Contemporary Concise Review 2023: Environmental and occupational lung diseases.

Air pollutants have various effects on human health in environmental and occupational settings. Air pollutants can be a risk factor for incidence, exacerbation/aggravation and death due to various lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), hypersensitivity pneumonitis or pneumonia (HP), pulmonary fibrosis such as pneumoconiosis and malignant respiratory diseases such as lung cancer and malignant pleural mesothelioma. Environmental and occupational respiratory diseases are crucial clinical and social issues worldwide, although the burden of respiratory disease due to environmental and occupational causes varies depending on country/region, demographic variables, geographical location, industrial structure and socioeconomic situation. The correct recognition of environmental and occupational lung diseases and taking appropriate measures are essential to their effective prevention.

Clinical factors associated with viral shedding time of SARS-CoV-2 Omicron variant in Japan.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 exhibits increased infectivity compared with all prior variants, and the timing of quarantine release should be carefully considered. However, to date, only two Chinese studies have analyzed the association between the viral shedding time (VST) and risk factors among patients infected with the Omicron variant. These studies included only limited numbers of severe cases and no analysis of underlying diseases and immunosuppressive drug use. Therefore, the current study aimed to analyze them in Japan. This retrospective observational study was conducted at the University of Occupational and Environmental Health, Japan, from January 2022 to October 2022 and included 87 hospitalized patients and 305 healthcare workers (HCWs) with coronavirus 2019 (COVID-19). In comparison with HCWs, hospitalized patients were significantly older and had a higher proportion of severe COVID-19 cases and significantly longer VST. A simple regression analysis showed that severe, current, or ex-smoking status, cardiovascular diseases, chronic kidney disease, and use of corticosteroids for underlying diseases were significantly correlated with a longer VST. Moreover, multiple linear regression analysis revealed that cardiovascular diseases, chronic kidney disease, and corticosteroid use were significantly associated with a longer VST. Therefore, COVID-19 patients with these underlying diseases may require a longer isolation period and the timing of quarantine release should be carefully considered.

Epidemiologic evaluation of pulmonary paragonimiasis in Japan using a Japanese nationwide administrative database.

BACKGROUND: Paragonimiasis is a parasitic disease primarily contracted through consumption of undercooked freshwater crustaceans or wild boar meat. Large-scale nationwide epidemiological data on paragonimiasis are lacking. In this study, we aimed to investigate the nationwide epidemiology of hospitalized patients with paragonimiasis in Japan using a comprehensive nationwide Japanese administrative database. METHODS: We evaluated the Japanese Diagnosis Procedure Combination (DPC) data of patients diagnosed with pulmonary paragonimiasis between April 1, 2012 and March 30, 2020. The patients' address and information, including age, sex, treatment (medication: praziquantel; surgery: open thoracotomy or intracranial mass extirpation), Japan coma scale, comorbidities, and length of hospital stay, were extracted. RESULTS: Of the 49.6 million hospitalized patients, data were extracted on 73 patients with paragonimiasis, of whom 36 were male and 37 were female. The mean age was 49.7 years and the mean length of stay was 12.5 days. The most frequent comorbidity was pleural effusion (31.5 %), followed by pneumothorax (13.7 %). The sites of ectopic paragonimiasis in organs other than the lung included the liver (5.5 %), skin (4.1 %), and brain (2.7 %). Geographically, most patients were from the Kyushu region (54.8 %), followed by the Kanto region (22.0 %). Fukuoka Prefecture had the highest number of patients (22.0 %) by prefecture. During the study period, an average of 9.1 patients/year were hospitalized with lung paragonimiasis in Japan. CONCLUSION: Paragonimiasis has not completely disappeared in Japan; thus, physicians should be aware of paragonimiasis in the Kyushu region, especially in the Fukuoka Prefecture.

Efficacy and safety of lascufloxacin for nursing- and healthcare-associated pneumonia: A single-arm, open-label clinical trial.

BACKGROUND: Nursing- and healthcare-associated pneumonia (NHCAP) constitutes most of the pneumonia in elderly patients including aspiration pneumonia in Japan. Lascufloxacin (LSFX) possesses broad antibacterial activity against respiratory pathogens, such as Streptococcus spp. And anaerobes inside the oral cavity. However, the efficacy and safety of LSFX in NHCAP treatment remains unknown. We aimed to evaluate the efficacy and safety of LSFX tablets in the treatment of patients with NHCAP. METHODS: In this single-arm, open-label, uncontrolled study, LSFX was administered to patients with NHCAP at 24 facilities. The study participants were orally administered 75 mg LSFX once daily for 7 days. The primary endpoint was the clinical efficacy at the time of test of cure (TOC). The secondary endpoints included clinical efficacy at the time of end of treatment (EOT), early clinical efficacy, microbiological efficacy, and safety analysis. RESULT: During the study period, 75 patients provided written informed consent to participate and were included. Finally, 56 and 71 patients were eligible for clinical efficacy and safety analyses, respectively. The median age of the patients was significantly high at 86 years. All patients were classified as having moderate disease severity using the A-DROP scoring system. LSFX tablets demonstrated high efficacy rates of 78.6 % at TOC and 89.3 % at EOT. The risk factors for resistant bacteria or aspiration pneumonia did not affect clinical efficacy. No severe adverse events associated with the study drugs were observed. CONCLUSION: Oral LSFX is an acceptable treatment option for moderate NHCAP in elderly patients who can take oral medications.

The Effects of Endoplasmic Reticulum Stress via Intratracheal Instillation of Water-Soluble Acrylic Acid Polymer on the Lungs of Rats.

Polyacrylic acid (PAA), an organic chemical, has been used as an intermediate in the manufacture of pharmaceuticals and cosmetics. It has been suggested recently that PAA has a high pulmonary inflammatory and fibrotic potential. Although endoplasmic reticulum stress is induced by various external and intracellular stimuli, there have been no reports examining the relationship between PAA-induced lung injury and endoplasmic reticulum stress. F344 rats were intratracheally instilled with dispersed PAA (molecular weight: 269,000) at low (0.5 mg/mL) and high (2.5 mg/mL) doses, and they were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months after exposure. PAA caused extensive inflammation and fibrotic changes in the lungs' histopathology over a month following instillation. Compared to the control group, the mRNA levels of endoplasmic reticulum stress markers Bip and Chop in BALF were significantly increased in the exposure group. In fluorescent immunostaining, both Bip and Chop exhibited co-localization with macrophages. Intratracheal instillation of PAA induced neutrophil inflammation and fibrosis in the rat lung, suggesting that PAA with molecular weight 269,000 may lead to pulmonary disorder. Furthermore, the presence of endoplasmic reticulum stress in macrophages was suggested to be involved in PAA-induced lung injury.

Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2019-2020: General view of the pathogens' antibacterial susceptibility.

The trends and prevalence of antimicrobial susceptibility of pathogens vary by country, region, and time. Long-term regular surveillance is required to investigate trends in the antimicrobial resistance of various isolated bacterial pathogens. We report the results of a nationwide surveillance on the antimicrobial susceptibility of bacterial respiratory pathogens in Japan conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology. The isolates were collected from clinical specimens obtained from adult patients who visited a collaborating medical facility between June 2019 and December 2020 and were diagnosed with respiratory tract infections by a physician. Antimicrobial susceptibility testing was performed in a centralized laboratory according to the methods recommended by the Clinical and Laboratory Standards Institute. Susceptibility testing was performed for 932 strains (201 Staphylococcus aureus, 158 Streptococcus pneumoniae, 6 S. pyogenes, 136 Haemophilus influenzae, 127 Moraxella catarrhalis, 141 Klebsiella pneumoniae, and 163 Pseudomonas aeruginosa) collected from 32 facilities in Japan. The proportions of methicillin-resistant S. aureus and penicillin-resistant S. pneumoniae were 35.3% and 0%, respectively. In H. influenzae, 16.2% and 16.9% were ß-lactamase-producing ampicillin resistant and ß-lactamase-negative ampicillin resistant, respectively. Extended-spectrum ß-lactamase-producing K. pneumoniae accounted for 5.0% of all K. pneumoniae infections. Carbapenemase-producing K. pneumoniae and multi-drug-resistant P. aeruginosa with metallo-ß-lactamase were not detected in this study. This surveillance will be a useful reference for treating respiratory infections in Japan and will provide evidence to enhance the appropriate use of antimicrobial agents.

Association of cigarette smoking with increased use of heated tobacco products in middle-aged and older adults with self-reported chronic obstructive pulmonary disease, asthma, and asthma-COPD overlap in Japan, 2022: the JASTIS study.

BACKGROUND: Smoking cessation is the most important intervention in chronic obstructive pulmonary disease (COPD), asthma, and asthma-COPD overlap (ACO); however, high rates of current cigarette smoking are observed in adults with these respiratory diseases. Meanwhile, rapidly increasing use of heated tobacco products (HTPs) is observed in Japan; however, the status of HTPs use has not been fully understood in adults with COPD, asthma, and ACO. This study aimed to reveal the association between COPD, asthma, and ACO and HTPs use in adults. METHODS: Data on Japanese individuals ≥ 40 years old obtained from the Japan Society and New Tobacco Internet Survey were analyzed. The prevalence of HTPs use in adults with COPD, asthma, and ACO, among individuals categorized into three groups according to cigarette smoking (never, former, and current), was calculated and the relationship between each disease and HTPs use were evaluated. The clinical diagnosis of these diseases was based on the self-reported diagnosis, as obtained from questionnaires. RESULTS: A total of 19,308 individuals were included. The proportions of never, past, and current cigarettes smokers were 10,900 (56.5%), 4,903 (25.4%), and 3,505 (18.2%), respectively, and that of HTPs use was 1,813 (9.4%). In current cigarettes smokers, the adjusted odds ratios (ORs) of HTPs use was 2.88 (95% CI [confidence interval], 1.86-4.47), 1.23 (95% CI, 0.99-1.52), and 5.81 (95% CI, 3.12-10.82) in adults with COPD, asthma, and ACO compared to those without these respiratory diseases, respectively. Meanwhile, in past cigarettes smokers, the adjusted ORs of HTPs use was 0.51 (95% CI, 0.24-1.08), 0.69 (95% CI, 0.53-0.88), and 0.25 (95% CI, 0.06-1.07) in adults with COPD, asthma, and ACO, respectively. CONCLUSIONS: HTPs use is more prevalent among current cigarettes smokers with COPD, asthma, and ACO compared to those without these respiratory diseases. Complete cessation of smoking both cigarettes and HTPs is the only way to achieve complete smoking cessation, therefore, adults with COPD, asthma, and ACO need to make greater efforts to quit smoking.

Clinical significance of serum autoantibodies in patients with sarcoidosis.

BACKGROUND: The association between sarcoidosis and autoimmunity has been reported for years. However, the significance of autoantibodies in the pathophysiology and clinical management of sarcoidosis is not well understood. No autoantibodies that can be used as serologic biomarkers to diagnose the disease, monitor the state of the disease, and predict the prognosis of patients are established. METHODS: We performed a comprehensive analysis of serum autoantibodies and analyzed their associations with clinical features of sarcoidosis. RESULTS: Patients with systemic autoimmune rheumatic diseases-associated autoantibodies had a higher prevalence of advanced radiographic stage and consolidations in high-resolution computed tomography than patients without autoantibodies (p < .05). Age, sex, clinical history, pulmonary function tests, serum angiotensin-converting enzyme levels, rheumatoid factor, and the number of involved organs were not significantly different between the two groups. CONCLUSIONS: There may be an association between autoantibodies and more advanced pulmonary lesions in patients with sarcoidosis. Further investigations are needed to establish the significance of autoantibodies.

Oxidative stress causes muscle structural alterations via p38 MAPK signaling in COPD mouse model.

INTRODUCTION: Sarcopenia is a complication of Chronic Obstructive Pulmonary Disease (COPD) that negatively affects physical activity and quality of life. However, the underlying mechanism by which COPD affects skeletal muscles remains to be elucidated. Therefore, we investigated the association between oxidative stress and structural alterations in muscles in elastase-induced emphysema mouse models. MATERIALS AND METHODS: Twelve-week-old male C57BL/6J mice were treated with either intratracheal porcine pancreatic elastase (PPE) dissolved in saline, or saline alone. The mice were euthanized 12 weeks after treatment, and the lungs and limb muscles were used for protein analysis of oxidative stress, p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway and muscle atrophy signaling pathway related with oxidative stress. Furthermore, C57BL/6J mice treated with PPE or saline were analyzed for the effects of oral administration of astaxanthin or p38 inhibitor. RESULTS: The weight of the soleus muscle, proportion of type I muscle fibers, and cross-sectional areas of muscle fibers in the PPE group were lower than those in the control group. Oxidative stress marker levels in the PPE group were elevated in skeletal muscles. The p38 MAPK signaling pathway was activated in the soleus muscles, leading to the activation of the ubiquitin-proteasome system and autophagy. Astaxanthin and p38 inhibitors attenuated alterations in muscle structure through the deactivation of the p38 MAPK signaling pathway. CONCLUSIONS: This study provides first evidence in COPD mouse model that oxidative stress trigger a series of muscle structural changes. Our findings suggest a novel target for sarcopenia in COPD.

Medication Wastage in a University Hospital in Japan.

Medication wastage is a global issue; however, there are few reports in Japanese hospitals. The purpose of this study was to clarify the situation of medication wastage at our university hospital. We investigated the numbers, costs, reasons, occurrence departments, and involvement of high-priced medications of medication wastage for two years. We analyzed 6730 cases and the total cost was 22782027 Japanese yen (JPY). The most common reasons for medication wastage were change or discontinuation of medication after preparation and breakage or contamination due to dropping. The highest cost was expired medications. The department with the highest number of cases was the hospital wards; however, the hospital pharmacy department accounted for the majority of the costs and most of the reasons were expired medications. Medication wastage of 50000 JPY or more per case was only 1.3% of the total but accounted for 70.7% of the cost and medication wastage of 100000 JPY or more per case was only 0.7% of the total but accounted for 58.6% of the cost. These findings indicate that expired medications in the hospital pharmacy department have the largest impact on medication wastage from the viewpoint of economic loss, and suggest the need for efforts on medication management focusing on high-priced medications. The challenge of minimizing medication wastage should be addressed from the perspectives of both hospital management and the effective use of resources.

Inflammogenic effect of polyacrylic acid in rat lung following intratracheal instillation.

BACKGROUND: Some organic chemicals are known to cause allergic disorders such as bronchial asthma and hypersensitivity pneumonitis, and it has been considered that they do not cause irreversible pulmonary fibrosis. It has recently been reported, however, that cross-linked acrylic acid-based polymer, an organic chemical, might cause serious interstitial lung diseases, including pulmonary fibrosis. We investigated whether or not intratracheal instillation exposure to cross-linked polyacrylic acid (CL-PAA) can cause lung disorder in rats. METHODS: Male F344 rats were intratracheally instilled with dispersed CL-PAA at low (0.2 mg/rat) and high (1.0 mg/rat) doses, and were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months after exposure to examine inflammatory and fibrotic responses and related gene expressions in the lungs. Rat lungs exposed to crystalline silica, asbestos (chrysotile), and NiO and CeO2 nanoparticles were used as comparators. RESULTS: Persistent increases in total cell count, neutrophil count and neutrophil percentage, and in the concentration of the cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2 and C-X-C motif chemokine 5 (CXCL5), which correlated with lung tissue gene expression, were observed in bronchoalveolar lavage fluid (BALF) from 3 days until at least 1 month following CL-PAA intratracheal instillation. Persistent increases in heme oxygenase-1 (HO-1) in the lung tissue were also observed from 3 days to 6 months after exposure. Histopathological findings of the lungs demonstrated that extensive inflammation at 3 days was greater than that in exposure to silica, NiO nanoparticles and CeO2 nanoparticles, and equal to or greater than that in asbestos (chrysotile) exposure, and the inflammation continued until 1 month. Fibrotic changes also progressed after 1 month postexposure. CONCLUSION: Our results suggested that CL-PAA potentially causes strong neutrophil inflammation in the rat and human lung.

Mortality changes for patients with pneumococcal pneumonia from 2012 to 2017 in Japan.

INTRODUCTION: Pneumococcal pneumonia has a high morbidity and mortality in adults, especially those ≥65 years old. In the past decade, pneumococcal vaccination programs have been initiated worldwide, however, few data concerning mortality changes are available in pneumococcal pneumonia patients and there are no reports clarifying these current changes in Japan. METHODS: Japanese patients ≥65 years old hospitalized with pneumococcal pneumonia between April 2012 and March 2018 were analyzed using the Diagnostic Procedure Combination database. In-hospital mortality was evaluated, and the odds ratios for this outcome in each fiscal year compared with that in 2012 was analyzed using multivariable logistic regression models. RESULTS: Between 2012 and 2017, data of 47,375 pneumococcal pneumonia patients ≥65 years old were extracted. The incidence per 1000 person-years for in-hospital mortality was 60.4 in 2012, 56.8 in 2013, 63.2 in 2014, 56.1 in 2015, 73.0 in 2016, and 67.4 in 2017 and the odds ratios for in-hospital mortality in 2013, 2014, 2015, 2016, and 2017 compared with that in 2012 were 1.00, 1.05, 1.04, 1.06, and 0.98, respectively. There were no significant differences between 2012 and each year from 2013 to 2017. Low BMI; low ADL score; high A-DROP score; comorbid malignancy and heart failure; the coexistence of invasive pneumococcal infection; and the use of invasive mechanical ventilation were independent risk factors for in-hospital mortality. CONCLUSIONS: There were no changes in in-hospital mortality in pneumococcal pneumonia patients between 2012 or each year from 2013 to 2017 and further epidemiological observations are necessary.

Comparative study of bacterial flora in bronchoalveolar lavage fluid of pneumonia patients based on their pneumonia subtypes and comorbidities using 16S ribosomal RNA gene analysis.

INTRODUCTION: The culture method is the gold standard for identifying pathogenic bacteria in patients with pneumonia but often does not reflect the exact bacterial flora in pulmonary lesions of pneumonia, partly owing to easiness or difficulties in culturing certain bacterial species. We aimed to evaluate bacterial flora in bronchoalveolar lavage fluid (BALF) samples directly obtained from pneumonia lesions using 16S ribosomal RNA (rRNA) gene analysis to compare the results of the BALF culture method in each category of pneumonia. METHODS: Bacterial florae were detected by a combination of the culture method, and the clone library method using the 16S rRNA gene sequencing in BALF directly obtained from pneumonia lesions in pneumonia patients from April 2010 to March 2020 at the University of Occupational and Environmental Health, Japan, and affiliated hospitals. Clinical information of these patients was also collected, and lung microbiome was evaluated for each pneumonia category. RESULTS: Among 294 pneumonia patients (120 with community-acquired pneumonia (CAP), 101 with healthcare-associated pneumonia (HCAP), and 73 with hospital-acquired pneumonia (HAP)), significantly higher percentages of obligate anaerobes were detected in CAP than in HCAP and HAP patients by the clone library method. Corynebacterium species were significantly highly detected in HAP patients and patients with cerebrovascular diseases than in patients without, and Streptococcus pneumoniae was frequently detected in patients with diabetes mellitus. CONCLUSION: Obligate anaerobes may be underestimated in patients with CAP. Corynebacterium species should be regarded as the causative bacteria for pneumonia in patients with HAP and cerebrovascular diseases.

Reduced phagocytic activity of human alveolar macrophages infected with Mycobacterium avium complex.

INTRODUCTION: Co-infection of nontuberculous mycobacteria (NTM) with other bacteria is associated with increased frequency of hospitalization and reduced quality of life. However, the clinical significance of co-infection with NTM and other bacteria remains unclear. Here, we investigated the distribution of alveolar macrophage populations, characterized their phagocytic function in bronchoalveolar lavage fluid (BALF), and assessed the bactericidal function of macrophages infected with NTM using cell lines. METHODS: BALF samples were prospectively obtained from 30 patients with suspected NTM lung disease to evaluate phagocytic activities of macrophages using immunostaining. Bactericidal activities of Staphylococcus aureus (S. aureus) and Mycobacterium intracellulare (M. intracellulare)-infected or -non-infected macrophages were evaluated using macrophage cell lines. RESULTS: Eleven patients with Mycobacterium avium complex (MAC) infection and 19 patients with chronic lower respiratory tract infections except for NTM infection (controls) were enrolled. The percentage of non-polarized (HLA-DR+, CD40-, and CD163-) macrophages in patients infected with MAC was significantly higher than that in controls; non-polarized macrophages demonstrated an impaired ability to phagocytose S. aureus. In vitro experiments revealed higher intracellular S. aureus colony-forming unit counts and proinflammatory cytokine levels in M. intracellulare-infected macrophages than in non-NTM-infected macrophages. Electron microscopy showed morphologically damaged macrophages and M. intracellulare and S. aureus growing in the same phagosome. CONCLUSION: The proportion of alveolar macrophages (HLA-DR+, CD40-, and CD163-) with impaired phagocytosis increased in MAC-infected individuals. M. intracellulare-infected macrophages reduced bactericidal activity in vitro. Dysfunction of alveolar macrophages may contribute to persistent infection by other bacteria, leading to MAC lung disease progression.

Effects of additive corticosteroid therapy on 90-day survival in patients with community-onset pneumonia.

INTRODUCTION: Systemic corticosteroid therapy is occasionally used as an additive therapy, especially for patients with severe pneumonia. However, its recommendation for use in patients with pneumonia varies worldwide, and its efficacy is unclear. METHODS: Adult Japanese patients hospitalized with community-onset pneumonia between January and December 2012 were analyzed using the Diagnostic Procedure Combination database. The patients were classified into mild-to-moderate and severe groups using the A-DROP (age, dehydration, respiration, orientation, and blood pressure) system. The 90-day survival rate was evaluated between the presence or absence of corticosteroid treatment using the Kaplan-Meier method in the overall, mild-to-moderate and severe groups, respectively. The patients' clinical characteristics were adjusted between the two groups using the inverse probability of treatment weighting method. RESULTS: Among 123,811, 110,534 patients were classified as mild-to-moderate grade (corticosteroid group: 8,465, non-corticosteroid group: 102,069) and 13,277 patients were classified as severe grade (corticosteroid group: 1,338, non-corticosteroid group: 11,939). The 90-day survival rate was higher in the non-corticosteroid group than in the corticosteroid group in patients with pneumonia of overall grade (weighted hazard ratio [HR]: 1.36; P < 0.001) and those with mild-to-moderate grade (weighted HR: 1.46; P < 0.001). However, there were no significant differences in the outcomes between the two groups in those with severe grade (weighted HR: 1.08; P = 0.38). CONCLUSIONS: Additive systemic corticosteroid therapy may be related to poor 90-day prognosis in patients with mild-to-moderate grade community-onset pneumonia, although it may not be positively associated with its prognosis in those with severe grade.

Effect of Different Molecular Weights of Polyacrylic Acid on Rat Lung Following Intratracheal Instillation.

BACKGROUND: We conducted intratracheal instillations of different molecular weights of polyacrylic acid (PAA) into rats in order to examine what kinds of physicochemical characteristics of acrylic acid-based polymer affect responses in the lung. METHODS: F344 rats were intratracheally exposed to a high molecular weight (HMW) of 598 thousand g/mol or a low molecular weight (LMW) of 30.9 thousand g/mol PAA at low and high doses. Rats were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months post exposure. RESULTS: HMW PAA caused persistent increases in neutrophil influx, cytokine-induced neutrophil chemoattractants (CINC) in the bronchoalveolar lavage fluid (BALF), and heme oxygenase-1 (HO-1) in the lung tissue from 3 days to 3 months and 6 months following instillation. On the other hand, LMW PAA caused only transient increases in neutrophil influx, CINC in BALF, and HO-1 in the lung tissue from 3 days to up to 1 week or 1 month following instillation. Histopathological findings of the lungs demonstrated that the extensive inflammation and fibrotic changes caused by the HMW PAA was greater than that in exposure to the LMW PAA during the observation period. CONCLUSION: HMW PAA induced persistence of lung disorder, suggesting that molecular weight is a physicochemical characteristic of PAA-induced lung disorder.

Crosslinked Structure of Polyacrylic Acid Affects Pulmonary Fibrogenicity in Rats.

We conducted intratracheal instillations of polyacrylic acid (PAA) with crosslinking and non-crosslinking into rats in order to examine what kinds of physicochemical characteristics of acrylic-acid-based polymers affect responses in the lung. F344 rats were intratracheally exposed to similar molecular weights of crosslinked PAA (CL-PAA) (degree of crosslinking: ~0.1%) and non-crosslinked PAA (Non-CL-PAA) at low and high doses. Rats were sacrificed at 3 days, 1 week, 1 month, 3 months, and 6 months post-exposure. Both PAAs caused increases in neutrophil influx, cytokine-induced neutrophil chemoattractants (CINC) in the bronchoalveolar lavage fluid (BALF), and heme oxygenase-1 (HO-1) in the lung tissue from 3 days to 6 months following instillation. The release of lactate dehydrogenase (LDH) activity in the BALF was higher in the CL-PAA-exposed groups. Histopathological findings of the lungs demonstrated that the extensive fibrotic changes caused by CL-PAA were also greater than those in exposure to the Non-CL- PAA during the observation period. CL-PAA has more fibrogenicity of the lung, suggesting that crosslinking may be one of the physicochemical characteristic factors of PAA-induced lung disorder.

Pirfenidone plus inhaled N-acetylcysteine for idiopathic pulmonary fibrosis: a randomised trial.

BACKGROUND: A randomised controlled trial in Japan showed that inhaled N-acetylcysteine monotherapy stabilised serial decline in forced vital capacity (FVC) in some patients with early idiopathic pulmonary fibrosis (IPF). However, the efficacy and tolerability of combination therapy with an antifibrotic agent and inhaled N-acetylcysteine are unknown. METHODS: This 48-week, randomised, open-label, multicentre phase 3 trial compared the efficacy and tolerability of combination therapy with pirfenidone plus inhaled N-acetylcysteine 352.4 mg twice daily with the results for pirfenidone alone in patients with IPF. The primary end-point was annual rate of decline in FVC. Exploratory efficacy measurements included serial change in diffusing capacity of the lung for carbon monoxide (D LCO) and 6-min walk distance (6MWD), progression-free survival (PFS), incidence of acute exacerbation, and tolerability. RESULTS: 81 patients were randomly assigned in a 1:1 ratio to receive pirfenidone plus inhaled N-acetylcysteine (n=41) or pirfenidone (n=40). The 48-week rate of change in FVC was -300 mL and -123 mL, respectively (difference -178 mL, 95% CI -324--31 mL; p=0.018). Serial change in D LCO, 6MWD, PFS and incidence of acute exacerbation did not significantly differ between the two groups. The incidence of adverse events (n=19 (55.9%) for pirfenidone plus N-acetylcysteine; n=18 (50%) for pirfenidone alone) was similar between groups. CONCLUSIONS: Combination treatment with inhaled N-acetylcysteine and pirfenidone is likely to result in worse outcomes for IPF.

Exposure to PM2.5 is a risk factor for acute exacerbation of surgically diagnosed idiopathic pulmonary fibrosis: a case-control study.

BACKGROUND: Short-term exposure to ozone and nitrogen dioxide is a risk factor for acute exacerbation (AE) of idiopathic pulmonary fibrosis (AE-IPF). The comprehensive roles of exposure to fine particulate matter in AE-IPF remain unclear. We aim to investigate the association of short-term exposure to fine particulate matter with the incidence of AE-IPF and to determine the exposure-risk time window during 3 months before the diagnosis of AE-IPF. METHODS: IPF patients were retrospectively identified from the nationwide registry in Japan. We conducted a case-control study to assess the correlation between AE-IPF incidence and short-term exposure to eight air pollutants, including particulate matter < 2.5 µm (PM2.5). In the time-series data, we compared monthly mean exposure concentrations between months with AE (case months) and those without AE (control months). We used multilevel mixed-effects logistic regression models to consider individual and institutional-level variables, and also adjusted these models for several covariates, including temperature and humidity. An additional analysis with different monthly lag periods was conducted to determine the risk-exposure time window for 3 months before the diagnosis of AE-IPF. RESULTS: Overall, 152 patients with surgically diagnosed IPF were analyzed. AE-IPF was significantly associated with an increased mean exposure level of nitric oxide (NO) and PM2.5 30 days prior to AE diagnosis. Adjusted odds ratio (OR) with a 10 unit increase in NO was 1.46 [95% confidence interval (CI) 1.11-1.93], and PM2.5 was 2.56 (95% CI 1.27-5.15). Additional analysis revealed that AE-IPF was associated with exposure to NO during the lag periods lag 1, lag 2, lag 1-2, and lag 1-3, and PM2.5 during the lag periods lag 1 and lag 1-2. CONCLUSIONS: Our results show that PM2.5 is a risk factor for AE-IPF, and the risk-exposure time window related to AE-IPF may lie within 1-2 months before the AE diagnosis. Further investigation is needed on the novel findings regarding the exposure to NO and AE-IPF.

A fatal case of COVID-19-associated invasive pulmonary aspergillosis.

A 79-year-old Japanese man with polymyalgia rheumatica was admitted to hospital with coronavirus disease (COVID-19). On admission, he was treated with ciclesonide inhalation, ivermectin, and meropenem. He was intubated 6 days after admission, and methylprednisolone therapy was initiated (1000 mg/day). Hypoxemia and chest radiographic findings temporarily improved. However, chest computed tomography showed bilateral ground-glass attenuations, multiple nodules, and consolidation. Aspergillus fumigatus was cultured from the tracheal aspirate and he was diagnosed with COVID-19-associated invasive pulmonary aspergillosis (CAPA) and treated with liposomal amphotericin B. However, he died 28 days after admission.