cigarette smoke increased pulmonary GM-CSF and AM proliferation, and chronically increased pulmonary GM-CSF recapitulated the cardinal features of DIP, including AM accumulation, emphysema, secondary polycythemia, and increased mortality in mice. These observations suggest pulmonary GM-CSF may be involved in the pathogenesis of DIP.

A 65-year-old woman had a ground glass nodule, which was suspicious for lung cancer, in her right lung S6 by chest computed tomography. For diagnosis, video-assisted thoracoscopic surgery was performed, and the specimen showed a pathological pattern of lymphocytic interstitial pneumonia (LIP). Four years after surgery, new localized ground glass shadows gradually increased on the base of the lung. However, because she had no respiratory symptoms and had normal respiratory function, she was observed with no medication. Subsequently, no other underlying diseases associated with LIP developed. The ground glass nodule was the initial lesion of LIP.

Hereditary pulmonary alveolar proteinosis (PAP) is a genetic lung disease characterized by surfactant accumulation and respiratory failure arising from disruption of GM-CSF signaling. While mutations in either CSF2RA or CSF2RB (encoding GM-CSF receptor α or β chains, respectively) can cause PAP, α chain mutations are responsible in most patients. Pulmonary macrophage transplantation (PMT) is a promising new cell therapy in development; however, no studies have evaluated this approach for hereditary PAP (hPAP) caused by Csf2ra mutations. Here, we report on the preclinical safety, tolerability, and efficacy of lentiviral-vector (LV)-mediated Csf2ra expression in macrophages and PMT of gene-corrected macrophages (gene-PMT therapy) in Csf2ra gene-ablated (Csf2ra-/-) mice. Gene-PMT therapy resulted in a stable transgene integration and correction of GM-CSF signaling and functions in Csf2ra-/- macrophages in vitro and in vivo and resulted in engraftment and long-term persistence of gene-corrected macrophages in alveoli; restoration of pulmonary surfactant homeostasis; correction of PAP-specific cytologic, histologic, and biomarker abnormalities; and reduced inflammation associated with disease progression in untreated mice. No adverse consequences of gene-PMT therapy in Csf2ra-/- mice were observed. Results demonstrate that gene-PMT therapy of hPAP in Csf2ra-/- mice was highly efficacious, durable, safe, and well tolerated.