Relationship between serum IgA levels and low percentage forced expiratory volume in the first second in asthma.

Objective: Immunoglobulin A (IgA) is suggested to have pathogenic effects in respiratory inflammatory diseases, including asthma. We aimed to analyze the relationship between serum IgA, and clinical indicators and biomarkers of asthma.Methods: This study was a post hoc analysis of the NHOM Asthma Study. In this study, serum IgA was measured using serum samples stored. We determined an association between the serum IgA level and clinical variables and biomarkers using multivariate linear regression and analyzed the differences in clinical indices between IgA high- and IgA low-asthma.Results: In this study, 572 patients with asthma were included in the final analysis. Lower percentage forced expiratory volume in the first second (%FEV1), higher serum eotaxin levels, lower serum ST2 levels, and higher serum MIP-1ß levels, were independently and significantly associated with higher serum IgA levels among asthma patients by multivariate linear regression analysis (%FEV1, 95% confidence interval [CI], -8.18- -0.613, p < 0.05; eotaxin, 95% CI, 8.95-46.69, p < 0.001; ST2, 95% CI, -73.71- -7.37, p < 0.05; and MIP-1ß, 95% CI, 1.47-18.71, p < 0.05). Furthermore, IgA high-asthma (serum IgA ≥ 238 mg/dL, n = 270) and IgA low-asthma (serum IgA < 238 mg/dL, n = 302) were compared separately. %FEV1 was significantly lower, the percentage of atopy was higher, and serum MIP-1ß level was higher in IgA high-asthma.Conclusions: This study suggests that serum IgA may be involved in the worsening of asthma outcomes, as assessed by %FEV1 and enhanced inflammation via elevated serum MIP-1ß.

Low Serum IL-18 Levels May Predict the Effectiveness of Dupilumab in Severe Asthma.

Objective Dupilumab, a monoclonal antibody specific for the human interleukin (IL)-4 receptor α, is used to treat severe asthma, especially in patients with elevated blood eosinophil counts and fractional exhaled nitric oxide (FeNO). The therapeutic response to dupilumab is highly variable. In this study, we explored new serum biomarkers to accurately predict the effect of dupilumab and examine the effect of dupilumab based on changes in the clinical parameters and cytokine levels. Methods Seventeen patients with severe asthma treated with dupilumab were enrolled. Responders, defined as those with a >0.5-point decrease in the Asthma Control Questionnaire (ACQ) score after 6 months of treatment, were included. Results There were 10 responders and 7 non-responders. Serum type 2 cytokines were equivalent between responders and non-responders; the baseline serum IL-18 level was significantly lower in responders than in non-responders (responders, 194.9±51.0 pg/mL; non-responders, 323.4±122.7 pg/mL, p=0.013). The cut-off value of IL-18 at 230.5 pg/mL could be used to distinguish non-responders from responders (sensitivity 71.4, specificity 80.0, p=0.032). Conclusion A low baseline serum IL-18 level may be a useful predictor of an unfavorable response to dupilumab in terms of the ACQ-6.

Serum MMP3 and IL1-RA levels may be useful biomarkers for detecting asthma and chronic obstructive pulmonary disease overlap in patients with asthma.

Background: Asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO) is characterized by concurrent features of asthma and COPD. Since disease pathogenesis, severities, and treatments differ between asthma and ACO, it is important to differentiate them. Objective: To clarify and compare the characteristics of ACO and asthma and identify the serum biomarkers for differentiating them, especially in older patients. Methods: This study used the data of 639 participants from the nationwide cohort study, the NHOM-Asthma study, an asthma registry in Japan, with complete information on smoking history, respiratory function, and serum biomarkers. ACO was defined as the self-reported comorbidity of COPD or emphysema, or with obstructive pulmonary function and smoking history (pack-years≥10). The clinical characteristics of patients with ACO and asthma without COPD were compared. The serum biomarkers for differentiation were examined using receiver operating characteristic curves and multivariable analysis. The associations between the biomarkers and age were also analyzed. Results: Of the 639 asthma patients, 125 (19.6%) were diagnosed with ACO; these patients were older and male-dominant and had a higher prevalence of comorbidities such as hypertension, diabetes, and stroke. Among the serum biomarkers that were significantly different between ACO and asthma without COPD, the YKL-40/CHI3L1, MMP3, and IL-1RA levels showed a high area under the curve for discriminating ACO. Only the MMP3 and IL-1RA levels were significantly higher among ACO patients, regardless of age and sex; the YKL-40/CHI3L1 levels were not different due to the effect of age. Conclusion: MMP3 and IL-1RA may be useful serum biomarkers for distinguishing ACO from asthma.

Serum IgA augments adhesiveness of cultured lung microvascular endothelial cells and suppresses angiogenesis.

Immunoglobulin A (IgA) is important in local immunity and is also abundant in the blood. This study aimed to evaluate the effects of serum IgA on cultured lung microvascular endothelial cells (HMVEC-Ls), which are involved in the pathogenesis of inflammatory lung diseases. Serum IgA induced adhesion molecules and inflammatory cytokine production from HMVEC-Ls, and enhanced adhesion of peripheral blood mononuclear cells to HMVEC-Ls. In contrast, migration, proliferation, and tube formation of HMVEC-Ls were significantly suppressed by serum IgA. Experiments with siRNAs and western blotting revealed that two known IgA receptors, ß1,4-galactosyltransferase 1 (b4GALT1) and asialoglycoprotein receptor 1 (ASGR1), and mitogen-activated protein kinase and nuclear factor-kappa B pathways were partly involved in serum IgA-induced cytokine production by HMVEC-Ls. Collectively, serum IgA enhanced cytokine production and adhesiveness of HMVEC-L, with b4GALT1 and ASGR1 partially being involved, and suppressed angiogenesis. Thus, serum IgA may be targeted to treat inflammatory lung diseases.

Risk factors and interventions for developing recurrent pneumonia in older adults.

Background: Pneumonia is common among older adults and often recurrent. Several studies have been conducted on the risk factors for pneumonia; however, little is known about the risk factors for recurrent pneumonia. This study aimed to identify the risk factors for developing recurrent pneumonia among older adults and to investigate methods of prevention. Methods: We analysed the data of 256 patients aged 75 years or older who were admitted for pneumonia between June 2014 and May 2017. Moreover, we reviewed the medical records for the subsequent 3 years and defined the readmission caused by pneumonia as recurrent pneumonia. Risk factors for recurrent pneumonia were analysed using multivariable logistic regression analysis. Differences in the recurrence rate based on the types and use of hypnotics were also evaluated. Results: Of the 256 patients, 90 (35.2%) experienced recurrent pneumonia. A low body mass index (OR: 0.91; 95% CI: 0.83‒0.99), history of pneumonia (OR: 2.71; 95% CI: 1.23‒6.13), lung disease as a comorbidity (OR: 4.73; 95% CI: 2.13‒11.60), taking hypnotics (OR: 2.16; 95% CI: 1.18‒4.01) and taking histamine-1 receptor antagonist (H1RA) (OR: 2.38; 95% CI: 1.07‒5.39) were risk factors. Patients taking benzodiazepine as hypnotics were more likely to experience recurrent pneumonia than patients not taking hypnotics (OR: 2.29; 95% CI: 1.25-4.18). Conclusion: We identified several risk factors for recurrent pneumonia. Among them, restricting the use of H1RA and hypnotics, in particular benzodiazepines, may be useful in preventing the recurrence of pneumonia in adults aged 75 years or older.

Immunoglobulin A promotes IL-6 and IL-8 production, proliferation, and migration by the human bronchial smooth muscle cells.

Immunoglobulin A (IgA) is important in biological defense, mainly in the mucosal area, and plays pathogenic roles in various diseases by activating both inflammatory and structural cells. The current study aimed to validate the effects of IgA on the human bronchial smooth muscle cell (BSMC), which plays a major role in airway inflammation and remodeling. Serum IgA induced interleukin (IL)-6 and IL-8 production at both mRNA and protein levels, and enhanced cell proliferation and migration by the BSMCs. The synthetic phenotype markers were regulated and the contractile phenotype markers were downregulated by serum IgA. Mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt, and nuclear factor-κB pathways were involved in IgA-induced IL-6 and IL-8 production. The BSMCs expressed transferrin receptor (TfR), and TfR siRNA transfection inhibited IL-6 and IL-8 production by serum IgA. In summary, serum IgA is a potent activator of the BSMCs at least partially via TfR.

Marked Cognitive and Activities of Daily Living Improvement by Shunt Embolization in a Very Old Man with Portosystemic Encephalopathy Mimicking Alzheimer Disease: A Case Report.

A 91-year-old man with chronic cognitive impairment underwent shunt embolization for portosystemic encephalopathy (PSE). He experienced intermittent episodes of impaired consciousness and decreased cognitive function and activities of daily living (ADL), for which Alzheimer disease was suspected. On admission, he was in a coma and PSE was diagnosed based on his high ammonia level and the computed tomography findings. After shunt embolization, the patient fully recovered from the impaired consciousness and experienced no recurrence. The patient's Revised Hasegawa Dementia Scale and Mini-Mental State Examination scores improved significantly from 12 and 17 to 30 and 29 points, respectively. The Barthel Index score also improved from 55/100 to 85/100, suggesting a marked improvement in ADL. PSE progresses slowly in very old patients and may mimic the clinical course of Alzheimer disease but without liver enzyme abnormalities. Therefore, it should be distinguished in every dementia case.

Evaluation of tuberculosis diagnostic biomarkers in immunocompromised hosts based on cytokine levels in QuantiFERON-TB Gold Plus.

Tuberculosis (TB) remains a serious health concern globally. QuantiFERON-TB (QFT) is a diagnostic tool for TB detection, and its sensitivity is reduced in immunocompromised hosts with low T lymphocyte counts or abnormal T cell function. This study aimed to evaluate the correlation between T cell and cytokine levels in patients with active TB using QFT-Plus. Forty-five patients with active TB were enrolled, and the cytokines in QFT-Plus tube supernatants were quantified using the MAGPIX System. CD4+ T cell count negatively correlated with patient age (p < 0.001, r = -0.51). The levels of TB1-responsive interleukin-1 receptor antagonist (IL-1Ra) and IL-2 correlated with CD4+ T cell count, whereas the levels of TB2-responsive IL-1Ra and IFN-γ-induced protein 10 correlated with both CD4+ and CD8+ T cell counts. Cytokines that correlated with CD4+ and CD8+ T cell counts might not be suitable TB diagnostic biomarkers in immunocompromised hosts. Notably, cytokines that did not correlate with the T cell counts, such as monocyte chemoattractant protein-1, might be candidate biomarkers for TB in immunocompromised hosts. Our findings might help improve TB diagnosis, which could enable prompt treatment and minimize poor disease outcomes.

Identification of ANXA2 on epithelial cells as a new receptor for secretory IgA using immunoprecipitation and mass spectrometry.

Secretory immunoglobulin A plays an important role in the protection against exogenous pathogens and antigens, but it has also been reported to have pathogenic potential. We previously found that secretory immunoglobulin A accumulated in the peripheral lungs during idiopathic pulmonary fibrosis and that transferrin receptor/CD71 was partially involved in secretory immunoglobulin A-induced inflammatory cytokine production in A549 cells. This study aimed to identify the receptor responsible for the induction of cytokine production by secretory immunoglobulin A-stimulated airway epithelial cells. To this end, immunoprecipitation followed by time-of-flight mass spectrometry and peptide mass fingerprinting were performed and Annexin A2 was detected as a novel receptor for secretory immunoglobulin A. Enzyme-linked immunosorbent assay demonstrated binding of secretory immunoglobulin A to Annexin A2, and flow cytometry showed robust expression of Annexin A2 on the surface of BEAS-2B cells, A549 cells, and normal human bronchial/tracheal epithelial cells. Experiments in A549 cells using Annexin A2 small interfering RNA and neutralizing antibodies suggested that Annexin A2 was partially involved in the production of interleukin-8/CXCL8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 induced by secretory immunoglobulin A. Immunohistochemistry using lung sections revealed clear expression of Annexin A2 on airway epithelial cells, although the staining remained equivalent in idiopathic pulmonary fibrosis, asthma, and healthy control lungs. In conclusion, we identified that Annexin A2 expressed in airway epithelial cells is a novel receptor for secretory immunoglobulin A, which is involved in cytokine synthesis.

Influence of oral health on frailty in patients with type 2 diabetes aged 75 years or older.

BACKGROUND: Poor oral health conditions are known to affect frailty in the older adults. Diabetes is a risk factor for both poor oral health and frailty, therefore, oral health status may affect frailty in diabetic patients more than in the general population. The purpose of this study was to evaluate the influence of oral health and other factors on frailty and the relationship among oral health, diabetes and frailty in older adult patients with type 2 diabetes. METHODS: Patients with type 2 diabetes aged 75 years or older were included in this cross-sectional study. Eligible patients were surveyed by questionnaire for frailty, oral health status, and cognitive and living functions. Factors influencing pre-frailty, frailty, and individual frailty screening index (FSI) classes were evaluated. RESULTS: Of the 111 patients analyzed, 66 cases (59.5%) were categorized as robust, 33 cases (29.7%) as pre-frailty, and 12 cases (10.8%) as frailty. The oral frailty index, the cognitive and living functions score, and BMI were found to be factors influencing pre-frailty or frailty. In the evaluation of individual FSI classes, BMI had an influence on those with a FSI ≤2. The cognitive and living functions score was a factor influencing those with FSI ≤3. The oral frailty index was found to have a significant influence on all FSI classes. CONCLUSIONS: Poor oral health has an influence on frailty in patients with type 2 diabetes aged ≥75. In this patient population, as frailty progresses, the impact of oral health on frailty may increase. TRIAL REGISTRATION: This study was retrospectively registered in UMIN-CTR ( UMIN000044227 ).

DASC-21: a novel geriatric assessment for discriminating best supportive care in older patients with inoperable advanced non-small cell lung cancer.

OBJECTIVE: This study investigated whether the Dementia Assessment Sheet for the Community-based Integrated Care System is useful for decision-making or problem detection in the treatment and care of older patients with inoperable advanced non-small cell lung cancer compared with the current standard model using performance status. METHODS: This study retrospectively examined 1595 cases admitted to the Department of Respiratory Medicine at the Tokyo Metropolitan Geriatric Hospital between 26 July 2016 and 28 January 2020. Among these, 29 and 31 patients who received pharmacotherapies and best supportive care were extracted, respectively. The performance in identifying best supportive care using the Dementia Assessment Sheet for the Community-based Integrated Care System was evaluated in comparison with performance status. The ability to detect impairments in each Dementia Assessment Sheet for the Community-based Integrated Care System domain was also assessed. RESULTS: The Dementia Assessment Sheet for the Community-based Integrated Care System total score had an area under the curve of 0.831 (95% confidence interval, 0.694-0.914), which was statistically equivalent to performance status. The discriminatory cut-off value for identification of best supportive care was set at 29 with a sensitivity and specificity of 0.742 and 0.897, respectively. Dementia Assessment Sheet for the Community-based Integrated Care System total score showed good concordance with performance status especially when reported by family members or caregivers. Deficits other than activities of daily living were recognized (2.8-19.4%) in patients with good performance status. Impairments were more frequently detected when reported by family members or caregivers. CONCLUSIONS: The Dementia Assessment Sheet for the Community-based Integrated Care System discriminates the best supportive care for older patients with inoperable advanced non-small cell lung cancer. Moreover, it can identify vulnerabilities especially when reported by family members or caregivers that cannot be detected by performance status.

Myeloperoxidase anti-neutrophil cytoplasmic antibody-associated vasculitis with a unique imaging presentation of organizing pneumonia: A case report.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes a group of blood vessel inflammation diseases of autoimmune origin. Myeloperoxidase (MPO) ANCA is closely related to ANCA associated AAV. The MPO-ANCA positive AAV patients have lung involvement at high rates; however, there are only a few reported cases with organizing pneumonia (OP). A 78-year-old man was presented to our hospital due to a fever of 38 °C despite a whole month of antibiotics treatment. Chest computed tomography image revealed restricted consolidations visible in the middle lobe of the right lung and the upper lobe of the left lung, which suggested an OP pattern. MPO-ANCA and urine occult blood tests were positive. Histopathological examination of the transbronchial biopsy revealed OP and mucus plug. Histological findings on renal biopsy showed necrotizing glomerulonephritis related to AAV. The patient was diagnosed with MPO-ANCA positive AAV and was treated with systemic corticosteroid therapy, from which he recovered rapidly. Thus, when diagnosing OP, the possibility of AAV should be considered by ordering patients' serum ANCA and occult hematuria tests.

[An elderly case of squamous cell lung cancer treated continuously with pembrolizumab without any decline in the life function].

BACKGROUND: Whether or not immune checkpoint inhibitors are safe and effective for the elderly remains unclear, even though these drugs were approved two years ago for the treatment of advanced non-small cell lung cancer in Japan. Older cancer patients are vulnerable to chemotherapy, so their life function should be closely monitored before starting, continuing, or discontinuing cancer treatment. CASE: An 85-year-old man showed a wedge-shaped shadow in the apical portion of the left lung on chest computed tomography. Unfortunately, repeated bronchoscopy revealed no malignancy. The shadow progressed over about one year, so a third bronchoscopy was performed, leading to a diagnosis of squamous-cell carcinoma (cT3N2M1a, stage IVA). Because PD-L1 immunohistochemical staining was positive for 80%-90% of the tumor cells, the patient was treated with pembrolizumab as the first-line therapy, and the tumor dramatically regressed, notably without any decline in the patient's life functions. CONCLUSION: An elderly case of squamous-cell lung cancer was treated continuously with pembrolizumab without any decline in the patient's life function.