Asthma is a risk factor for general fatigue of long COVID in Japanese nation-wide cohort study.

BACKGROUND: Multiple prolonged symptoms are observed in patients who recover from an acute COVID-19 infection, which is defined as long COVID. General fatigue is frequently observed in patients with long COVID during acute and post-acute phases. This study aimed to identify the specific risk factors for general fatigue in long COVID. METHODS: Hospitalized patients with COVID-19 aged over 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. RESULTS: Among prolonged symptoms through 1-year follow-ups, general fatigue was the most interfering symptom in daily life. Patients with protracted fatigue at all follow-up periods had lower quality of life scores at the 12-month follow-up. Univariate logistic regression analysis of the presence or absence of general fatigue at the 3-month, 6-month, and 12-month follow-ups identified asthma, younger age, and female sex as risk factors for prolonged fatigue. Multivariable logistic regression analysis revealed that asthma was an independent risk factor for persistent fatigue during the 12-month follow-up period. Longitudinal changes in the symptoms of patients with or without asthma demonstrated that general fatigue, not cough and dyspnea, was significantly prolonged in patients with asthma. CONCLUSIONS: In a Japanese population with long COVID, prolonged general fatigue was closely linked to asthma. A preventive approach against COVID-19 is necessary to avoid sustained fatigue and minimize social and economic losses in patients with asthma.

Potential biomarker enhancing the activity of tuberculosis, hsa-miR-346.

OBJECTIVES: To determine the usefulness of hsa-miR-346, a potential biomarker enhancing the activity of non-tuberculous mycobacterial diseases, as a biomarker of tuberculosis activity. METHODS: We investigated whether hsa-miR-346 is secreted by human macrophages infected with Mycobacterium tuberculosis (M. tuberculosis) in an in vitro study. In addition, a cross-sectional study was conducted first to evaluate whether serum hsa-miR-346 is elevated in patients with tuberculosis compared with that in healthy individuals. Second, we conducted a retrospective study to evaluate whether anti-tuberculosis treatment reduces serum hsa-miR-346 levels. RESULTS: Log hsa-miR-346 levels were significantly elevated in the supernatant of human macrophages infected with M. tuberculosis in a dose-dependent manner. The mean serum log hsa-miR-346 levels were -15.48 (-15.76 to -15.21) in patients with tuberculosis and -16.12 (-16.29 to -15.95) in healthy volunteers, which significantly differed. In addition, hsa-miR-346 significantly decreased at 2 months from starting an anti-tuberculosis treatment. CONCLUSIONS: We consider hsa-miR-346 as a potential biomarker enhancing the tuberculosis activity.

Clinical Features and Prognosis of Nontuberculous Mycobacterial Pleuritis: A Multicenter Retrospective Study.

Rationale: The clinical features and prognosis of nontuberculous mycobacterial (NTM) pleuritis and pleural effusion combined with NTM lung disease remain unclear. Objectives: To investigate the clinical features and prognosis of NTM pleuritis. Methods: This retrospective observational study included patients with NTM pleuritis from January 2001 to June 2018 across eight hospitals in Japan. NTM pleuritis was defined by a positive NTM culture of pleural effusion samples. We matched patients with Mycobacterium avium complex (MAC) lung disease (MAC-LD) without pleuritis by sex and age to obtain comparative data and investigated the association between clinical parameters and the prognosis. Results: We identified 64 patients with NTM pleuritis (median age, 73 yr; 37 female patients). The median follow-up duration was 11 months, and 27 patients died. Patients with MAC pleuritis had a significantly lower survival rate than matched patients with MAC-LD without pleuritis. Multivariate analysis revealed that pleuritis (adjusted hazard ratio, 6.99; 95% confidence interval [CI], 2.58-19.00) and underlying pulmonary diseases (adjusted hazard ratio, 3.01; 95% CI, 1.44-6.28) were independently associated with all-cause mortality in patients with MAC-LD. Conclusions: The prognosis of MAC pleuritis is poorer than that of MAC-LD without pleuritis. Pleuritis is an independent prognostic factor in patients with MAC-LD.

Characteristics of patients with increasing COPD assessment test scores within 3 years.

BACKGROUND: The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a subjective measure of quality of life. The aim of this study was to examine the characteristics of COPD patients with increasing CAT scores within 3 years. METHODS: Keio University and its affiliate hospitals conducted an observational COPD cohort study over 3 years. St. George's Respiratory Questionnaire (SGRQ) and CAT were completed at baseline and annually thereafter. Patients who had at least 3 CAT scores were included (n = 315). The ΔCAT score/year and ΔSGRQ score/year were calculated by the slope between each of the measures and the date of measurement. RESULTS: The median ΔCAT score/year was 0.4, and ΔCAT score/year was significantly correlated with ΔSGRQ total score/year. Using an annual cut-off CAT score of +2 points, patients who deteriorated (n = 79) were older, had lower %FEV1, and more severe emphysema on computed tomography scan at baseline than patients who did not deteriorate. The baseline value was not a determinant of subsequent changes in the CAT score. Longitudinal changes in the CAT score were positively correlated with those in the SGRQ score. CONCLUSIONS: Old age and severe COPD, not the CAT score at one time point, predicted worsening quality of life.

hsa-miR-346 is a potential serum biomarker of Mycobacterium avium complex pulmonary disease activity.

MicroRNA (miRNA) has been recently recognized as a biomarker of various diseases; however, there are no known miRNAs associated with Mycobacterium avium complex (MAC) pulmonary disease. In addition, there are no known biomarkers to precisely reflect disease activity after the diagnosis of MAC pulmonary disease. Thus, we sought to identify a miRNA which is a candidate biomarker of MAC pulmonary disease activity. Serum hsa-miR-346 concentrations of 16 patients with M. avium pulmonary disease were significantly higher than those of 16 healthy controls (p = 0.047). The secretion of hsa-miR-346 increased in a multiplicity of infection-dependent manner in M. avium-infected macrophages. Serum hsa-miR-346 levels of 5 patients with bacterial conversion at the end of follow-up were significantly lower than those at the beginning of the follow-up (p = 0.043). In addition, the longitudinal change in serum hsa-miR-346 concentration correlated with bacterial load in 2 patients with M. avium pulmonary disease. Based on our results, it is supposed that MAC-infected macrophages in pulmonary lesions produce hsa-miR-346, which is then secreted into the bloodstream. The magnitude of this process could be quantitatively controlled by the bacterial load, suggesting that serum hsa-miR-346 is a potentially useful biomarker of MAC pulmonary disease activity.

[A CASE OF MILIARY TUBERCULOSIS ASSOCIATED WITH HEPATOSPLENIC ABSCESSES APPEARING DURING ANTI-TUBERCULOUS TREATMENT].

A 27-year-old man with a 4-month history of treatment for miliary tuberculosis at another hospital was admitted to our hospital for continued treatment. Computed tomography showed new lesions in the S8 area of the liver and spleen, despite resolution of chest radiographic findings. Because these new lesions were still present after 8 months of treatment, we performed laparoscopic drainage of the liver abscess. Purulent material drained from the lesion revealed positive polymerase chain reaction results for Mycobacterium tuberculosis, and identification of granuloma with infiltrating lymphocytes and plasma cells confirmed the diagnosis of tubercular liver abscess. Pathological changes in the spleen over the clinical course were also regarded as representing tubercular abscess. Postoperative course was good, and tuberculosis treatment ended after 12 months. Tubercular liver abscess subsequently showed prominent reduction, and the tubercular splenic abscess disappeared on abdominal ultrasonography. Tubercular hepatosplenic abscesses appearing during tubercular treatment are rare. We report this valuable case in which laparoscopic drainage of a liver abscess proved useful for diagnosis and treatment.

[A case having chyliform pleural effusion caused by former tuberculous pleurisy].

A 49-year-old male who had been treated for pulmonary tuberculosis and tuberculous pleurisy in 2007 was referred to our hospital with the complaint of dyspnea on exertion in Nov. 2009. Chest X-ray showed increased pleural effusion compared with that remaining after the previous treatment of pleurisy in 2008. A chest CT revealed that fluid collection was surrounded by thickened pleura. Thoracocentesis was performed, and yellow milky liquid was obtained. The pleural effusion contained few cells. The triglyceride concentration was 83 mg/dl, and the cholesterol level was very high at 628 mg/dl. Based on these findings we diagnosed this case as chyliform pleural effusion. Both smear of acid-fast bacilli and PCR-TB test of the pleural effusion were positive, but culture was negative for mycobacterium, suggesting that this chyliform pleural effusion was produced by the former episode of tuberculous pleurisy, not by the recent reactivation of tuberculous pleurisy. The ADA concentration in the pleural effusion was high at 91.7 IU/l. No increase in the amount of pleural effusion was observed after thoracocentesis without any anti-tuberculosis therapy.

[A case of tuberculous pleurisy with transient new intra-pulmonary lesions during anti-tuberculosis therapy].

A 24-year-old man who had been treated 3 months for tuberculous pleurisy presented with thoracic back pain. Chest CT showed a new lesion abutting the pleura, despite the disappearance of pleural effusion. Two weeks later, the mass abutting the pleura progressed to form a new intrapulmonary infiltrative shadow. A transbronchial lung biopsy was performed and the histopathologic examination of the specimen from this lesion revealed granulomatous inflammation without caseous necrosis or acid-fast bacilli. No acid-fast bacilli were cultured from the bronchoalveolar lavage fluid. Anti-tuberculosis medication was continued without change, and the lesions finally resolved. More than 3 years have passed since the completion of anti-tuberculosis chemotherapy, and no recurrence has been observed. We believe that these lesions were pulmonary tuberculomas and transient intra-pulmonary infiltration due to non-specific inflammation, caused secondarily by an excessive immune response, as in paradoxical worsening.

Various adhesion molecules impair microvascular leukocyte kinetics in ventilator-induced lung injury.

Although the endothelial expression of various adhesion molecules substantially differs between pulmonary microvessels, their importance for neutrophil and lymphocyte sequestration in ventilator-induced lung injury (VILI) has not been systematically analyzed. We investigated the kinetics of polymorphonuclear cells (PMN) and mononuclear cells (MN) in the acinar microcirculation of the isolated rat lung with VILI by real-time confocal laser fluorescence microscopy, with or without inhibition of ICAM-1, VCAM-1, or P-selectin by monoclonal antibodies (MAb). Adhesion molecules in each microvessel were estimated by intravital fluorescence microscopy or immunohistochemical staining. In high tidal volume-ventilated lungs, 1) ICAM-1, VCAM-1, and P-selectin were differently upregulated in venules, arterioles, and capillaries; 2) venular PMN rolling was improved by inhibition of ICAM-1, VCAM-1, or P-selectin, whereas arteriolar PMN rolling was improved by ICAM-1 or VCAM-1 inhibition; 3) capillary PMN entrapment was ameliorated only by anti-ICAM-1 MAb; and 4) MN rolling in venules and arterioles and MN entrapment in capillaries were improved by ICAM-1 and VCAM-1 inhibition. In conclusion, the contribution of endothelial adhesion molecules to abnormal leukocyte behavior in VILI-injured microcirculation is microvessel and leukocyte specific. ICAM-1- and VCAM-1-dependent, but P-selectin-independent, arteriolar PMN rolling, which is expected to reflect the initial stage of tissue injury, should be taken as a phenomenon unique to ventilator-associated lung injury.

[Current status of the criteria for discharging patients with pulmonary tuberculosis--results of questionnaire survey on the criteria for discharging patients from tuberculosis wards of the hospitals in Kanto area].

INTRODUCTION: Emphasis in treating patients with infectious pulmonary tuberculosis has come to be laid on the execution of reliable standard chemotherapy. As a result, hospitalization for a prolonged period has become unnecessary any more. However, few attempts have been made so far on the determination of discharging criteria. METHODS: We performed a questionnaire survey to hospitals with wards for tuberculosis in Kanto area and asked questions on the current status of discharging criteria. RESULTS: The effective response rate to the survey was 63.0 %. Sputum smear examination carried out mainly by Ziehl-Neelsen method and fluorescence method in 17.2% and 72.4 % of the hospitals, respectively. Sputum culture examination was carried out using mainly Ogawa medium and a liquid medium in 62.1% and 27.6% of the hospitals, respectively. Discharging criteria were standardized in 79.3% of hospitals. Negative sputum smear was used as the criterion for determining discharge in 11 sets of criteria. Negative sputum culture was used as the criterion for determining discharge in 17 sets of criteria. In the remaining one hospital, patients were to be discharged after 2-month treatment. There was no consistency in the procedure and the frequency of sputum examinations, how many negative results are needed to confirm negative status and the criteria for judgment. CONCLUSION: These results suggest that further evaluation must be made on the treatment outcome at each hospital, and the standard discharging criteria should be worked out taking into account the capacity of each hospital and the care situation of local community.

Inhibition of c-Jun NH2-terminal kinase activity improves ischemia/reperfusion injury in rat lungs.

Although c-Jun NH(2)-terminal kinase (JNK) has been implicated in the pathogenesis of transplantation-induced ischemia/reperfusion (I/R) injury in various organs, its significance in lung transplantation has not been conclusively elucidated. We therefore attempted to measure the transitional changes in JNK and AP-1 activities in I/R-injured lungs. Subsequently, we assessed the effects of JNK inhibition by the three agents including SP600125 on the degree of lung injury assessed by means of various biological markers in bronchoalveolar lavage fluid and histological examination including detection of apoptosis. In addition, we evaluated the changes in p38, extracellular signal-regulated kinase, and NF-kappaB-DNA binding activity. I/R injury was established in the isolated rat lung preserved in modified Euro-Collins solution at 4 degrees C for 4 h followed by reperfusion at 37 degrees C for 3 h. We found that AP-1 was transiently activated during ischemia but showed sustained activation during reperfusion, leading to significant lung injury and apoptosis. The change in AP-1 was generally in parallel with that of JNK, which was activated in epithelial cells (bronchial and alveolar), alveolar macrophages, and smooth muscle cells (bronchial and vascular) on immunohistochemical examination. The change in NF-kappaB qualitatively differed from that of AP-1. Protein leakage, release of lactate dehydrogenase and TNF-alpha into bronchoalveolar lavage fluid, and lung injury were improved, and apoptosis was suppressed by JNK inhibition. In conclusion, JNK plays a pivotal role in mediating lung injury caused by I/R. Therefore, inhibition of JNK activity has potential as an effective therapeutic strategy for preventing I/R injury during lung transplantation.

A broad-spectrum caspase inhibitor attenuates allergic airway inflammation in murine asthma model.

Asthma is characterized by acute and chronic airway inflammation, and the severity of the airway hyperreactivity correlates with the degree of inflammation. Many of the features of lung inflammation observed in human asthma are reproduced in OVA-sensitized/challenged mice. T lymphocytes, particularly Th2 cells, are critically involved in the genesis of the allergic response to inhaled Ag. In addition to antiapoptotic effects, broad-spectrum caspase inhibitors inhibit T cell activation in vitro. We investigated the effect of the broad-spectrum caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), on airway inflammation in OVA-sensitized/challenged mice. OVA-sensitized mice treated with z-VAD-fmk immediately before allergen challenge showed marked reduction in inflammatory cell infiltration in the airways and pulmonary blood vessels, mucus production, and Th2 cytokine production. We hypothesized that the caspase inhibitor prevented T cell activation, resulting in the reduction of cytokine production and eosinophil infiltration. Treatment with z-VAD-fmk in vivo prevented subsequent T cell activation ex vivo. We propose that caspase inhibitors may offer a novel therapeutic approach to T cell-dependent inflammatory airway diseases.

Hypercapnic acidosis attenuates endotoxin-induced nuclear factor-[kappa]B activation.

Although permissive hypercapnia improves the prognosis of patients with acute respiratory distress syndrome, it has not been conclusively determined whether hypercapnic acidosis (HA) is harmful or beneficial to sustained inflammation of the lung. The present study was designed to explore the molecular mechanism of HA in modifying lipopolysaccharide (LPS)-associated signals in pulmonary endothelial cells. LPS elicited degradation of inhibitory protein kappaB (IkappaB)-alpha, but not IkappaB-beta, resulting in activation of nuclear factor (NF)-kappaB in human pulmonary artery endothelial cells. Exposure to HA significantly attenuated LPS-induced NF-kappaB activation through suppressing IkappaB-alpha degradation. Isocapnic acidosis and buffered hypercapnia showed qualitatively similar but quantitatively smaller effects. HA did not attenuate the LPS-enhanced activation of activator protein-1. Following the reduced NF-kappaB activation, HA suppressed the mRNA and protein levels of intercellular adhesion molecule-1 and interleukin-8, resulting in a decrease in both lactate dehydrogenase release into the medium and neutrophil adherence to LPS-activated human pulmonary artery endothelial cells. In contrast, HA did not inhibit LPS-enhanced neutrophil expression of integrin, Mac-1. Based on these findings, we concluded that hypercapnic acidosis would have anti-inflammatory effects essentially through a mechanism inhibiting NF-kappaB activation, leading to downregulation of intercellular adhesion molecule-1 and interleukin-8, which in turn inhibits neutrophil adherence to pulmonary endothelial cells.