PURPOSE:Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs. METHODS:We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs. RESULTS:Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor. CONCLUSION:Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.

The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection–triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1–expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)–containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.

Introduction: The quantification of right-to-left shunts (RLSs) in patients with a pulmonary arteriovenous malformation (PAVM) is important with respect to diagnosis and follow-up evaluations. Recently, RLSs are measured by lung perfusion scintigraphy (LPS). Coil embolization is recommended for first-line treatment of PAVMs, during which arterial and mixed venous blood sampling is readily available. Therefore, RLSs can be calculated by means of the Fick principle. Aims: The aim of this study was to determine the association between arterial and mixed venous blood gas analysis, RLSs calculated using the Fick principle, and RLSs measured by LPS. Methods: Fifty-six patients (mean age, 50.9 ± 20.9 y; 12 males) with proven PAVMs underwent LPS for measurement of the RLS fraction and arterial and mixed venous blood gas analysis prior to PAVM coil embolization from 2016-2020. The relationships between the RLS fraction by LPS, the RLS fraction calculated using the Fick principle ([98-SaO2]/[98-SvO2]), the alveolar-arterial oxygen difference (A-aDO2), and the arterial and mixed venous blood gas analysis were evaluated. Results: The RLS fraction as determined by LPS and the Fick principle were 9.48±3.14% and 14.38±8.09%, respectively. The A-aDO2 was 22.70±11.03mmHg. No correlation existed between the RLS fraction based on LPS and the Fick principle (r=0.184, P=0.178). In contrast, the A-aDO2, PaO2, and PaCO2 had a significant correlation between the RLS fraction measured by LPS (r=0.521 and P<0.0001, r=-0.264 and P=0.049, and r=-0.488 and P=0.0001, respectively). Conclusions: The A-aDO2 and PaCO2 can be substituted for the measurement of the RLS fraction by LPS.

Hepatopulmonary syndrome (HPS) and pulmonary arteriovenous malformation (PAVM) are hypoxemic diseases caused by right-to-left shunting but are rarely concomitant with pulmonary hypertension (PH). A 66-year-old woman with chronic hepatitis C was scheduled to undergo liver transplantation. She was referred to our department for hypoxia and an abnormal shadow in the right lung found on a preoperative examination. She was diagnosed with HPS and a PAVM in the right middle lobe. After liver transplantation, PH temporarily developed, but the pulmonary arterial pressure normalized after coil embolization. Combined HPS and PAVM may cause unique changes in pulmonary hemodynamics during treatment.

Backgroud: Multi-detector computed tomography (MDCT) can detect the loss of lung tissue associated with emphysema as a low-attenuation area (LAA) and the thickness of airways as the wall area percentage (WA%). The percentage of small pulmonary vessels less than 5 mm2 (%CSA<5) has been recently recognized as a parameter for expressing pulmonary perfusion. Objective: We aimed to analyze the longitudinal changes in structural abnormalities using CT parameters and analyze the effect of exacerbation and smoking cessation on structural changes in COPD patients. Methods: We performed pulmonary function tests, MDCT in 58 patients with COPD at the time of their enrollment and two years later. We analyzed the change in clinical parameters and examined the effect of exacerbations and smoking cessation on the structural changes. Results: The parameters of emphysematous changes significantly increased. The WA% at the distal airways significantly decreased and the %CSA<5 significantly increased over the same period, especially in ex-smokers. The parameters of emphysematous change were greater in patients with exacerbations and continued to progress even after smoking cessation. In contrast, the WA% and %CSA<5 did not change in proportion to emphysema progression. Conclusion: The WA% at the distal bronchi and the %CSA<5 did not change in parallel with parameters of LAA. Airway disease and vascular remodeling may be reversible to some extent by smoking cessation and appropriate treatment. Optimal management may have a greater effect on pulmonary vascularity and airway disease than parenchymal deconstruction in the early stage of COPD.

Rationale: A useful semiquantitative method of using computed tomographic (CT) images to evaluate therapeutic response in pulmonary alveolar proteinosis (PAP) has not been established, although the extent score or grading score of ground-glass opacities has been used. Objectives: The purpose of this study was to establish a semiquantitative method for evaluating therapeutic response in PAP. Methods: CT scans were obtained within 1 month before and after therapy from 32 patients with PAP who participated in a multicenter phase II trial of granulocyte-macrophage colony-stimulating factor inhalation therapy. The scans were evaluated by two chest radiologists independently. Increased parenchymal opacity was evaluated on the basis of its intensity and extent (CT grade), and the severity scores were compared with CT scores based on the extent alone (CT extent), as well as on the basis of physiological and serological results. Results: CT grade score and CT extent score had significant correlationwith diffusing capacity of the lung for carbon monoxide percent predicted (% DLCO), Pa-O2, VC percent predicted (% VC), Krebs von den Lungen (KL)-6, and surfactant protein D. The change in CT grade score between pre-and post-treatment examinations (Delta CT grade) correlated better with difference of Pa-O2 between pre-and post-treatment examinations (Delta Pa-O2) than Delta CT extent (difference of CT extent score between pre-and post-treatment examinations). In univariate analysis, Delta CT grade, Delta CT extent, Delta KL-6, Delta%DLCO, Delta%VC, and change in surfactant protein D correlated significantly with Delta Pa-O2. Inmultivariate analysis, Delta CT grade and DKL-6 correlated more closely with Delta Pa-O2. Conclusions: Although a number of CT variables were collected, the currently proposed grading system that correlates well with Pa-O2 should be viewed as a retrospective scoring system that needs future validation with another PAP cohort.

Background Recent advances in multidetector computed tomography (MDCT) facilitate acquiring important clinical information for managing patients with COPD. MDCT can detect the loss of lung tissue associated with emphysema as a low-attenuation area (LAA) and the thickness of airways as the wall area percentage (WA%). The percentage of small pulmonary vessels <5 mm2 (% cross-sectional area [CSA] <5) has been recently recognized as a parameter for expressing pulmonary perfusion. We aimed to analyze the longitudinal changes in structural abnormalities using these CT parameters and analyze the effect of exacerbation and smoking cessation on structural changes in COPD patients. Methods We performed pulmonary function tests (PFTs), an MDCT, and a COPD assessment test (CAT) in 58 patients with COPD at the time of their enrollment at the hospital and 2 years later. We analyzed the change in clinical parameters including CT indices and examined the effect of exacerbations and smoking cessation on the structural changes. Results The CAT score and forced expiratory volume in 1 second (FEV1) did not significantly change during the follow-up period. The parameters of emphysematous changes significantly increased. On the other hand, the WA% at the distal airways significantly decreased or tended to decrease, and the %CSA <5 slightly but significantly increased over the same period, especially in ex-smokers. The parameters of emphysematous change were greater in patients with exacerbations and continued to progress even after smoking cessation. In contrast, the WA% and %CSA <5 did not change in proportion to emphysema progression. Conclusion The WA% at the distal bronchi and the %CSA <5 did not change in parallel with parameters of LAA over the same period. We propose that airway disease and vascular remodeling may be reversible to some extent by smoking cessation and appropriate treatment. Optimal management may have a greater effect on pulmonary vascularity and airway disease than parenchymal deconstruction in the early stage of COPD.

Objective Osteoporosis, which is now recognized as a major comorbidity of chronic obstructive pulmonary disease (COPD), must be diagnosed by appropriate methods. The aims of this study were to clarify the relationships between bone mineral density (BMD) and COPD-related clinical variables and to explore the association of BMD with the updated Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification in men. Methods We enrolled 50 Japanese men with clinically stable COPD who underwent dual-energy X-ray absorptiometry (DEXA), pulmonary function testing, and computerized tomography (CT) and who had completed a questionnaire (COPD assessment test [CAT]). We determined the association between the T-score and other tested parameters and compared the BMD of patients in each GOLD category. Results Twenty-three of the 50 patients (46.0%) were diagnosed with osteopenia, and 7 (14.0%) were diagnosed with osteoporosis. The BMD findings were significantly correlated with the CAT score, forced expiratory volume in 1 second percentage predicted (FEV1% predicted), low attenuation volume percentage (LAV%), and percentage of cross-sectional area of small pulmonary vessels (%CSA) on CT images. Notably, the median T-score of the GOLD category D participants was significantly lower than that of the participants in each of the other categories (A [-0.98], B [-1.06], C [-1.05], and D [-2.19], p<0.05). Conclusion Reduced BMD was associated with airflow limitation, extent of radiographic findings, and a poor quality of life (QOL) in patients with COPD. The BMD of GOLD category D patients was the lowest of all of the patients evaluated, and category D patients may benefit from active intervention for osteoporosis.

(1) Background: Preventative treatment for Pneumocystis jirovecii pneumonia (PCP) has been recommended for patients receiving ≥20 mg/day prednisolone. We describe a patient who developed PCP while receiving a dose of 15 mg/day prednisolone, and consider criteria for the initiation of preventative therapy for PCP in patients with autoimmune hepatitis (AIH) treated with prednisolone.(2) Case Report: A 71-year-old woman initially possessed dark-colored urine, white stool, and decreased appetite, which indicated hepatic dysfunction. Further comprehensive investigation suggested a diagnosis of acute hepatitis with probable autoimmune etiology. Treatment was initiated at 60 mg/day prednisolone. Following a positive response by the patient, the dose was gradually reduced to 15 mg/day. Seventy days after the start of prednisolone treatment, respiratory symptoms appeared, and PCP was diagnosed following examination of bronchoalveolar lavage samples. The patient responded positively to treatment with sulfamethoxazole/trimethoprim combination therapy.(3) Conclusions: Preventative therapy for PCP may be indicated for AIH patients treated with steroids with (1) a dose of prednisolone of 12–15 mg/day or more, (2) a CD4+ lymphocyte count of 200–250/mm3 or less, or (3) a total lymphocyte count of 600/mm3 or less.

Background: Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is associated with rapid decline in lung function, poorer health-related quality-of-life outcomes, and frequent exacerbations, compared to COPD alone. Although the numbers of patients with ACOS have increased, there is little established evidence regarding diagnostic criteria and treatment options. Thus, the aim of our study was to clarify the clinical, physiological, and radiological features of patients with ACOS.Methods: We examined a total of 100 patients with COPD and 40 patients with ACOS, who were selected based on clinical criteria. All patients underwent baseline testing, including a COPD assessment test, pulmonary function tests, and multidetector row computed tomography imaging. Percentage of low attenuation volume, percentage of wall area, and percentage of total cross-sectional area of pulmonary vessels less than 5 mm(2) (% CSA <5) were determined using multidetector row computed tomography. ACOS patients were administered a fixed dose of budesonide/formoterol (160/4.5 mu g, two inhalations; twice daily) for 12 weeks, after which the ACOS patients underwent multidetector row computed tomography to measure the same parameters.Results: At baseline, the ACOS patients and COPD patients had a similar degree of airflow limitation, vital capacity, and residual volume. ACOS patients had higher COPD assessment test scores, percentage of wall area, and % CSA,5 than COPD patients. Compared to baseline, budesonide/formoterol treatment significantly increased the forced expiratory volume in 1 second and decreased the degree of airway wall thickness (percentage of wall area) as well as pulmonary microvascular density (% CSA,5) in ACOS patients.Conclusion: Our results suggest that ACOS is characterized by an airway lesion-dominant phenotype, in contrast to COPD. Higher % CSA,5 might be a characteristic feature of ACOS.

Background: This study aimed to investigate the predictors of quality of life (QOL) in patients with chronic thromboembolic pulmonary hypertension (CTEPH), changes in QOL after surgical and medical treatments, and the relationship between baseline QOL and survival.Methods and Results: QOL was measured in 128 patients with CTEPH (male/female: 42/86, age: 56+/-12 years, surgical/medical: 65/63) using the Short-Form 36 (SF-36) questionnaire. Multiple regression analysis showed pulmonary vascular resistance (PVR) and 6-min walking distance (6MWD) were associated with physical functioning (PF) (P<0.01) and physical component summary (PCS) (P<0.01). In the surgical group, 7 subscales and 2 summary scores improved significantly, and in the medical group 6 subscales and the mental component summary, although the change in QOL was greater in the surgical group. The patients in the conventional therapy group with higher PF had significantly better survival than those with lower PF (5-years survival: 89.5% vs. 50.8%, P=0.002). This difference in survival was not observed in the group receiving pulmonary arterial hypertension (PAH)-specific therapy (100% vs. 100%, P=0.746).Conclusions: PVR and 6MWD were associated with PF or PCS in CTEPH patients. QOL improved after surgical or medical therapy, with a greater change in the surgical group. PAH-specific therapy improved survival in patients with lower PF at diagnosis.

Background The COPD assessment test (CAT) score is a key component of the multifactorial assessment of COPD in the Global initiative for chronic Obstructive Lung Disease (GOLD) guidelines of 2014. Nevertheless, little is known regarding the differences among COPD categories in terms of clinical parameters such as pulmonary function or radiological findings. Thus, our aims in this study were to evaluate the associations between CAT scores and pulmonary clinical parameters, and to investigate factors that could discriminate between a “less symptomatic group” (categories A and C) and a “more symptomatic group” (categories B and D) among stable COPD patients. Methods We enrolled 200 outpatients at Chiba University Hospital. Study subjects were assessed by CAT, pulmonary function testing, and multidetector computed tomography (MDCT). We assessed possible correlations between these indices. Results CAT scores were negatively correlated with percentage of the forced expiratory volume in 1 second predicted value (FEV1 %predicted) and percentage of the diffusing capacity for carbon monoxide per liter of lung volume predicted value (DLCO/VA [%predicted]) results and positively correlated with low attenuation volume percentage (LAV%) and residual volume to total lung capacity ratios (RV/TLC). In the “more symptomatic group” (category B or D), the mean DLCO/VA (%predicted) was significantly lower and the mean LAV% and RV/TLC was significantly higher than those in the “less symptomatic group” (category A or C), respectively. Interestingly, those in category B had higher mean LAV% compared to those in category C. Conclusion CAT scores were significantly correlated with pulmonary function parameters and emphysematous changes on MDCT. The new GOLD classification system would be a step toward a phenotypic approach, especially taking into account the degree of emphysema and hyperinflation.

Aims: The aim of this study is to evaluate the clinical features and provide estimates of the prevalence of patients diagnosed for pulmonary arterial hypertension (PAH) in Japan. Methods: A nationwide epidemiological survey of PAH was performed using clinical personal records in 2012. Some 2299 patients with PAH were covered by public insurance (2012), according to the data from the Japan Intractable Diseases Information Center. The forms from 1377 patients (new: 389, recurrent: 988) were collected (2012). Results: The prevalence of PAH in Japan was estimated to be 15.6 per million. The male-female ratio was 1:2.17, showing a predominance of women with the disorder. The average age was 53.0±19.4 in 2012, older than the previous survey in 2004 (41.9 ± 19.5). The average age had been aging for 12.1 years in those 8 years. The ratio of elderly patients (older than 65 years) was 33.3% in 2012 and it was 18.3% in 2004. It increased remarkably. The average age of PAH at diagnosis (44.5 ± 23.6) in 2012 was aged than previous survey (38.1 ± 20.8) in 2006. Idiopathic and heritable PAH were the most common type of PAH (66.6%) and PAH associated with congenital heart disease (16.3%) and PAH associated with connective tissue diseases are common (11.1%).Most of the PAH analyzed cases were at a severity level of WHO class II or III. There were more patients who treated with combination therapy (58%) than monotherapy (42%). Conclusions: The average age of PAH patients aged rapidly in Japan.

Pulmonary arterial hypertension (PAH) is a rare complication, but a significant prognostic factor in patients with Sjögren's syndrome (SjS). Despite its efficacy, the long-term use of intravenous epoprostenol is sometimes complicated by adverse effects, such as catheter-related infection. This case involves a 38-year-old woman with PAH associated with SjS (PAH-SjS) who was transitioned from treatment with long-term intravenous epoprostenol therapy to combination oral therapy containing bosentan and tadalafil. She has remained in stable condition for more than two years following epoprostenol discontinuation. The details of this report suggest that long-term epoprostenol therapy can be safely tapered off and replaced with combination oral therapy in carefully selected patients with PAH-SjS.

BACKGROUND:Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by subcutaneous injection or inhaled therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) has been demonstrated to be safe and efficacious in several reports. However, some reports of subcutaneous injection described transient benefit in most instances. The durability of response to inhaled GM-CSF therapy is not well characterized.METHODS:To elucidate the risk factors for recurrence of aPAP after GM-CSF inhalation, 35 patients were followed up, monitoring for the use of any additional PAP therapies and disease severity score every 6 months. Physiologic, serologic, and radiologic features of the patients were analyzed for the findings of 30-month observation after the end of inhalation therapy.RESULTS:During the observation, 23 patients remained free from additional treatments, and twelve patients required additional treatments. There were no significant differences in age, sex, symptoms, oxygenation indexes, or anti-GM-CSF antibody levels at the beginning of treatment between the two groups. Baseline vital capacity (% predicted, %VC) were higher among those who required additional treatment (P<.01). Those patients not requiring additional treatment maintained the improved disease severity score initially achieved. A significant difference in the time to additional treatment between the high %VC group (%VC≥80.5) and the low %VC group was seen by a Kaplan-Meier analysis and a log-rank test (P<.0005).CONCLUSIONS:These results demonstrate that inhaled GM-CSF therapy sustained remission of aPAP in more than one-half of cases, and baseline %VC might be a prognostic factor for disease recurrence.TRIAL REGISTRY:ISRCTN Register and JMACCT Clinical Trial Registry; No.: ISRCTN18931678 and JMAIIA00013; URL: http://www.isrctn.org and http://www.jmacct.med.or.jp.

Background: It is unclear whether abnormalities of coagulation or fibrinolysis are associated with disease progression of chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to investigate the association of these factors with the severity and prognosis of CTEPH. Methods and Results: Between 1986 and 2011, plasma fibrinogen and plasminogen were measured in 89 of 106 consecutive patients with inoperable CTEPH (17 men; mean age, 55.9 +/- 14.1 years old; mean pulmonary arterial pressure, 44.0 +/- 12.4 mmHg) and the association of level with severity and prognosis were also examined. Seventeen patients had high fibrinogen and low plasminogen (medians, >= 291 mg/dl and <101%, respectively). These patients had significantly lower cardiac index (2.26 +/- 0.68 vs. 2.70 +/- 0.57 L.min(-1).m(-2), P=0.007), higher pulmonary vascular resistance (PVR; 13.29 +/- 7.54 vs. 9.15 +/- 4.14 Wood units, P=0.003), and poor survival (5-year survival, 35.3% vs. 88.0%, P<0.001) compared to the other 72 patients. Additional analysis showed significantly poor survival in these patients compared with the other patients who did not have modern therapy. On multivariate analysis plasma fibrinogen, plasminogen and PVR were independent predictors of survival in medically treated patients. Conclusions: High plasma fibrinogen and low plasminogen are associated with poor survival in CTEPH patients without modern therapy.