The diagnostic impact of fractional exhaled nitric oxide for asthmatic cough in nontuberculous mycobacterial pulmonary disease.

BACKGROUND: Measurement of exhaled nitric oxide (FeNO) is a potentially useful diagnostic test for asthma. However, no study has explored the relationship between FeNO and respiratory symptoms of nontuberculous mycobacterial pulmonary disease (NTM-PD) complicated with asthma. The objective of this study was to assess the utility of measuring FeNO levels in patients with NTM-PD complicated by asthma. METHODS: In this single-center retrospective cohort study, 140 NTM-PD patients with FeNO measured were enrolled. We selected NTM-PD patients who complicated with asthma as the NTM+BA group, defined using the following criteria: NTM patients with symptoms consistent with asthma, and NTM patients with symptomatic improvement after diagnostic therapy with ICS ± a long-acting beta 2-agonist (LABA). We then calculated a diagnostic cutoff point to distinguish between the NTM+BA groups and the NTM groups (all others). High-resolution computed tomography (HRCT) images were evaluated using the CT scoring system and their association with FeNO was examined. RESULTS: A total of 89 patients were included in the study. (31 in the NTM+BA group and 58 in the NTM group). Compared with the NTM group, the NTM+BA group had higher rates of allergic disease (51.6% vs. 22.4%; p=0.0085) and higher FeNO values (median, 23 [interquartile range {IQR}, 15.0-43.0] ppb vs. median, 17 [IQR, 11.8-23.0] ppb; p=0.015). With diagnostic asthma care using mainly ICS/LABA with reference to the FeNO, most patients (91.0%, 20/22) in the NTM-preceding subgroup in the NTM+BA group demonstrated a prompt improvement of their symptoms and AFB culture findings did not worsen (Culture positive rate (%): Pre-treatment: 59.1% vs. Post-treatment: 40.9%, p=0.3660) at 6 months after starting diagnostic therapy. The optimal diagnostic cutoff point of FeNO to distinguish between the two groups was calculated as 21.5 ppb by the ROC curve (sensitivity 75%, specificity 71.93%, p<0.0001; area under the curve: 0.7989). No significant correlation was observed between FeNO and the severity of CT images in the patients. CONCLUSIONS: A certain number of patients with NTM-PD showed exacerbated respiratory symptoms due to asthmatic complications. Elevated FeNO levels suggest asthma complications, even in patients with NTM.

Body positioning-related laryngeal narrowing pattern and expiratory mechanical constraints in advanced chronic obstructive pulmonary disease: A case report.

We previously reported that laryngeal widening led to improved exercise tolerance in COPD. However, it is not clear whether laryngeal narrowing occurs as a compensatory response to tracheal movement or is affected by posture. Here, we report the case of an advanced COPD patient whose more prolonged expiration in a head-forward leaning position compared with that in a neck-extended position occurred with an excessive duration of severe laryngeal narrowing without tracheal obstruction, which led to exercise intolerance with expiratory mechanical constraints. This case provided useful insights into the regulation of the upper airway with body positioning for improving exercise tolerance.

Diagnosis and Management of Drug-Induced Interstitial Lung Disease Associated with Amikacin Liposome Inhalation Suspension in Refractory Mycobacterium Avium Complex Pulmonary Disease: A Case Report.

Amikacin liposome inhalation suspension (ALIS) is a key drug for the treatment of refractory Mycobacterium avium complex pulmonary disease (MAC-PD). Although cases of drug-induced interstitial lung disease (DIILD) by ALIS have been reported, its diagnosis is challenging due to overlapping existing pulmonary shadows, airway bleeding, exacerbation of underlying conditions, and the potential for various concurrent infections. A 72-year-old woman started treatment with ALIS for refractory MAC-PD. Three weeks later, she had a fever, cough, and appetite loss. She was hospitalized because multiple infiltrative opacities were observed on chest X-ray and chest computed tomography. Because the opacities worsened after empiric antibiotic therapy with broad-spectrum antibiotics, we initiated corticosteroid therapy, suspecting DIILD caused by ALIS, although drug lymphocyte stimulation tests for ALIS and amikacin were negative. Three days later, we found signs of improvement and quickly tapered the corticosteroids. After obtaining informed consent, we performed a drug provocation test of ALIS. Seven days later, she exhibited fever, an increased peripheral white blood cell count, and elevated serum C-reactive protein level, all of which returned to baseline 4 days after stopping ALIS, leading to a diagnosis of DIILD caused by ALIS in this patient. DIILD caused by ALIS is rare but should be carefully diagnosed to ensure that patients with refractory MAC-PD do not miss the opportunity to receive ALIS treatment.

Laryngeal widening and adequate ventilation by expiratory pressure load training improve aerobic capacity in COPD: a randomised controlled trial.

RATIONALE: Despite strategies acting on peripheral airway obstruction in chronic obstructive pulmonary disease (COPD), exercise intolerance remains inadequately improved. We hypothesised that laryngeal narrowing is a potential treatment target of expiratory pressure load training (EPT) to improve exercise intolerance in COPD. METHODS: The effect of 3-month EPT was assessed in 47 patients with COPD divided into Global Initiative for Chronic Obstructive Lung Disease (GOLD) mild-to-moderate (I-II) and severe-to-very severe (III-IV), randomly allocating 1:1 to EPT or control groups. The primary outcome was endurance time in the constant work rate exercise test in GOLD III-IV patients. RESULTS: Compared with controls, EPT increased: (1) endurance time, with estimated treatment effect: +703 (95% CI: 379 to 1031) s, p=0.0008 (GOLD I-II); +390 (95% CI: 205 to 574) s, p=0.0006 (GOLD III-IV); (2) peak oxygen uptake (p=0.0086 in GOLD I-II; p=0.0004 in GOLD III-IV); (3) glottic dilatation ratio at maximum collapse on laryngoscopy in the submaximal exercise (p=0.0062 in GOLD I-II; p=0.0001 in GOLD III-IV); and (4) the inflection point of expiratory tidal volume relative to minute ventilation during the incremental exercise (p=0.0015 in GOLD I-II; p=0.0075 in GOLD III-IV). Across GOLD grades, the responses of glottic dilatation ratio at maximum collapse and the expiratory tidal volume at the inflection point were selected as more influential variables correlating with the improvement in peak oxygen uptake and endurance time, respectively. CONCLUSION: These results show that EPT improved aerobic capacity and endurance time with larger laryngeal widening and adequate ventilation despite advanced COPD. TRIAL REGISTRATION NUMBER: UMIN000041250.

A randomized phase 2 study on demeclocycline in patients with mild-to-moderate COVID-19.

Tetracyclines exhibit anti-viral, anti-inflammatory, and immunomodulatory activities via various mechanisms. The present study investigated the efficacy and safety of demeclocycline in patients hospitalized with mild-to-moderate COVID-19 via an open-label, multicenter, parallel-group, randomized controlled phase 2 trial. Primary and secondary outcomes included changes from baseline (day 1, before the study treatment) in lymphocytes, cytokines, and SARS-CoV-2 RNA on day 8. Seven, seven, and six patients in the control, demeclocycline 150 mg daily, and demeclocycline 300 mg daily groups, respectively, were included in the modified intention-to-treat population that was followed until day 29. A significant change of 191.3/µL in the number of CD4+ T cells from day 1 to day 8 was observed in the demeclocycline 150 mg group (95% CI 5.1/µL-377.6/µL) (p = 0.023), whereas that in the control group was 47.8/µL (95% CI - 151.2/µL to 246.8/µL), which was not significant (p = 0.271). The change rates of CD4+ T cells negatively correlated with those of IL-6 in the demeclocycline-treated groups (R = - 0.807, p = 0.009). All treatment-emergent adverse events were of mild-to-moderate severity. The present results indicate that the treatment of mild-to-moderate COVID-19 patients with demeclocycline elicits immune responses conducive to recovery from COVID-19 with good tolerability.Trial registration: This study was registered with the Japan Registry of Clinical Trials (Trial registration number: jRCTs051200049; Date of the first registration: 26/08/2020).

MGIT-seq for the Identification of Nontuberculous Mycobacteria and Drug Resistance: a Prospective Study.

Because nontuberculous mycobacterial pulmonary disease is a considerable health burden, a simple and clinically applicable analytical protocol enabling the identification of subspecies and drug-resistant disease is required to determine the treatment strategy. We aimed to develop a simplified workflow consisting only of direct sequencing of mycobacterial growth indicator tube cultures (MGIT-seq). In total, 138 patients were prospectively enrolled between April 2021 and May 2022, and culture-positive MGIT broths were subjected to sequencing using MinION, a portable next-generation sequencer. Sequence analysis was conducted to identify species using core genome multilocus sequence typing and to predict macrolide and amikacin (AMK) resistance based on previously reported mutations in rrl, rrs, and erm(41). The results were compared to clinical tests for species identification and drug susceptibility. A total of 116 patients with positive MGIT cultures were included in the analysis. MGIT-seq yielded 99.1% accuracy in species-level identification and identified 98 isolates (84.5%) at the subspecies level. Macrolide and AMK resistance were detected in 19.4% and 1.9% of Mycobacterium avium complex (MAC) and Mycobacterium abscessus isolates. The predicted macrolide and AMK resistance was consistent with the results of conventional drug susceptibility tests, with specificities of 97.6% and 100.0%, respectively. Direct MGIT-seq has achieved comprehensive identification and drug resistance detection of nontuberculous mycobacteria, which could be applicable to determine the treatment strategy by a single test in clinical practice.

Chronic Pulmonary Disease Caused by Tsukamurella toyonakaense.

Unidentified Mycobacterium species are sometimes detected in respiratory specimens. We identified a novel Tsukamurella species (Tsukamurella sp. TY48, RIMD 2001001, CIP 111916T), Tsukamurella toyonakaense, from a patient given a misdiagnosis of nontuberculous mycobacterial pulmonary disease caused by unidentified mycobacteria. Genomic identification of this Tsukamurella species helped clarify its clinical characteristics and epidemiology.

Mycobacterium senriense sp. nov., a slowly growing, non-scotochromogenic species, isolated from sputum of an elderly man.

A slowly growing mycobacteria, identified as strain TY59T, was isolated from sputum of an elderly man with pneumonia. Sequencing of the 16S rRNA gene indicated that this strain was similar to members of the Mycobacterium avium complex and closely related species. Strain TY59T has highest 16S rRNA gene sequence similarities to the type strains of Mycobacterium colombiense (99.80 % sequence similarity), Mycobacterium vulneris (99.74 %), Mycobacterium timonense (99.54 %), Mycobacterium avium subsp. avium (99.54 %) and Mycobacterium avium subsp. silvaticum (99.54 %). Analysis of the internal transcribed spacer (ITS) and DNA-directed RNA polymerase subunit beta (rpoB) sequences gave similar results to the 16S rRNA gene analysis. The closest species to strain TY59T were M. colombiense and M. vulneris with 97.90-98.25 % identity in ITS and 96.4-96.6 % in rpoB. The strain's 65 kDa heat shock protein (hsp65) gene was different from those of M. vulneris, M. colombiense and M. avium subsp. silvaticum with 72.4-74.2 % identity. Average nucleotide identity results showed a 93.4 % match to M. vulneris as the maximum value. Phenotypically, the non-chromogenicity, rough colonies, growth at 42 °C, negative results for nitrate reduction, ß-glucosidase and Tween 80 hydrolysis, and positive results for catalase activity set this strain apart from closely related species. We propose that Mycobacterium senriense sp. nov. is a novel species of slowly growing mycobacteria. The type strain is TY59T (RIMD 1371001T=CIP 111917T).

Increased Oxygen Extraction by Pulmonary Rehabilitation Improves Exercise Tolerance and Ventilatory Efficiency in Advanced Chronic Obstructive Pulmonary Disease.

BACKGROUND: In cardiopulmonary exercise testing (CPET), oxygen uptake (V'O2) is calculated using the product of minute ventilation (V'E) and the difference between inspiratory and expiratory O2 concentrations (ΔFO2). However, little is known about the response of ΔFO2 to pulmonary rehabilitation (PR). The aim of the present study was (1) to investigate whether PR increases peak V'O2, based on whether ΔFO2 or V'E at peak exercise increase after PR, and (2) to investigate whether an improvement in ΔFO2 correlates with an improvement in ventilatory efficiency. METHODS: A total of 38 patients with severe and very severe COPD, whose PR responses were evaluated by CPET, were retrospectively analyzed. RESULTS: After PR, peak V'O2 was increased in 14 patients. The difference in ΔFO2 at peak exercise following PR correlated with the difference in peak V'O2 (r = 0.4884, p = 0.0019), the difference in V'E/V'CO2-nadir (r = -0.7057, p < 0.0001), and the difference in V'E-V'CO2 slope (r = -0.4578, p = 0.0039), but it did not correlate with the difference in peak V'E. CONCLUSIONS: The increased O2 extraction following PR correlated with improved exercise tolerance and ventilatory efficiency. In advanced COPD patients, a new strategy for improving O2 extraction ability might be effective in those in whom ventilatory ability can be only minimally increased.

The Diagnosis of Nontuberculous Mycobacterial Pulmonary Disease by Single Bacterial Isolation Plus Anti-GPL-Core IgA Antibody.

Although serum anti-glycopeptidolipid (GPL)-core IgA antibody is a highly specific test for infection with Mycobacterium avium complex (MAC), Mycobacterium abscessus, and its subspecies abscessus, subsp. massiliense, and subsp. bolletii (MAB), its use for the definitive diagnosis of MAC pulmonary disease (PD) and MAB-PD are unknown. To clarify the diagnostic accuracy of the anti-GPL-core IgA antibody test among patients with radiologically suspected MAC-PD or MAB-PD who already have a single positive sputum culture test. The first isolations of MAC and MAB from patients with radiologically suspected MAC-PD or MAB-PD at the Osaka Toneyama Medical Center between January 2006 and December 2020 were collected. Patients were enrolled when their serum anti-GPL-core IgA antibody was measured during the 3 months before and after the first isolation. We retrospectively compared the results of anti-GPL-core IgA antibody testing with the final diagnoses based on the current guidelines. We included 976 patients for analysis. The serum anti-GPL-core IgA antibody was positive in 699 patients (71.6%). The positive predictive value of anti-GPL-core IgA antibody for the diagnosis of MAC-PD or MAB-PD was 97.4%. The median time required for the second positive culture after the first isolation was 51 days (interquartile range 12 to 196 days). The positive serum anti-GPL-core IgA antibody test allowed an early and definitive diagnosis of MAC-PD or MAB-PD in those who already had a single positive sputum culture test. IMPORTANCE To satisfy the microbiologic criteria of the current diagnostic guideline for nontuberculous mycobacterial pulmonary disease (PD), at least two positive sputum cultures of the same species of mycobacteria from sputum are required to avoid the casual isolation of mycobacteria. This study showed that the positivity of a serum anti-glycopeptidolipid (GPL)-core IgA antibody test has an excellent diagnostic ability among patients with radiologically suspected Mycobacterium avium complex (MAC)-PD or Mycobacterium abscessus (MAB)-PD who already had a single positive sputum culture test. The usage of single culture isolation plus anti-GPL-core IgA antibody as another diagnostic criterion has a time, cost, and effort-saving effect. Furthermore, it will facilitate the diagnosis of MAC-PD or MAB-PD in the early stage of disease because serum anti-GPL-core IgA antibody becomes high in these patients. Therefore, we proposed adding single culture isolation plus anti-GPL-core IgA antibody as "combined microbiological and serological criteria" to the diagnostic guidelines for MAC-PD and MAB-PD.

Impact of bronchial wall thickness on airflow obstruction in bronchiectasis.

The association between airflow obstruction and bronchial dilation has been researched in bronchiectasis. However, the impact of bronchial wall thickening on airflow obstruction has not been thoroughly investigated. This study assessed the underlying mechanism of airflow obstruction in bronchiectasis due to abnormal bronchial wall thickening using oscillometry. A total of 98 patients with bronchiectasis were retrospectively reviewed. At the time of diagnosis, spirometric and oscillometric parameters, high-resolution computed tomography scores, and clinical characteristics were collected. The bronchial diameter, bronchial wall thickness, and extent of emphysema were evaluated semi-quantitatively. Correlations between patient data and characteristics were analyzed. Thirty-three patients with airflow obstruction showed higher respiratory resistance, more negative respiratory reactance (Xrs) at 5 Hz (X5), and higher bronchial wall thickness score than those without airflow obstruction. The bronchial wall thickness score negatively affected forced expiration volume in 1 s /forced vital capacity and X5. Abnormal bronchial wall thickening might make Xrs more negative and progress airflow obstruction in bronchiectasis.

Pleural Effusion Caused by Mycolicibacterium mageritense in an Immunocompetent Host: A Case Report.

Mycolicibacterium mageritense (M. mageritense) is a rare species among rapidly growing mycobacteria, and M. mageritense pleurisy is very rare. Here, we report for the first time, an immunocompetent patient with pleurisy caused by M. mageritense. The patient had no history of immunodeficiency and no recurrence of lung cancer after surgery. However, 8 months after surgery, he developed a new lung shadow and pleurisy. Although whole-genome analysis of the colony cultured from the patient's pleural fluid revealed M. mageritense, we could not identify it in time, resulting in a poor outcome. M. mageritense pleurisy in this case might have occurred via a bulla rupture of the lung lesion because computed tomography of the patient's chest showed pneumothorax and a lung lesion in contact with thoracic cavity. This case emphasized that nontuberculous mycobacterial pleurisy should be considered in the differential diagnoses of pleural effusion even in immunocompetent patients. Advancement of comprehensive and rapid analyses of genomic data from clinical specimens will lead to better treatment strategies.

Pulmonary eosinophilia may indicate onset stage of allergic bronchopulmonary aspergillosis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) and chronic eosinophilic pneumonia (CEP) both display peripheral eosinophilia as well as pulmonary infiltration, together described as pulmonary eosinophilia, and differentiation is sometimes problematic. This study therefore examined the distinctions between ABPA with and without CEP-like shadows. METHODS: This retrospective cohort study from a single center included 25 outpatients (median age, 65 years) with ABPA diagnosed between April 2015 and March 2019, using criteria proposed by the International Society of Human and Animal Mycology (ISHAM), which focuses on positive specific IgE for Aspergillus fumigatus. Patients were assigned to either the eosinophilic pneumonia (EP) group or Non-EP group, defined according to findings on high-resolution computed tomography (HRCT). The EP group included patients with HRCT findings compatible with CEP; i.e., the presence of peripheral consolidation (p-consolidation) or ground-glass opacities (GGO), with no evidence of high-attenuation mucus. The Non-EP group comprised the remaining patients, who showed classical findings of ABPA such as mucoid impaction. Differences between the groups were analyzed. RESULTS: Baseline characteristics, frequency of a history of CEP (EP, 50% vs. Non-EP, 26%) and tentative diagnosis of CEP before diagnosis of ABPA (67% vs. 16%) did not differ significantly between groups. Although elevated absolute eosinophil count and Aspergillus-specific immunoglobulin E titers did not differ significantly between groups, the Non-EP group showed a strong positive correlation between these values (R = 0.7878, p = 0.0003). The Non-EP group displayed significantly higher levels of the fungal marker beta-D glucan (median, 11.7 pg/ml; interquartile range, 6.7-18.4 pg/ml) than the EP group (median, 6.6 pg/ml; interquartile range, 5.2-9.3 pg/ml). Both groups exhibited frequent recurrence of shadows on X-rays but no cases in the EP group had progressed to the Non-EP group at the time of relapse. CONCLUSIONS: The ABPA subgroup with imaging findings resembling CEP experienced frequent recurrences, as in typical ABPA. In pulmonary eosinophilia, even if there are no shadows indicating apparent mucous change, the Aspergillus-specific immunoglobulin E level is important in obtaining an accurate diagnosis and in the selection of appropriate therapies for this type of ABPA.

Corrigendum: Oxygen Extraction Based on Inspiratory and Expiratory Gas Analysis Identifies Ventilatory Inefficiency in Chronic Obstructive Pulmonary Disease.

[This corrects the article DOI: 10.3389/fphys.2021.703977.].

Oxygen Extraction Based on Inspiratory and Expiratory Gas Analysis Identifies Ventilatory Inefficiency in Chronic Obstructive Pulmonary Disease.

Aims: In contrast to cardiovascular disease, low rather than high ventilatory inefficiency, evaluated by the minute ventilation-carbon dioxide output (V'E-V'CO2)-slope, has been recognized as being related to greater disease severity in chronic obstructive pulmonary disease (COPD). To better care for patients with cardiopulmonary disease, understanding the physiological correlation between ventilatory inefficiency and exercise limitation is necessary, but remains inadequate. Given that oxygen uptake (V'O2) evaluated by cardiopulmonary exercise testing (CPET) depends on both the ventilatory capability and oxygen extraction, i.e., the difference between inspiratory and expiratory oxygen concentration (ΔFO2), the aim of this study was to investigate the correlations between V'E-V'CO2-slope and the ΔFO2 during exercise and their physiological implications in patients with COPD. Methods: A total of 156 COPD patients (mean age, 70.9 ± 7.2 years) with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I-IV and 16 controls underwent CPET with blood gas analysis. Results: With the progression of COPD, mechanical ventilatory constraints together with a slower respiratory frequency led to exertional respiratory acidosis. In GOLD IV cases, (1) decrease in the dependence of reduced peak V'O2 on V'E led to an increase in its dependence on peak ΔFO2 during exercise; and (2) the ΔFO2-V'CO2-slope became steeper, correlating with the severity of exertional respiratory acidosis (r = 0.6359, p < 0.0001). No significant differences in peak exercise ΔFO2 or V'E-V'CO2-slope were observed among the various GOLD stages. In all subjects, including controls, peak exercise ΔFO2 had the strongest correlation with the V'E-V'CO2-slope (r = -0.8835, p < 0.0001) and correlated well with body mass index (r = 0.3871, p < 0.0001), although it did not correlate with the heart rate-V'CO2-relationship and V'E. Conclusions: Ventilatory efficiency related to CO2 clearance might depend on exertional oxygen extraction in the body. Measuring ΔFO2 might be a key component for identifying ventilatory inefficiency and oxygen availability. Increasing ΔFO2 would help to improve ventilatory inefficiency and exercise tolerance separately from cardiac and ventilatory capability in COPD patients.

Serum GPL core antibody levels are associated with disease activity and treatment outcomes in Mycobacterium avium complex lung disease following first line antibiotic treatment.

BACKGROUND: No objective serum biomarkers of disease course or treatment outcome of Mycobacterium avium complex lung disease (MAC-LD) presently exist. Serum IgA antibody levels against the glycopeptidolipid (GPL) core have good diagnostic accuracy for MAC-LD. However, their usefulness for monitoring and predicting disease course and outcome of MAC-LD following first-line antibiotic treatment remains unclear. METHODS: We conducted a single-center retrospective cohort study to investigate the utility of serial measurements of GPL core IgA antibodies for monitoring disease course in 133 patients with MAC-LD following first-line antibiotic treatment. RESULTS: Patients were classified into treatment failure [n = 46 (34.6%)], recurrence [n = 19 (14.3%)], or treatment success [n = 68 (51.1%)] groups according to bacteriological outcomes after chemotherapy. Pretreatment serum anti-GPL core IgA levels in the treatment success group were similar to those in the treatment failure and recurrence groups (P = 0.6431 and P = 0.9045, respectively). In the treatment success group, serum anti-GPL core IgA levels were significantly and continuously reduced after initiating antibiotic treatment. No significant reductions in anti-GPL core IgA levels were observed in either the treatment failure or recurrence groups. Reduced levels of GPL core antibodies following antibiotic treatment correlated well with treatment outcomes (P = 0.0045). CONCLUSION: In this study, by performing serial measurements, we found that GPL core antibody levels were associated with disease activity and treatment outcomes in patients with MAC-LD. Time course analysis of anti-GPL core IgA levels clearly differentiated between patients who achieved treatment success and those who experienced treatment failure or disease recurrence.

Pleuroparenchymal fibroelastosis in Mycobacterium avium complex pulmonary disease: clinical characteristics and prognostic impact.

The association between Mycobacterium avium complex pulmonary disease (MAC-PD) and pleuroparenchymal fibroelastosis (PPFE) has been reported previously, and interstitial pneumonia as a comorbidity is associated with a worse prognosis. However, no study has thoroughly reported on PPFE associated with MAC-PD. The present study investigated the prevalence, clinical characteristics, and prognostic impact of PPFE in patients with MAC-PD. A total of 224 patients, newly diagnosed with MAC-PD, were retrospectively reviewed. At the time of diagnosis, chest high-resolution computed tomography (HRCT), sputum examination, and clinical characteristics were collected. The extent of PPFE and MAC-PD was evaluated semi-quantitatively using HRCT scores. Risk factor analysis for clinical or radiological deterioration necessitating multidrug antimicrobial treatment within 3 years, and all-cause mortality within 5 years, from the initial diagnosis was performed based on the PPFE score. PPFE was observed in 59 out of 224 patients (26.3%). A higher PPFE score was a risk factor for dyspnoea, fatigue, and lower body mass index (BMI) (p<0.05). Although PPFE score did not correlate with clinical or radiological deterioration within 3 years (p=0.576), a higher PPFE score (adjusted OR 1.66, 95% CI 1.06-2.60, p=0.028) and lower BMI (adjusted OR 0.61, 95% CI 0.39-0.94, p=0.028) increased the risk of 5-year mortality. PPFE is a relatively common complication and an independent poor prognostic factor of MAC-PD. This study highlights the need for further studies investigating whether the presence of PPFE can be a clinical indicator for initiating treatment of MAC-PD.

First line treatment selection modifies disease course and long-term clinical outcomes in Mycobacterium avium complex pulmonary disease.

The combination of rifamycin (RFP), ethambutol (EB), and macrolides is currently the standard regimen for treatment of Mycobacterium avium complex pulmonary disease (MAC-PD). However, poor adherence to the standardized regimens recommended by current guidelines have been reported. We undertook a single-centred retrospective cohort study to evaluate the long-term outcomes in 295 patients with MAC-PD following first line treatment with standard (RFP, EB, clarithromycin [CAM]) or alternative (EB and CAM with or without fluoroquinolones (FQs) or RFP, CAM, and FQs) regimens. In this cohort, 80.7% were treated with standard regimens and 19.3% were treated with alternative regimens. After heterogeneity was statistically corrected using propensity scores, outcomes were superior in patients treated with standard regimens. Furthermore, alternative regimens were significantly and independently associated with sputum non-conversion, treatment failure and emergence of CAM resistance. Multivariate cox regression analysis revealed that older age, male, old tuberculosis, diabetes mellitus, higher C-reactive protein, and cavity were positively associated with mortality, while higher body mass index and M. avium infection were negatively associated with mortality. These data suggest that, although different combination regimens are not associated with mortality, first line administration of a standard RFP + EB + macrolide regimen offers the best chance of preventing disease progression in MAC-PD patients.

Induced hepatic stellate cell integrin, α8ß1, enhances cellular contractility and TGFß activity in liver fibrosis.

No effective therapy exists for fatal fibrosis. New therapeutic targets are needed for hepatic fibrosis because the incidence keeps increasing. The activation and differentiation of fibroblasts into myofibroblasts that causes excessive matrix deposition is central to fibrosis. Here, we investigated whether (and which) integrin receptors for matrix proteins activate hepatic stellate cells (HSCs). First, integrin α-subunits were investigated systematically for their expression over the course of HSC activation and their distribution on fibroblasts and other systemic primary cells. The most upregulated in plate culture-activated HSCs and specifically expressed across fibroblast linages was the α8 subunit. An anti-α8 neutralizing mAb was evaluated in three different murine fibrosis models: for cytotoxic (CCl4 treatment), non-alcoholic steatohepatitis-associated and cholestatic fibrosis. In all models, pathology and fibrosis markers (hydroxyproline and α-smooth muscle actin) were improved following the mAb injection. We also CCl4 -treated mice with inducible Itga8-/-; these mice were protected from increased hydroxyproline levels. Furthermore, ITGA8 was upregulated in specimens from 90 patients with liver fibrosis, indicating the relevance of our findings to liver fibrosis in people. Mechanistically, inhibition or ligand engagement of HSC α8 suppressed and enhanced myofibroblast differentiation, respectively, and HSC/fibroblast α8 activated latent TGFß. Finally, integrin α8ß1 potentially fulfils the growing need for anti-fibrotic drugs and is an integrin not to be ignored. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Oscillometry and computed tomography findings in patients with idiopathic pulmonary fibrosis.

Although the utility of oscillometry for predicting disease severity in idiopathic pulmonary fibrosis (IPF) had been researched, little has been reported on the mechanism of why respiratory impedance reflects disease severity. In addition, traction bronchiectasis has been considered to reduce respiratory resistance and correlate negatively with airflow obstruction, but this hypothesis has not been validated. The present study aimed to investigate the correlations between oscillometric parameters and fibrosis-related lung abnormalities in IPF and to assess the utility of oscillometry as a surrogate marker for traction bronchiectasis and airflow obstruction. Eighty Japanese patients with IPF underwent high-resolution computed tomography (HRCT), spirometry, and oscillometry and were retrospectively investigated. Fibrosis-related HRCT findings were scored regarding airspace consolidation, honeycombing, architectural distortion, traction bronchiectasis, and fibrosis. Correlations between the HRCT scores, spirometric parameters, and oscillometric parameters were analysed. Respiratory reactance correlated positively with all fibrosis-related HRCT scores. Vital capacity and forced vital capacity (FVC) correlated negatively with oscillometric parameters and HRCT scores, reflecting the severity of restrictive ventilatory deficiency. Respiratory resistance was not related to any of the HRCT scores or forced expiratory volume in 1 s/FVC. However, forced expiratory volume in 1 s/FVC correlated positively with HRCT scores, which showed that airflow obstruction became milder as the disease progressed. In conclusion, respiratory reactance reflects fibrosis and restrictive ventilatory deficiency in IPF. Moreover, respiratory resistance is independent of traction bronchiectasis and airflow obstruction in patients with IPF, which implies that respiratory resistance might reflect different properties of the airways.