Published papers

Pneumocystis pneumonia (PCP) primarily affects immunosuppressed patients, with trimethoprim-sulfamethoxazole (TMP-SMX) commonly used for prophylaxis. However, there is insufficient information on PCP occurrence despite TMP-SMX prophylaxis. We encountered a 57-year-old woman with locally advanced breast cancer developing PCP despite prophylactic intake of TMP-SMX, during treatment with prednisolone for Stevens-Johnson syndrome (SJS) induced by pembrolizumab. This case underscores the need to pay attention to the possibility of PCP development even during TMP-SMX prophylaxis. Dosage and duration adjustments according to the patient's condition and weight may be required.

The incidence of nontuberculous mycobacterial pulmonary disease (NTMPD) is increasing worldwide. Secondary spontaneous pneumothorax occurs as a complication of underlying lung disease and is associated with higher morbidity, mortality, and recurrence than primary spontaneous pneumothorax. We here investigated the clinical features and long-term outcomes of pneumothorax associated with NTMPD.We conducted a retrospective study on consecutive adult patients with pneumothorax associated with NTMPD at Fukujuji Hospital and Keio University Hospital from January 1992 to December 2013. We reviewed the medical records of 69 such patients to obtain clinical characteristics, radiological findings, and long-term outcomes, including pneumothorax recurrence and mortality.The median age of the patients was 68 years; 34 patients were women. The median body mass index was 16.8 kg/m. Underlying pulmonary diseases mainly included chronic obstructive pulmonary disease and pulmonary tuberculosis. On computed tomography, nodules and bronchiectasis were observed in 46 (98%) and 45 (96%) patients, respectively. Consolidation, pleural thickening, interlobular septal thickening, and cavities were most common, and observed in 40 (85%), 40 (85%), 37 (79%), and 36 (77%) patients, respectively. Regarding pneumothorax treatment outcomes, complete and incomplete lung expansion were observed in 49 patients (71%) and 15 patients (22%), respectively. The survival rate after pneumothorax was 48% at 5 years. By the end of the follow-up, 33 patients had died, and the median survival was 4.4 years with a median follow-up period of 1.7 years. The rate of absence of recurrence after the first pneumothorax was 59% at 3 years. By the end of the follow-up, 18 patients had experienced pneumothorax recurrence. Furthermore, 12/18 patients (66%) with recurrent pneumothorax died during the study period. Twenty-three patients (70%) died because of NTMPD progression. Low body mass index (BMI) was a negative prognostic factor for pneumothorax associated with NTMPD in multivariate analysis (HR 0.79, 95% CI 0.64-0.96; P = 0.018)Patients with pneumothorax associated with NTMPD have advanced disease, a high rate of pneumothorax recurrence, and poor prognosis, regardless of the pneumothorax treatment used. Further improvements in early diagnosis of NTMPD and appropriate management in both NTMPD and NTMPD-associated pneumothorax are needed.

BACKGROUND: In the Berlin definition, acute respiratory distress syndrome (ARDS) is stratified into three stages according to oxygenation severity at the onset. The relevance between ARDS severity and prognosis varies among published reports and has not been verified, especially in Asian patients. METHODS: In this study, we examined the associations between the Berlin definition criteria and prognosis and clinical parameters, including high-resolution computed tomography (HRCT) scores of fibroproliferative changes of the lungs. One hundred fifty-three patients (45 females; mean age, 67 y/o), who met the Berlin definition and received treatment in our intensive care unit between January 2012 and December 2015, were enrolled. RESULTS: The severity of ARDS was mild in 42 patients, moderate in 71, and severe in 40. The underlying diseases included pneumonia in 56 patients and aspiration in 43. Forty-two (27.5%) patients were deceased within 30 days, and the 30-day mortality was 10% in mild ARDS, 23% in moderate, and 55% in severe, which were significantly different (P <  0.05). In the non-survivors, APACHE II, SOFA, and SAPS II scores were higher than in the survivors (P <  0.001). Multivariate analyses revealed that elevated blood lactate level (≥ 2.0 mmol/L) and increased HRCT scores were significantly associated with weaning failure and 30-day mortality of the patients with ARDS. CONCLUSIONS: These results suggested that the severity criteria in the Berlin definition might be associated with the prognosis of the patients. Blood lactate levels and HRCT score might be predictive of the outcome of patients with ARDS.

OBJECTIVES: To compare the characteristics and prognosis of patients with nontuberculous mycobacterial (NTM) pulmonary disease (PD) with pleuroparenchymal fibroelastosis (PPFE) with those of patients with nodular/bronchiectatic (NB) and fibrocavitary (FC) NTM-PD. METHODS: This multicenter, retrospective, observational study enrolled 32 patients with NTM-PPFE (median age: 70.5 years, 15 females) from six institutions in Japan from January 2003 to December 2018. Their clinical characteristics, and response to therapy were compared with age- and sex-matched cohorts of patients with non-cavitary NB and cavitary NB/FC NTM-PD. RESULTS: Patients with NTM-PPFE had a lower body mass index and a higher standard NTM-PD therapy initiation rate than patients with other NTM-PD types. Sputum culture conversion rates were comparable between groups; however, patients with NTM-PPFE had a higher incidence of treatment-related adverse events, including optic neuropathy associated with high-dose ethambutol therapy, lower percent predicted forced vital capacity values, higher serum Krebs von den Lungen 6 (KL-6) levels, and poorer treatment outcomes than the other groups. Cox regression revealed that NTM-PPFE was an independent risk factor for death/pneumothorax (adjusted hazard ratio: 35.3, 95% confidence interval: 3.90-4692). CONCLUSIONS: NTM-PPFE is a unique NTM-PD phenotype with a poorer prognosis than the NB and FC phenotypes.

Purpose: Amikacin liposome inhalation suspension (ALIS), which efficiently allows amikacin to reach the pulmonary periphery for effect while minimising systemic adverse effects, was recently approved for treating Mycobacterium avium complex (MAC) infections. The international Phase 3 open-label clinical trials showed promising results, contributing to sputum culture conversion, but few studies have examined the efficacy and adverse effects of ALIS using real-world data. We identified the clinical outcome and adverse effects of ALIS in the early phase of treatment, for more effective and safe use in clinical practice. Patients and Methods: The study population consisted of patients with MAC lung disease (MAC-LD), introduced to ALIS therapy after July 2021 at Keio University Hospital due to poor response to multidrug therapy. The sputum smear/culture results, symptoms, adverse effects, and the serum amikacin concentrations of the early phase of ALIS inhalation therapy were examined. Results: A total of 11 patients (9 women; median age 64.6 years) were included in this study. The median disease duration of MAC-LD was 13.7 years, and all patients exhibited a positive culture at the beginning of ALIS inhalation. Three of the six patients (50.0%) who were initially sputum-smear-positive were confirmed to have become sputum-smear-negative within one month, including one culture conversion. ALIS inhalation therapy caused some adverse effects in nine patients (81.8%); however, no serious systemic adverse effects were observed. The most common adverse effect was hoarseness (72.7%), which mostly occurred around 1 week after initiation. The medians of peak serum amikacin concentrations were 1.4 and 2.3 μg/mL for the first and third inhalations, respectively. Trough serum concentrations just before the third inhalation were <1.2 μg/mL in all patients. Conclusion: ALIS therapy might be a treatment option for patients with refractory MAC infection with long disease duration and a poor response to guideline-based therapy.

BACKGROUND: Computed tomography (CT) imaging is widely used for diagnosing and determining the severity of coronavirus disease 2019 (COVID-19). Chest CT imaging can be used to calculate the epicardial adipose tissue (EAT) and upper abdominal visceral adipose tissue (Abd-VAT) areas. The EAT is the main source of inflammatory cytokines involved in chest inflammatory diseases; thus, the EAT area might be a more useful severity predictor than the Abd-VAT area for COVID-19. However, to the best of our knowledge, there are no large-scale reports that sufficiently consider this issue. In addition, there are no reports on the characteristics of patients with normal body mass index (BMI) and high adipose tissue. AIM: The purpose of this study was to analyze whether the EAT area, among various adipose tissues, was the most associated factor with COVID-19 severity. Using a multicenter COVID-19 patient database, we analyzed the associations of chest subcutaneous, chest visceral, abdominal subcutaneous, and Abd-VAT areas with COVID-19 outcomes. In addition, the clinical significance of central obesity, commonly disregarded by BMI, was examined. METHODS: This retrospective cohort study evaluated patients with COVID-19 aged ≥18 years In Japan. Data including from chest CT images collected between February 2020 and October 2022 in four hospitals of the Japan COVID-19 Task Force were analyzed. Patient characteristics and COVID-19 severity were compared according to the adipose tissue areas (chest and abdominal subcutaneous adipose tissue [Chest-SAT and Abd-SAT], EAT, and Abd-VAT) calculated from chest CT images. RESULTS: We included 1077 patients in the analysis. Patients with risk factors of severe COVID-19 such as old age, male sex, and comorbidities had significantly higher areas of EAT and Abd-VAT. High EAT area but not high Abd-VAT area was significantly associated with COVID-19 severity (adjusted odds ratio (aOR): 2.66, 95 % confidence interval [CI]: 1.19-5.93). There was no strong correlation between BMI and VAT. Patients with high VAT area accounted for 40.7 % of the non-obesity population (BMI < 25 kg/m2). High EAT area was also significantly associated with COVID-19 severity in the non-obesity population (aOR: 2.50, 95 % CI: 1.17-5.34). CONCLUSIONS: Our study indicated that VAT is significantly associated with COVID-19 severity and that EAT is the best potential predictor for risk stratification in COVID-19 among adipose tissue areas. Body composition assessment using EAT is an appropriate marker for identifying obesity patients overlooked by BMI. Considering the next pandemic of the global health crisis, our findings open new avenues for implementing appropriate body composition assessments based on CT imaging.

BACKGROUND: This study assessed longitudinal national data on mortality due to nontuberculous mycobacteriosis (NTMosis) and bronchiectasis and the association between the two diseases. METHODS: We analysed the national death statistics of Japan from 1970 to 2015. The International Classification of Disease (ICD) codes were used to extract the relevant data. Crude mortality, age-adjusted mortality and standardised mortality rates were calculated using vital statistics and the population in 2000. We also identified domestic publications related to NTMosis and bronchiectasis with an internet-based search system. RESULTS: The total number of bronchiectasis-related deaths remained at the same level, which was approximately 1000, for 45 years, although the number of deaths has consistently decreased in males but increased in females since the mid-1990s. A substantial increasing trend in females was also observed for NTMosis in the same period. The age-adjusted mortality data showed an increase in mortality in women due to NTMosis and confirmed the trend in bronchiectasis in women. The patterns in the number of domestic reports showed a recent slight increase in bronchiectasis and a marked increase in NTMosis. CONCLUSIONS: The trends in bronchiectasis-related mortality differed by sex. The epidemiological trends in the two diseases were associated, especially in elderly females since the mid-1990s. It is suggested that pulmonary NTMosis without pre-existing bronchiectasis might be a leading cause of postinfectious bronchiectasis in Japan.

ABSTRACT Background Chest computed tomography (CT) is a valuable tool for diagnosing and predicting the severity of coronavirus disease 2019 (COVID‐19) and assessing extrapulmonary organs. Reduced muscle mass and visceral fat accumulation are important features of a body composition phenotype in which obesity and muscle loss coexist, but their relationship with COVID‐19 outcomes remains unclear. In this study, we aimed to investigate the association between the erector spinae muscle (ESM) to epicardial adipose tissue (EAT) ratio (ESM/EAT) on chest CT and disease severity in patients with COVID‐19. Methods We analysed data from 1074 COVID‐19 patients enrolled in the Japan COVID‐19 Task Force database. The primary outcome was the rate of critical outcomes (requiring high‐flow oxygen therapy, invasive ventilator support or death). The incidence of critical outcomes was compared between patients with high and low ESM/EAT ratios. Results The low ESM/EAT group (n = 353) had a higher incidence of critical outcomes (13.3% vs. 5.13%, p < 0.001) and mortality (2.55% vs. 0.69%, p = 0.019) than the high ESM/EAT group (n = 721). In multivariable analysis, the low ESM/EAT ratio was associated with critical outcomes (adjusted odds ratio [aOR] 2.11, 95% confidence interval [CI] 1.22–3.66) independently of the known COVID‐19 severity factors including age, sex, body mass index (BMI), smoking history, lifestyle‐related comorbidities and pneumonia volume. Conclusion The low ESM/EAT ratio in COVID‐19 patients can be obtained on chest CT and used to predict critical outcomes after disease onset, demonstrating the importance of detailed body composition assessments in COVID‐19 practice.

Background: Research on whether gastrointestinal symptoms correlate with the severity of Coronavirus Disease 2019 (COVID-19) has been inconclusive. This study aimed to clarify any associations between gastrointestinal symptoms and the prognosis of COVID-19. Methods: We collected data from the Japanese nationwide registry for COVID-19 to conduct a retrospective cohort study. Data from 3498 Japanese COVID-19 patients, diagnosed at 74 facilities between February 2020 and August 2022, were analyzed in this study. Hospitalized patients were followed up until discharge or transfer to another hospital. Outpatients were observed until the end of treatment. Associations between gastrointestinal symptoms and clinical outcomes were investigated using multivariable-adjusted logistic regression models. Results: The prevalence of diarrhea, nausea/vomiting, abdominal pain, and melena were 16.6% (581/3498), 8.9% (311/3498), 3.5% (121/3498), and 0.7% (23/3498), respectively. In the univariable analysis, admission to intensive care unit (ICU) and requirement for mechanical ventilation were less common in patients with diarrhea than those without (ICU, 15.7% vs. 20.6% (p = 0.006); mechanical ventilation, 7.9% vs. 11.4% (p = 0.013)). In the multivariable-adjusted analysis, diarrhea was associated with lower likelihood of ICU admission (adjusted odds ratio (aOR), 0.70; 95% confidence interval (CI), 0.53–0.92) and mechanical ventilation (aOR, 0.61; 95% CI, 0.42–0.89). Similar results were obtained in a sensitivity analysis with another logistic regression model that adjusted for 14 possible covariates with diarrhea (ICU; aOR, 0.70; 95% CI, 0.53–0.93; mechanical ventilation; aOR 0.62; 95% CI, 0.42–0.92). Conclusions: Diarrhea was associated with better clinical outcomes in COVID-19 patients.

RATIONALE: Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear. OBJECTIVES: We aimed to identify host susceptibility loci for Mycobacterium avium complex (MAC), the most common NTM pathogen. METHODS: This genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping. RESULTS: The GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64×10-13, OR 0.54), which is in an intronic region of the calcineurin-like EF-hand protein 2 (CHP2). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. Additionally, this SNP was significantly associated with the disease in patients of Korean (p=2.18×10-12, OR 0.54) and European (p=5.12×10-03, OR 0.63) ancestry. CONCLUSIONS: We identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.

OBJECTIVES: Smoking and chronic obstructive pulmonary disease (COPD) are risk factors of severe coronavirus disease 2019 (COVID-19). However, limited literature exists on the effect of COPD and smoking on COVID-19 outcomes. This study examined the impact of smoking exposure in pack-years (PY) and COPD on COVID-19 outcomes among smokers in Japan. METHODS: The study included 1266 smokers enrolled by the Japan COVID-19 Task Force between February 2020 and December 2021. PY and COPD status were self-reported by patients. Patients were classified into the non-COPD (n=1151) and COPD (n=115) groups; the non-COPD group was further classified into <10 PY (n=293), 10-30 PY (n=497), and >30 PY (n=361). The study outcome was the need for invasive mechanical ventilation (IMV). RESULTS: The incidence of IMV increased with increasing PY and was highest in the COPD group (<10 PY=7.8%, 10-30 PY=12.3%, >30 PY=15.2%, COPD=26.1%; p<0.001). Significant association was found for IMV requirement in the >30 PY and COPD groups through univariate (odds ratio [OR]: >30 PY=2.11, COPD=4.14) and multivariate (OR: >30 PY=2.38; COPD=7.94) analyses. Increasing PY number was also associated with increased IMV requirement in patients aged <65 y. CONCLUSIONS: Cumulative smoking exposure was positively associated with COVID-19 outcomes in smokers.

BACKGROUND: Various prolonged systemic symptoms, forming the long coronavirus disease (COVID), have been observed in patients who have recovered from the acute phase of COVID-19. Although previous studies have reported that COVID-19 impacts health-related quality of life (HRQoL), the associations of long COVID symptoms and clinical characteristics with HRQoL remain unclear. This study aimed to clarify these associations using nationwide Japanese epidemiological data. METHODS: A prospective nationwide cohort study was conducted on patients with COVID-19 between January 2020 and February 2021 at 26 participating medical institutions in Japan. Various long COVID symptoms and HRQoL scores at 3, 6, and 12 months following diagnosis were collected from 986 participants. Generalized estimating equations (GEE) were used to explore the association between HRQoL scores evaluated using the short form-8 (SF-8), long COVID symptoms, and baseline clinical characteristics. RESULTS: Patients who had one long COVID symptom showed a significantly lower physical component summary score (PCS) and mental component summary score (MCS) compared with those without any symptoms at all time points after diagnosis. GEE revealed that long COVID symptoms, including dyspnea, fatigue, headache, and muscle weakness, were significantly associated with worse PCS, whereas poor concentration, sleep disorders, fatigue, and headache were significantly associated with worse MCS. Severity-related baseline parameters for patients with COVID-19 were significantly associated with worse PCS scores, although these factors were not significantly associated with worse MCS scores. CONCLUSIONS: Long COVID symptoms were associated with lower physical and mental HRQoL. Severe outcomes of COVID-19 impacted PCS but not MCS.

BACKGROUND: Although cases of respiratory bacterial infections associated with coronavirus disease 2019 (COVID-19) have often been reported, their impact on the clinical course remains unclear. Herein, we evaluated and analyzed the complication rates of bacterial infections, causative organisms, patient backgrounds, and clinical outcome in Japanese patients with COVID-19. METHODS: We performed a retrospective cohort study that included inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021) and obtained demographic, epidemiological, and microbiological results and the clinical course and analyzed the cases of COVID-19 complicated by respiratory bacterial infections. RESULTS: Of the 1,863 patients with COVID-19 included in the analysis, 140 (7.5%) had respiratory bacterial infections. Community-acquired co-infection at COVID-19 diagnosis was uncommon (55/1,863, 3.0%) and was mainly caused by Staphylococcus aureus, Klebsiella pneumoniae and Streptococcus pneumoniae. Hospital-acquired bacterial secondary infections, mostly caused by Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia, were diagnosed in 86 patients (4.6%). Severity-associated comorbidities were frequently observed in hospital-acquired secondary infection cases, including hypertension, diabetes, and chronic kidney disease. The study results suggest that the neutrophil-lymphocyte ratio (> 5.28) may be useful in diagnosing complications of respiratory bacterial infections. COVID-19 patients with community-acquired or hospital-acquired secondary infections had significantly increased mortality. CONCLUSIONS: Respiratory bacterial co-infections and secondary infections are uncommon in patients with COVID-19 but may worsen outcomes. Assessment of bacterial complications is important in hospitalized patients with COVID-19, and the study findings are meaningful for the appropriate use of antimicrobial agents and management strategies.

We aimed to elucidate the dynamic changes in short-chain fatty acids (SCFA) produced by the gut microbiota following smoking exposure and their role in chronic obstructive pulmonary disease (COPD) pathogenesis. SCFA concentrations were measured in human plasma, comparing non-smokers (n = 6) and smokers (n = 12). Using a mouse COPD model induced by cigarette smoke exposure or elastase-induced emphysema, we modulated SCFA levels through dietary interventions and antibiotics to evaluate their effects on inflammation and alveolar destruction. Human smokers showed lower plasma SCFA concentrations than non-smokers, with plasma propionic acid positively correlating with forced expiratory volume in 1 s/forced vital capacity. Three-month smoking-exposed mice demonstrated altered gut microbiota and significantly reduced fecal SCFA concentrations compared to air-exposed controls. In these mice, a high-fiber diet increased fecal SCFAs and mitigated inflammation and alveolar destruction, while antibiotics decreased fecal SCFAs and exacerbated disease features. However, in the elastase-induced model, fecal SCFA concentration remained unchanged, and high-fiber diet or antibiotic interventions had no significant effect. These findings suggest that smoking exposure alters gut microbiota and SCFA production through its systemic effects. The anti-inflammatory properties of SCFAs may play a role in COPD pathogenesis, highlighting their potential as therapeutic targets.