Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases. Analysis of the blood DNA virome in patients with COVID-19 and autoimmune disease associates endogenous HHV-6 (eHHV-6) and high anellovirus load with increased disease risk, most notably for systemic lupus erythematosus. eHHV-6 carriers show a distinct immune response.
Introduction: Although health status and mortality are important outcomes in patients with advanced pulmonary diseases receiving noninvasive ventilation (NIV), their relationship has not been thoroughly investigated. Hypothesis: We hypothesized that health status assessment using questionnaires specific for chronic respiratory failure would predict mortality in patients receiving NIV. Methods: We prospectively recruited 56 stable outpatients treated with NIV for chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease and/or pulmonary tuberculosis sequelae. Arterial blood gas, pulmonary function and health status using four different questionnaires, dyspnea and psychological status were measured at baseline. Results: In cross-sectional comparisons of four health status questionnaires, the Severe Respiratory Insufficiency (SRI) questionnaire had the lowest floor and ceiling effects. During the three-year follow-up, 16 patients (29%) died. Univariate analysis revealed that low body mass index (BMI), high arterial carbon dioxide pressure, low forced vital capacity, low health status, and severe dyspnea and depression were significantly related to mortality. Stepwise multivariate analyses indicated that SRI summary was the most significant predictor of mortality, followed by BMI. Conclusion: Health status was significantly related to three-year mortality independently of under-nutrition, hypercapnia and low pulmonary function in hypercapnic patients with severe respiratory insufficiency receiving NIV. SRI was more significantly related with mortality than other health status questionnaires, and had a balanced score distribution.
Drug-induced lung injury (DLI) can result from a vast number of agents, and sometimes presents findings similar to those of acute respiratory distress syndrome (ARDS). Previous studies have reported that circulating levels of soluble thrombomodulin (TM) reflect endothelial injuries, which play key roles in the development of ARDS. We hypothesized that endothelial injuries are an important aspect of pathogenesis in severe DLI. The primary aim of this study was to examine the associations between soluble TM and disease severity in DLI patients.Of the 2580 patients who underwent a bronchoalveolar lavage (BAL) procedure at Tosei General Hospital between May 2007 and February 2015, we retrospectively analysed the data of 68 DLI patients. Soluble TM in plasma and BAL fluid (BALF), and other biomarkers were included in our analysis.At the time of diagnosis, 39 patients (57%) had respiratory failure (partial pressure of oxygen/inspiratory oxygen fraction ratio, PaO2 /FiO2 ratio < 300). There was a significant negative linear correlation between the PaO2 /FiO2 ratio and soluble TM in BALF (r = -0.448, P < 0.001). In a stepwise multiple regression analysis, soluble TM in BALF and surfactant protein D (SP-D) were the only independent determinants of the PaO2 /FiO2 ratio. Additionally, in a multivariate logistic regression model, soluble TM in BALF (adjusted OR (aOR): 7.48, 95% CI: 1.60-34.98) and SP-D (aOR: 5.31, 95% CI: 1.40-20.15) was an independent predictor of respiratory failure (PaO2 /FiO2 ratio < 300).Soluble TM in BALF is an independent predictor of severe DLI. These findings underscore the importance of pulmonary endothelial injuries in the pathogenesis of severe DLI.
Health status and mortality are important outcomes in patients with advanced pulmonary diseases receiving noninvasive ventilation (NIV). However, their relationship has not been thoroughly investigated.The present study prospectively recruited 56 stable outpatients treated with NIV for chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease and/or pulmonary tuberculosis sequelae. At baseline, health status was measured by the Medical Outcomes Study 36-item short form, a generic questionnaire; the St. George's Respiratory Questionnaire (SGRQ), a respiratory-specific questionnaire; and two respiratory failure-specific questionnaires, the Maugeri Respiratory Failure questionnaire and the Severe Respiratory Insufficiency (SRI) questionnaire. Arterial blood gas, pulmonary function, dyspnea and psychological status were also measured.In cross-sectional comparisons of the four health status questionnaires, the SGRQ and SRI questionnaire had lower floor and ceiling effects. During the 3-year follow-up, 16 patients (29%) died. Health status shown by the SGRQ and SRI was significantly predictive of mortality, independently of the physiological measures of low body mass index (BMI), hypercapnia, and low pulmonary function. Stepwise multivariate analyses indicated that the SRI summary score was the most significant predictor of mortality (P = 0.0006) followed by BMI (P = 0.012).There was a significant relationship between health status and 3-year mortality in patients with NIV, independently of under-nutrition, hypercapnia and low pulmonary function. Health status measurement is important not only to comprehensively evaluate disease severity in relation to its close association with mortality, but also to elucidate factors that improve the survival of patients with advanced respiratory diseases.
SUMMARY Although the clinical effects of the tulobuterol patch have been reported to include an increase in morning peak expiratory flow (PEF) values and a decrease of symptoms and the frequency of the rescue use of inhaled short‐acting b 2 ‐adrenoceptor agonists, no trials comparing the efficacy of the tulobuterol patch to other standard inhaled long‐acting b 2 ‐adrenoceptor agonists have yet been conducted. The aim of the present study was to compare the clinical effects of the patch formulation of tulobuterol with those of inhaled salmeterol in moderate to severe asthma. Fifty‐four patients with moderate to severe asthma, whose conditions were suboptimally controlled despite receiving inhaled corticosteroids, were recruited. The study was a prospective, randomized trial of cross‐over design comparing the effects of 4 weeks treatment with tulobuterol patch, 2 mg once daily, and salmeterol, 50 mg twice daily. The mean prebronchodilator morning PEF during the last 14 days of each treatment period and health‐related quality of life (HRQoL) were the primary outcome variables. The HRQoL was assessed using the St George's Respiratory Questionnaire. Forty‐four patients (81.5%) completed the trial and were included in the analysis. The mean morning PEF and HRQoL score were significantly improved in both the salmeterol ( P < 0.0001 and P < 0.05, respectively) and the tulobuterol patch ( P < 0.01 and P < 0.05, respectively) treatment periods compared with the run‐in period. Although the mean morning PEF was significantly higher in the salmeterol‐treated group than in the tulobuterol‐treated group ( P < 0.001), the HRQoL scores were comparable. The tulobuterol patch may be useful as a controller medication in addition to inhaled corticosteroids in moderate to severe asthma.
We report a case with Langerhans cell histiocytosis appearing as an extra-pleural tumor. A 20-year-old man was transferred to our hospital because of right chest pain and fever. His chest X-ray showed an extra-pleural mass and chest CT scan showed a mass lesion with right 7th rib fracture. 67Gallium and bone scintigram showed uptake at the same site. We performed a CT-guided puncture biopsy. Pathological findings of the specimen showed diffuse proliferation of histiocytoid cells with some eosinophils. The histiocytes were positive for S-100 protein and CD1a on immunohistochemical stain. Langerhans cell histiocytosis was diagnosed. There was no other involvement of the disease except the rib. The tumor resolved only with smoking cessation and no recurrence was observed during the follow-up period. An association between smoking and progressions of the rib disease was suggested.
<b><i>Background:</i></b> The optimal treatment method for interstitial pneumonia (IP) with connective tissue disease (CTD) remains controversial. In addition, a clinically meaningful end point to judge drug efficacy has not been fully investigated. <b><i>Objectives:</i></b> The aim of this study was to evaluate, from various aspects, the therapeutic benefit and tolerability of combined therapy with cyclosporin A (CsA) and low-dose prednisolone (PSL) for chronic fibrosing CTD-IP patients. <b><i>Methods:</i></b> A total of 26 CTD-IP patients diagnosed by surgical lung biopsy and subsequently treated with the above combination therapy were retrospectively reviewed. The therapeutic regimen comprised methylprednisolone induction therapy for 2-4 weeks, followed by a combined therapy of CsA with low-dose PSL for 1 year. Evaluation of the therapeutic benefit was based on not only pulmonary function but also exercise capacity, health-related quality of life and dyspnea. <b><i>Results:</i></b> After 1 year of therapy, clinically significant improvements in forced vital capacity (≥10%), carbon monoxide diffusing capacity of the lung (≥15%), 6-min walk distance (≥28 m), and St. George's Respiratory Questionnaire (≤-7) were observed in 61.5, 69.2, 61.5 and 69.2% of the patients, respectively. All measurements showed statistically significant improvements compared with baseline values. The 1-year treatment did not need to be discontinued in any patients due to unacceptable toxicity, and no deaths occurred. <b><i>Conclusions:</i></b> Combined therapy with CsA and low-dose PSL for CTD-IP patients was well-tolerated and patients displayed a noteworthy response.
