Published papers

BACKGROUND: In bronchiectasis patients, chronic Pseudomonas aeruginosa (PA) infection has been associated with worse health-related quality of life (HRQL), but little is known about Mycobacterium avium complex lung disease (MACLD) patients in this context. This study aimed to evaluate HRQL and investigate the impact of chronic PA infection in MACLD patients. METHODS: This cross-sectional study was conducted using the Registry of Prospective Cohort Study including MACLD patients. The 36-item Short-Form health survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ) were administered to assess clinical outcomes. Clinical variables included treatment and sputum culture status, pulmonary function tests, cavitary lesions, and modified Reiff scores on high-resolution computed tomography. RESULTS: The study included 244 MACLD patients (median age, 68 years; 196 women), 19 of whom had chronic PA infection. Modified Reiff score was higher in patients with chronic infection than in those without (P = 0.028). Regarding SF-36 scores, physical functioning subscale scores were significantly lower in patients with chronic infection (P = 0.029). Additionally, SGRQ symptoms, impact, and total scores were significantly higher in patients with chronic infection. During analysis of covariance comparisons, SGRQ symptoms and impact scores were significantly higher for patients with chronic infection (P = 0.043 and 0.021, respectively). CONCLUSIONS: MACLD patients with chronic PA infection exhibited significantly higher SGRQ scores, indicating impaired HRQL. Chronic PA infection was significantly associated with the severity of bronchiectasis.

Rationale: Patients with noncavitary nodular bronchiectatic (NB) Mycobacterium avium complex pulmonary disease (MAC-PD) are treated intermittently three times a week, although no randomized controlled trials have been conducted comparing three times weekly to daily therapy. Objectives: To assess the tolerability, safety, and efficacy of intermittent versus daily treatment in patients with previously untreated noncavitary NB MAC-PD Methods: In an open-label study, patients were randomly assigned to the intermittent therapy group receiving clarithromycin 1000 mg, rifampicin 600 mg, and ethambutol 25 mg/kg (maximum 1000 mg) three days a week, or the daily therapy group receiving clarithromycin 800 mg, rifampicin 450 mg, and ethambutol 15 mg/kg (maximum 750 mg) daily for one year. The primary endpoint was the proportion of patients requiring modification of the initial treatment regimen. Results: Twenty-one Japanese hospitals participated in the study, enrolling 141 patients between May 2019 and December 2021. The full analysis set included 138 participants (intermittent therapy = 70; daily therapy = 68). There were no significant differences between the intermittent and daily therapy groups in terms of the regimen modification rate (20.0% (14/70) versus 33.8% (23/68); adjusted odds ratio 0.48, 95% confidence interval 0.22 to 1.05; p=0.06) or culture conversion (70.3% vs. 80.0%, p=0.53), time to culture conversion (28.0 vs. 28.5 days, p=0.89), improvement in chest CT findings (60.9% vs. 71.0%, p=0.30), or clarithromycin resistance development (1.4% vs. 0%, p=1.00). Elevated AST (16.9% vs. 41.2%, p=0.003) and ALT (18.3% vs. 44.1%, p=0.002) were more common in the daily treatment group, while elevated bilirubin (11.3% vs. 1.5%, p=0.04) and dysgeusia (14.1% vs. 1.5%, p=0.01) were more common in the intermittent treatment group. The daily treatment group exhibited a greater absolute change in the 36-Item Short Form Survey physical aspect score (-2.5 points) than the intermittent treatment group (2.1 points) (p=0.01). Conclusion: Intermittent treatment was not significantly better tolerated than daily treatment for noncavitary NB MAC-PD. However, further studies with larger numbers of patients are needed. Clinical trial registration available at: https://jrct.niph.go.jp/en-top. ID: jRCTs031190008.

Intimal sarcoma is a rare disease with a poor prognosis. We herein report the case of a 71-year-old man with intimal sarcoma of the pulmonary artery treated with pazopanib. The tumor showed regression after 1 month of treatment. Hand-foot syndrome led to cessation of pazopanib, which triggered a disease flare. Pazopanib should be considered in patients with intimal sarcoma of the pulmonary artery that is unresectable or recurrent after surgery or cytotoxic chemotherapy. We must be careful about drug cessation, as it can lead to a disease flare.

Mycobacterium heckeshornense is a slow-growing mycobacterial species for which pathogenic features are unclear. Here, we report the complete genome sequence of an M. heckeshornense type strain. This sequence will provide essential information for future taxonomic and comparative genome studies of these mycobacteria.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly since 2019, and the number of reports regarding long COVID has increased. Although the distribution of long COVID depends on patient characteristics, epidemiological data on Japanese patients are limited. Hence, this study aimed to investigate the distribution of long COVID in Japanese patients. This study is the first nationwide Japanese prospective cohort study on long COVID. METHODS: This multicenter, prospective cohort study enrolled hospitalized COVID-19 patients aged ≥18 years at 26 Japanese medical institutions. In total, 1200 patients were enrolled. Clinical information and patient-reported outcomes were collected from medical records, paper questionnaires, and smartphone applications. RESULTS: We collected data from 1066 cases with both medical records and patient-reported outcomes. The proportion of patients with at least one symptom decreased chronologically from 93.9% (947/1009) during hospitalization to 46.3% (433/935), 40.5% (350/865), and 33.0% (239/724) at 3, 6, and 12 months, respectively. Patients with at least one long COVID symptom showed lower quality of life and scored higher on assessments for depression, anxiety, and fear of COVID-19. Female sex, middle age (41-64 years), oxygen requirement, and critical condition during hospitalization were risk factors for long COVID. CONCLUSIONS: This study elucidated the symptom distribution and risks of long COVID in the Japanese population. This study provides reference data for future studies of long COVID in Japan.

BACKGROUND: Coronary artery calcification (CAC) detected through chest computed tomography (CT) strongly predicts cardiovascular events in asymptomatic individuals undergoing primary prevention. Few studies with limited sample sizes have investigated the predictive value of CAC for cardiovascular complications in COVID-19. This study examined the impact of CAC on cardiovascular complications using a large-scale COVID-19 database. METHODS AND RESULTS: This multicenter retrospective cohort study used data from the Japan COVID-19 Task Force database. After exclusion based on missing information, 1,109 patients with COVID-19 were included. The Agatston score was used to evaluate CAC, dividing the population into 3 groups based on calcification degree (no, moderate, and severe CAC). The primary outcome was cardiovascular complications; the secondary outcome was critical outcomes. The severe CAC group had a higher rate of cardiovascular complications than the other groups. Multivariable analysis, considering COVID-19 severity factors, identified severe CAC as independently associated with cardiovascular complications but not with critical outcomes. Subgroup analysis revealed that, in patients without hypertension, diabetes, cardiovascular disease, or chronic kidney disease, severe CAC was significantly correlated with cardiovascular complications, whereas this association was not observed in patients with these underlying conditions. CONCLUSIONS: Patients with COVID-19 and severe CAC had increased cardiovascular complications, and identifying cardiovascular and pulmonary findings on chest CT is essential. Measuring CAC via non-electrocardiogram-gated CT helps predict patient risk.

BACKGROUND: Multiple prolonged symptoms are observed in patients who recover from acute coronavirus disease 2019 (COVID-19), defined as long COVID. Cough and sputum are presented by patients with long COVID during the acute and post-acute phases. This study aimed to identify specific risk factors for cough and sputum in patients with long COVID. METHODS: Hospitalized patients with COVID-19 aged 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: At the 3-, 6-, and 12-month follow-ups, there were no differences in the incidence rates of wet and dry coughs. In contrast, the proportion of patients presenting sputum without coughing increased over time compared to those with sputum and coughing. Univariate analyses of cough and sputum at all follow-up visits identified intermittent mandatory ventilation (IMV), smoking, and older age as risk factors for prolonged symptoms. At the 12-month follow-up, persistent cough and sputum were associated with the characteristics of severe COVID-19 based on imaging findings, renal and liver dysfunction, pulmonary thromboembolism, and higher serum levels of LDH, KL-6, and HbA1C. The Kaplan-Meier curves showed that the severity of acute COVID-19 infection was correlated with prolonged cough and sputum production. Multivariable logistic regression analysis showed that IMV ventilator management were independent risk factors for prolonged cough and sputum at 12 months. CONCLUSIONS: In a Japanese population with long COVID, prolonged cough and sputum production were closely associated with severe COVID-19. These findings emphasize that a preventive approach including appropriate vaccination and contact precaution and further development of therapeutic drugs for COVID-19 are highly recommended for patients with risk factors for severe infection to avoid persistent respiratory symptoms.

INTRODUCTION: Since the SARS-CoV-2 Omicron variant became dominant, assessing COVID-19 vaccine effectiveness (VE) against severe disease using hospitalization as an outcome became more challenging due to incidental infections via admission screening and variable admission criteria, resulting in a wide range of estimates. To address this, the World Health Organization (WHO) guidance recommends the use of outcomes that are more specific to severe pneumonia such as oxygen use and mechanical ventilation. METHODS: A case-control study was conducted in 24 hospitals in Japan for the Delta-dominant period (August-November 2021; "Delta") and early Omicron (BA.1/BA.2)-dominant period (January-June 2022; "Omicron"). Detailed chart review/interviews were conducted in January-May 2023. VE was measured using various outcomes including disease requiring oxygen therapy, disease requiring invasive mechanical ventilation (IMV), death, outcome restricting to "true" severe COVID-19 (where oxygen requirement is due to COVID-19 rather than another condition(s)), and progression from oxygen use to IMV or death among COVID-19 patients. RESULTS: The analysis included 2125 individuals with respiratory failure (1608 cases [75.7%]; 99.2% of vaccinees received mRNA vaccines). During Delta, 2 doses provided high protection for up to 6 months (oxygen requirement: 95.2% [95% CI:88.7-98.0%] [restricted to "true" severe COVID-19: 95.5% {89.3-98.1%}]; IMV: 99.6% [97.3-99.9%]; fatal: 98.6% [92.3-99.7%]). During Omicron, 3 doses provided high protection for up to 6 months (oxygen requirement: 85.5% [68.8-93.3%] ["true" severe COVID-19: 88.1% {73.6-94.7%}]; IMV: 97.9% [85.9-99.7%]; fatal: 99.6% [95.2-99.97]). There was a trend towards higher VE for more severe and specific outcomes. CONCLUSION: Multiple outcomes pointed towards high protection of 2 doses during Delta and 3 doses during Omicron. These results demonstrate the importance of using severe and specific outcomes to accurately measure VE against severe COVID-19, as recommended in WHO guidance in settings of intense transmission as seen during Omicron.

Pulmonary manifestations in patients with allergic bronchopulmonary aspergillosis (ABPA) and nontuberculous mycobacterial-pulmonary disease (NTM-PD) include bronchiectasis and mucus plugging. A 68-year-old woman, treated with antibiotics and inhaled corticosteroids for NTM-PD and asthma, presented with fever and wheezing. ABPA was diagnosed based on laboratory findings (elevated peripheral blood eosinophil counts and serum total IgE levels and positive Aspergillus-specific IgE and IgG) and imaging observation of a high-attenuation mucus plug. Systemic prednisolone was avoided to prevent NTM-PD progression. Dupilumab, a monoclonal antibody that blocks IL-4/13, was introduced to improve the clinical findings. Herein, we discuss the pathophysiological mechanisms underlying this rare comorbidity.

Background: Nontuberculous mycobacterial pulmonary disease (NTM-PD) often develops in patients with rheumatoid arthritis (RA), especially during immunosuppressive treatment, including biological disease-modifying antirheumatic drugs. NTM-PD is associated with airway lesions such as bronchiectasis, which is frequently seen in RA patients. Distinguishing which diseases cause the pulmonary lesion is difficult. However, there are limited reports of the development of RA during the follow-up of NTM-PD and how biological agents should be administered in these conditions, especially with cavitary lesions. Case Presentation: A 62-year-old woman with hemosputum was referred to our hospital, where she was diagnosed with Mycobacterium avium pulmonary disease. She began treatment with several antibiotics, including clarithromycin, ethambutol, rifampicin, and amikacin. In the course of treatment, M. avium became macrolide-resistant. Five years after beginning antibiotic treatment, she felt arthralgia in the fingers and wrists and had a high titer of rheumatoid factor and anticitrullinated peptide antibody, with which we diagnosed RA. Methotrexate, prednisolone, and iguratimod were subsequently administered, but the activity of RA gradually worsened. Meanwhile, M. avium changed to a macrolide-susceptible strain, her sputum smear results remained almost negative, and the NTM-PD disease was well controlled with antimicrobial therapy, despite her having cavitary lesions. Therefore, we started using CTLA4-Ig (abatacept). RA symptoms were substantially ameliorated. The pulmonary lesions and NTM-PD worsened mildly, but her pulmonary symptoms were stable. Conclusion: Physicians should be mindful of the etiologies of bronchiectasis, including RA, even in patients with a long-term history of treatment for bronchiectasis and NTM-PD. When NTM-PD is well controlled, even with remaining cavitary lesions, abatacept may be an option for patients with RA based on a comprehensive assessment of disease progression using NTM sputum smear/culture, computed tomography findings, and treatment response.

OBJECTIVES: We investigated the occurrence of non-respiratory bacterial and fungal secondary infections, causative organisms, impact on clinical outcomes, and association between the secondary pathogens and mortality in hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: This was a retrospective cohort study that included data from inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021). We obtained demographic, epidemiological, and microbiological data throughout the course of hospitalization and analyzed the cases of COVID-19 complicated by non-respiratory bacterial infections. RESULTS: Of the 1914 patients included, non-respiratory bacterial infections with COVID-19 were diagnosed in 81 patients (4.2%). Of these, 59 (3.1%) were secondary infections. Bacteremia was the most frequent bacterial infection, occurring in 33 cases (55.9%), followed by urinary tract infections in 16 cases (27.1%). Staphylococcus epidermidis was the most common causative organism of bacteremia. Patients with COVID-19 with non-respiratory secondary bacterial infections had significantly higher mortality, and a multivariate logistic regression analysis demonstrated that those with bacteremia (aOdds Ratio = 15.3 [5.97-39.1]) were at higher risk of death. Multivariate logistic regression analysis showed that age, male sex, use of steroids to treat COVID-19, and intensive care unit admission increased the risk for nosocomial bacteremia. CONCLUSIONS: Secondary bacteremia is an important complication that may lead to poor prognosis in cases with COVID-19. An appropriate medical management strategy must be established, especially for patients with concomitant predisposing factors.

Direct reprogramming is a breakthrough technology that can alter the fate of cells without the passage of stem cells. However, direct reprogramming of somatic cells into pulmonary alveolar epithelial cells has not yet been achieved. Here, we report the direct reprogramming of mouse tail tips and embryonic fibroblasts into induced pulmonary alveolar epithelial-like cells (iPULs) using four transcription factor-coding genes (Nkx2-1, Foxa1, Foxa2, and Gata6) and three-dimensional culture. The iPULs showed lamellar body-like structures and displayed key properties of pulmonary alveolar epithelial cells. Although the potential for iPULs to morphologically differentiate into alveolar epithelial type 1 cells was limited in vitro, the intratracheal administration of iPULs in a bleomycin-induced mouse model of pulmonary fibrosis led to their integration into the alveolar surface, where they formed both alveolar epithelial type 1 and type 2-like cells. Thus, reprogrammed fibroblasts may represent a new source of pulmonary alveolar epithelial cells for regenerative medicine.

Mycobacterium xenopi is a slow-growing mycobacterial organism for which pathogenic features are unclear. Here, we report the complete genome sequence of an M. xenopi type strain. This sequence will provide essential information for future taxonomic and comparative genome studies of these mycobacteria.

After publication of the original article [1], we were notified that units of testosterone in main text and abstract and units of DHEA-S in Fig. 1 and Table 4 are incorrect.

BACKGROUND: As lung cancer development in patients with nontuberculous mycobacterial lung disease (NTM-LD) has never been reported, we investigated its incidence and clinical characteristics. METHODS: Prospective observational cohort registry (from June 2012 to June 2017), and retrospective identification by the International Classification of Diseases, tenth revision (between March 2010 and March 2018), were used to identify NTM-LD patients aged ≥20 years who developed lung cancer. RESULTS: Eight patients (two men and six women, one with smoking history), having Mycobacterium avium complex lung disease (MAC-LD) were identified. Four were identified from retrospective chart reviews and four from the prospective observational cohort registry (n = 361, 289 women; 311 never-smokers). All patients underwent chest computed tomography (CT) at least once a year. The incidence rate of lung cancer developing in NTM-LD patients was 124.6 per 100,000 patient-years, which was higher than the lung cancer rate in Japan. The mean age at diagnosis of MAC-LD and lung cancer was 63.6 and 74.4 years, respectively. The most common lung cancer types were adenocarcinoma (six patients) followed by squamous cell carcinoma (two patients). Lung cancer was diagnosed at early and advanced clinical stages in seven and one patients, respectively. Outcomes were favorable, except in two patients: one with advanced stage disease, and another with poor performance status. CONCLUSIONS: We identified the clinical characteristics of eight MAC-LD patients who developed lung cancer. NTM-LD may be a risk factor for lung cancer development. Periodic follow-up with chest CT might contribute to early diagnosis and curative therapy for lung cancer.

A 72-year-old man was admitted due to dyspnea on exertion with interstitial shadows and elevated serum creatinine kinase (CK). Despite a close examination, which included magnetic resonance imaging (MRI), we could not diagnose myopathy. Prednisolone was administered and gradually tapered. One year later, anti-signal recognition particle (SRP) antibody was confirmed and he was re-admitted for hypoxemia with elevated CK. MRI revealed muscle edema and a histopathological examination of a muscle biopsy specimen showed necrotizing myopathy. Prednisolone, cyclosporine, and intravenous immunoglobulin were administered. Physicians should carefully monitor muscle symptoms and serum CK levels in cases of interstitial lung disease with anti-SRP antibodies.