COVID-19 in Patients with Pre-Existing Interstitial Lung Disease: Potential Value of a Steroid-Based Treatment Strategy.

The prognosis of patients with coronavirus disease 2019 (COVID-19) and pre-existing interstitial lung disease (preILD) is poor, and no effective treatment strategy has been determined. The aim of this study was to assess the effectiveness of a steroid-based treatment strategy for patients with COVID-19 and preILD. We retrospectively reviewed the medical records of 610 consecutive patients with COVID-19 treated at our institution between 1 March 2020 and 30 October 2021 and identified 7 patients with preILD, all of whom were treated with corticosteroids and remdesivir. All the patients were men with a median age of 63 years. Three of four patients with severe disease required invasive positive-pressure ventilation (n = 2) or nasal high-flow therapy (n = 1). All three patients could be weaned from respiratory support; however, one died in hospital. The remaining patient with severe COVID-19 had a do-not-resuscitate order in place and died while hospitalized. All three patients with moderate COVID-19 were discharged. The 30-day mortality was 0%, and the mortality rate during the entire observation period was 28.5%. The prognosis of our patients with COVID-19 and preILD has been better than in previous reports. Our management strategy using corticosteroids may have improved these patients' prognosis.

Hemosiderin-Laden Macrophages in Bronchoalveolar Lavage: Predictive Role for Acute Exacerbation of Idiopathic Interstitial Pneumonias.

Background: Hemosiderin-laden macrophages (HLMs) have been identified in the bronchoalveolar lavage fluid (BALF) of patients with idiopathic pulmonary fibrosis (IPF). This retrospective study examined the ability of HLMs in BALF to predict the acute exacerbation (AE) of chronic idiopathic interstitial pneumonias (IIPs). Methods: Two hundred and twenty-one patients with IIP diagnosed by bronchoscopy were enrolled in the study (IPF, n = 87; IIPs other than IPF, n = 134). Giemsa stain was used to detect HLMs in BALF specimens. Prussian blue stain was used to quantify HLMs in BALF, and a hemosiderin score (HS) was given to the specimens containing HLMs. Results: Twenty-four patients had a positive HS (range: 7‒132). The receiver-operating characteristic curve analysis identified the cutoff HS value for predicting the AE of IIPs to be 61.5. Seven cases had a higher HS (≥61.5) and 214 had a lower HS. AE occurred significantly earlier in the higher HS group (4/7 cases) than in the lower HS group (41/214 cases) during a median observation period of 1239 days (log-rank test, p = 0.026). Multivariate Cox proportional hazard regression analysis showed that a higher HS was a significant predictor of AE in addition to IPF, percent predicted forced vital capacity, and modified Medical Research Council score. The C-statistics for the prediction of AE did not significantly improve by all the above parameters with HS as compared without HS. Conclusions: A higher HS was a significant predictor of AE in IIPs but did not significantly improve the predictive ability of other parameters.

Clinical characteristics of COVID-19 in Osaka, Japan: Comparison of the first-third waves with the fourth wave.

BACKGROUND: The fourth wave of COVID-19 in Osaka Prefecture, Japan, caused a medical crisis. Here, we aim to identify the risk factors for COVID-19 severity and compare patients between the first-third waves and the fourth wave. METHODS: We performed an observational retrospective study of COVID-19 cases at the National Hospital Organization Kinki-Chuo Chest Medical Center. RESULTS: We identified 404 patients (median age: 71.0 years [interquartile range: 56.0-80.0]), of whom 199 (49.1%) had mild disease, 142 (35.2%) had moderate disease, and 63 (15.6%) had severe disease. The overall mortality rate was 5.4% (22/404). Based on multivariate logistic regression analysis, cardiovascular disease, fever, dyspnea, and several inflammatory biomarkers were independent risk factors for moderate to severe disease. For every 1 mg/dL increase in C-reactive protein, 10 IU/L increase in lactate dehydrogenase, and 100 ng/mL increase in ferritin, the risk for moderate to severe disease increased by 18.3%, 12.9%, and 8.9%, respectively. Overall disease severity in the fourth wave was higher than in the first-third waves. However, there was no significant difference in mortality. Because of a shortage of beds, four of the 28 severe patients (14.3%) in the fourth wave could not be transferred to the advanced hospital. CONCLUSIONS: Cardiovascular disease, fever, dyspnea, and several inflammatory biomarkers were risk factors for moderate to severe COVID-19 in our cohort. During the fourth wave, COVID-19 severity worsened, increasing the number of patients who could not be transferred to beds for severe cases, resulting in a medical crisis in Osaka.

B cell-activating factors in autoimmune pulmonary alveolar proteinosis.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (APAP) results from the suppression of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling by a neutralizing autoantibody against GM-CSF. B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are involved in immunoglobulin G production and are overproduced in various autoimmune disorders. We hypothesized that BAFF and/or APRIL levels would be elevated in serum and bronchoalveolar lavage fluid (BALF) and serum and BALF levels of BAFF and APRIL respond to the treatments (whole lung lavage (WLL) or inhalation of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF)) in patients with APAP. SUBJECTS AND METHODS: BAFF and APRIL levels in serum and BALF from 110 patients with APAP were measured at baseline and during and after treatment, using an enzyme-linked immunosorbent assay kit. We enrolled 34 healthy volunteers as serum cytokine controls, and 13 disease controls for BALF. Associations of BAFF and APRIL levels with clinical measures were assessed to clarify their clinical roles. RESULTS: In patients with APAP, serum BAFF and APRIL levels were significantly increased relative to healthy volunteers (p < 0.0001 and p < 0.05, respectively), and BALF BAFF and APRIL levels were significantly increased versus disease controls (p < 0.0001 and p < 0.01, respectively). Serum BAFF levels (but not APRIL levels) were significantly correlated with Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-D, SP-A, and lactate dehydrogenase (p < 0.0001). There was no significant correlation between serum BAFF or APRIL levels and anti-GM-CSF autoantibody. BAFF and APRIL were negatively correlated with single-breath diffusion capacity for carbon monoxide (DLco) (p = 0.004) and forced vital capacity (p = 0.04), respectively. BAFF (but not APRIL) in BALF was negatively correlated with vital capacity (p = 0.04) and DLco (p = 0.006). There were significant correlations between disease severity and BAFF levels in serum (p = 0.04) and BALF (p = 0.007). Serum levels of anti-GM-CSF autoantibody, BAFF, and APRIL were not significantly affected by WLL or inhalation of recombinant human GM-CSF. CONCLUSIONS: BAFF and APRIL levels of sera and BALF in APAP were significantly increased compared with healthy volunteer and disease control, and the BAFF and APRIL pathway might have important specific roles in pathogenesis of APAP. Our data suggest a new perspective of future treatment for APAP.

Clinical significance of serum anti-granulocyte-macrophage colony-stimulating factor autoantibodies in patients with sarcoidosis and hypersensitivity pneumonitis.

BACKGROUND: Anti-granulocyte-macrophage colony-stimulating factor autoantibody (GMAb) has been recognized as a diagnostic biomarker for autoimmune pulmonary alveolar proteinosis (aPAP). The aims of this study were to know the incidence of increased level of serum GMAb in granulomatous lung diseases (sarcoidosis and hypersensitivity pneumonitis [HP]) and to clarify the role of GMAb. Consecutive individuals diagnosed with sarcoidosis (n = 92) and HP (n = 45) at National Hospital Organization Kinki-Chuo Chest Medical Center were retrospectively analyzed. We measured serum GMAb levels at the diagnosis. Cut-off values of GMAb discriminating aPAP (n = 110) from healthy controls (n = 31) were determined by receiver operating characteristic (ROC) curve analysis. We compared the clinical features of sarcoidosis and HP patients with GMAb levels above the cut-off value ("Elevated-GMAb") with those of patients whose GMAb levels below the cut-off value ("Low-GMAb"). Radiological and pathological findings in elevated-GMAb patients were re-evaluated to elucidate the role of GMAb in granulomatous lung diseases. RESULTS: Analysis of ROC indicated a sensitivity and specificity of 100% at GMAb level of 3.33 µg/mL for discriminating aPAP from healthy controls (area under curve = 1.000, p < 0.0001). The percentages of elevated-GMAb sarcoidosis and HP patients were 5.4% (n = 5) and 11.1% (n = 5), respectively. The number of comorbid sarcoidosis and HP patients with aPAP was two and one, respectively. Elevated-GMAb sarcoidosis patients presented with significantly higher serum levels of Krebs von den Lungen (KL)-6, surfactant protein-D (SP-D), lactate dehydrogenase, and the requirement of systemic corticosteroid therapy. Elevated-GMAb HP patients demonstrated older age, higher serum KL-6, SP-D, carcinoembryonic antigen, and cytokeratin fragment 21-1 levels, and a higher percentage of lymphocytes in bronchoalveolar lavage than low-GMAb patients. A subset of patients presented with radiological and pathological findings characteristic of aPAP. CONCLUSIONS: We demonstrated the percentage of elevated-GMAb sarcoidosis and HP patients who presented with several features suggestive of aPAP. Elevated-GMAb sarcoidosis and HP patients without definitive aPAP diagnosis may have subclinical or early-stage aPAP and may not necessarily indicate false positives. Upon diagnosis of sarcoidosis or HP, measurement of GMAb may be useful in detecting possible comorbidity of subclinical or early-onset aPAP.

Combination of virtual bronchoscopic navigation, endobronchial ultrasound, and rapid on-site evaluation for diagnosing small peripheral pulmonary lesions: a prospective phase II study.

BACKGROUND: The diagnostic yield of peripheral pulmonary lesions (PPLs) by flexible bronchoscopy (FB) is still insufficient. To improve the diagnostic yield of bronchoscopy, several techniques such as endobronchial ultrasound (EBUS), virtual bronchoscopic navigation (VBN), and rapid on-site evaluation (ROSE) have been examined. The primary purpose of the present study was to evaluate the usefulness of combining EBUS, VBN, and ROSE for diagnosing small PPLs. METHODS: Patients with PPLs 30 mm or less on chest computed tomography (CT) were prospectively enrolled. We determined the responsible bronchus for the target lesions using VBN before bronchoscopy was performed. EBUS and ROSE were performed during the examination to determine whether the bronchus and specimen were adequate. On the basis of previous studies, we assumed that the diagnostic yield of 85% among eligible patients would indicate potential usefulness, whereas, the diagnostic yield of 75% would indicate the lower limit of interest. The required number of patients was estimated as 45 for a one-sided α value of 0.2 and a ß value of 0.8. The primary study endpoint was the diagnostic yield. RESULTS: Between June 2014 and July 2015, we enrolled 50 patients in the present study, and we excluded 5 patients. The total diagnostic yield of 45 PPLs was 77.7%. In cases of lung cancer, the diagnostic yield was 84.2%. The sensitivity, specificity, positive predictive value, and negative predictive value of ROSE were 90.6%, 92.3%, 96.7%, and 80.0%, respectively. The diagnostic yield of PPLs from 20 to 30 mm was 87.5%, and the diagnostic yield of PPLs less than 20 mm was 66.7%. PPLs for which the probe was located within the lesion had the highest diagnostic yield. CONCLUSIONS: We could not demonstrate usefulness for diagnosing small PPLs by combining EBUS, VBN, and ROSE. However, combining these techniques may be useful for diagnosing lung cancer.

Heterogeneity of incidence and outcome of acute exacerbation in idiopathic interstitial pneumonia.

BACKGROUND AND OBJECTIVE: Acute exacerbations (AEs) of idiopathic pulmonary fibrosis (IPF) and other idiopathic interstitial pneumonia (IIP) have a poor prognosis. This study aims to clarify the incidence and prognosis of AE in IPF and the other IIP. METHODS: A total of 229 patients were enrolled, of whom 92 had IPF and 137 had 'IIP other than IPF' based on the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) 2011 IPF Guidelines. IIP other than IPF included 11 patients with a surgical lung biopsy (SLB) and the remainder without such a biopsy. IIP other than IPF was further classified into IIP with a 'possible usual interstitial pneumonia (UIP)' pattern on HRCT (n = 75) and IIP with 'inconsistent with UIP' pattern (n = 62) based on published guidelines. Predictors of AE and the prognosis after AE were examined in these groups. RESULTS: The 1-year incidence of AE in IPF, IIP with possible UIP HRCT patterns and IIP with inconsistent with UIP HRCT patterns was 16.5%, 8.9% and 4.0%, respectively. AE occurred significantly more frequently in IPF than in IIP with possible UIP and inconsistent with UIP HRCT patterns after adjustment for BMI, modified Medical Research Council score and %forced vital capacity. Prognosis of AE-IIP with possible UIP HRCT pattern was significantly worse than that of AE-IPF. CONCLUSION: Although AE occurred significantly less frequently in IIP with possible UIP and inconsistent with UIP HRCT patterns than in IPF, the prognosis of AE-IIP with possible UIP HRCT patterns might be worse than that of AE-IPF.

Small intestinal eosinophils regulate Th17 cells by producing IL-1 receptor antagonist.

Eosinophils play proinflammatory roles in helminth infections and allergic diseases. Under steady-state conditions, eosinophils are abundantly found in the small intestinal lamina propria, but their physiological function is largely unexplored. In this study, we found that small intestinal eosinophils down-regulate Th17 cells. Th17 cells in the small intestine were markedly increased in the ΔdblGATA-1 mice lacking eosinophils, and an inverse correlation was observed between the number of eosinophils and that of Th17 cells in the small intestine of wild-type mice. In addition, small intestinal eosinophils suppressed the in vitro differentiation of Th17 cells, as well as IL-17 production by small intestinal CD4(+)T cells. Unlike other small intestinal immune cells or circulating eosinophils, we found that small intestinal eosinophils have a unique ability to constitutively secrete high levels of IL-1 receptor antagonist (IL-1Ra), a natural inhibitor of IL-1ß. Moreover, small intestinal eosinophils isolated from IL-1Ra-deficient mice failed to suppress Th17 cells. Collectively, our results demonstrate that small intestinal eosinophils play a pivotal role in the maintenance of intestinal homeostasis by regulating Th17 cells via production of IL-1Ra.

Zinc tolerance and uptake by Arabidopsis halleri ssp. gemmifera grown in nutrient solution.

BACKGROUND, AIM, AND SCOPE: Zinc is an essential micronutrient element but its concentrations found in contaminated soils frequently exceed those required by the plant and soil organisms, and thus create danger to animal and human health. Phytoremediation is a technique, often employed in remediation of contaminated soils, which aims to remove heavy metals or other contaminants from soils or waters using plants. Arabidopsis (A.) halleri ssp. gemmifera is a plant recently found to be grown vigorously in heavy metal contaminated areas of Japan and it contained remarkably high amount of heavy metals in its shoots. However, the magnitude of Zn accumulation and tolerance in A. halleri ssp. gemmifera need to be investigated for its use as a phytoremediation plant. MATERIALS AND METHODS: A. halleri ssp. gemmifera was grown for 3 weeks into half-strength nutrient solution with Zn (as ZnSO(4)) levels ranging from 0.2 to 2,000 microM. The harvested plants were separated into shoots and roots, dried in the oven, and ground. The plant tissue was digested with nitric-perchloric acid, and the Zn concentration in the digested solution was measured by atomic absorption spectrophotometer. RESULTS AND DISCUSSION: The results showed no reduction in shoot and root dry weight when plants were grown at 0.2 to 2,000 microM Zn in the solution. The highest Zn concentration measured in the shoots was 26,400 mg kg(-1) at 1,000 microM Zn, while in the roots, it was 71,000 mg kg(-1) at 2,000 microM Zn treatment. Similar to the Zn concentration in plant parts, maximum Zn accumulation of 62 mg plant(-1) in the shoots and 22 mg plant(-1) in the roots was obtained at 1,000 and 2,000 microM Zn in the solution. The percentage of Zn translocation in shoot varied from 69% to 90% of the total Zn, indicating that the shoot was the major sink of Zn accumulation in this plant. CONCLUSIONS: The results of this study indicate that the growth of A. halleri ssp. gemmifera was not affected by the Zn level of up to 2,000 microM in the nutrient solution. The concentration of Zn found in shoot indicated that A. halleri ssp. gemmifera has an extraordinary ability to tolerate and accumulate Zn and hence a good candidate for the phytoremediation of Zn-polluted soil. RECOMMENDATIONS AND OUTLOOK: Based on the results presented in this study and earlier hydroponics, and field study, A. halleri ssp. gemmifera seems to be a potential heavy metals hyperaccumulator, and could be recommended to use for phytoremediation of Cd- and Zn-contaminated soils.