Successful Treatment of Eosinophilic Granulomatosis With Polyangiitis: A Case of Refractory Peripheral Neuropathy and Comorbid Chronic Progressive Pulmonary Aspergillosis Treated With Mepolizumab.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotizing vasculitis accompanied by granulomas and eosinophilic inflammation, exhibiting marked peripheral blood eosinophiliaandasthma. Neuropathy is a difficult-to-treat common manifestation that frequently remains after achieving clinical remission with current therapy in a subpopulation of patients with EGPA with or without life-threatening organ involvement. Refractory neuropathy regularly reduces the quality of life and requires glucocorticoids (GCs) and/or immunosuppressants for a long time. Long-term immunosuppressive therapy is a factor associated with a high risk of adverse effects. Mepolizumab, at three times the dose for severe asthma, provides benefits to induce the remission of relapsing or refractory EGPA and to reduce the doses of GC. Here, we present a case of EGPA successfully treated with mepolizumab at the reference dose for severe asthma. In this case, mepolizumab resolved peripheral neuropathy resistant to corticosteroids, immunosuppressants, and intravenous immunoglobulin and contributed to the improvement of comorbid chronic pulmonary aspergillosis during GC dose reduction.

Simultaneous bilateral spontaneous pneumothorax in a patient with anorexia nervosa.

Anorexia nervosa causes various complications accompanying weight loss and malnutrition. Although bilateral spontaneous pneumothorax (SBSP) is uncommon, caution is needed in anorexia nervosa because this complication can be fatal. We encountered a 17-year-old girl with SBSP from emphysematous pulmonary changes due to anorexia nervosa. She was hospitalized with SBSP during treatment for anorexia nervosa. Chest tube drainage was started on admission, but no improvement was achieved. Surgery was therefore performed. Lung lesions on surgical specimens demonstrated malnutrition-induced emphysematous changes, a risk factor for SBSP. Attention should be paid to the occurrence of SBSP during the clinical course of anorexia nervosa.

Medical Record Survey after Comprehensive Health Checkup Referral and Its Contribution to the Early Detection of Cancer.

Comprehensive health checkups in Japan are a preventive method to detect cancer and metabolic diseases. Unlike group medical examinations, individual examinations in health checkups are possible, with additional tests possible for disease detection. However, it is difficult to accurately ascertain the results from only the report after referral to a medical institution in individuals suspected of having cancer who need to be examined. We aimed to conduct a medical record survey of patients referred to the Hospital after undergoing a comprehensive health checkup and investigate the contribution of comprehensive health checkups to the detection of cancer more accurately. The subjects were 1763 examinees who were referred to various departments of our hospital because of doubtful cancer from 23,128 examinees who underwent comprehensive health checkups in our center from January 2018 to December 2022 for 5 years. The medical record survey demonstrated that cancer was detected in more than twice as many individuals as reported and other sources. Early-stage cancers require a significantly longer time to establish a definitive diagnosis. In conclusion, short-term reports from the referring hospital are insufficient for a final diagnosis, and long-term follow-up is extremely important to increase the diagnosis rates of cancer for comprehensive health checkups.

Immunosenescence, Inflammaging, and Lung Senescence in Asthma in the Elderly.

Prevalence of asthma in older adults is growing along with increasing global life expectancy. Due to poor clinical consequences such as high mortality, advancement in understanding the pathophysiology of asthma in older patients has been sought to provide prompt treatment for them. Age-related alterations of functions in the immune system and lung parenchyma occur throughout life. Alterations with advancing age are promoted by various stimuli, including pathobionts, fungi, viruses, pollutants, and damage-associated molecular patterns derived from impaired cells, abandoned cell debris, and senescent cells. Age-related changes in the innate and adaptive immune response, termed immunosenescence, includes impairment of phagocytosis and antigen presentation, enhancement of proinflammatory mediator generation, and production of senescence-associated secretory phenotype. Immnunosenescence could promote inflammaging (chronic low-grade inflammation) and contribute to late-onset adult asthma and asthma in the elderly, along with age-related pulmonary disease, such as chronic obstructive pulmonary disease and pulmonary fibrosis, due to lung parenchyma senescence. Aged patients with asthma exhibit local and systemic type 2 and non-type 2 inflammation, associated with clinical manifestations. Here, we discuss immunosenescence's contribution to the immune response and the combination of type 2 inflammation and inflammaging in asthma in the elderly and present an overview of age-related features in the immune system and lung structure.

Treatment Resistance in Severe Asthma Patients With a Combination of High Fraction of Exhaled Nitric Oxide and Low Blood Eosinophil Counts.

Background: Combining a fraction of exhaled nitric oxide (FeNO) and blood eosinophil count (B-EOS) may be a useful strategy for administration of biologics such as anti-IgE or anti-IL-5 to patients with type 2 inflammatory-predominant severe asthma and is important to be elucidated considering the increasing use of biologics. Methods: This cross-sectional study analyzed the clinical data from 114 adult patients with severe asthma, who were treated at Saitama Medical University Hospital. The eligible patients were stratified into four subgroups defined by thresholds of FeNO and blood eosinophil (B-EOS) counts to detect sputum eosinophilia, using the receiver operating characteristic curve analysis. A total of 75 patients with optimal samples were stratified into four subtypes defined by thresholds of sputum eosinophilia and neutrophilia. Clinical characteristics, pattern of biologics, and distribution of sputum subtypes were analyzed in the stratified subclasses according to the FeNO and B-EOS thresholds. The asthma exacerbation (AE)-free time of the FeNO/B-EOS subgroups and any biologics treatment including anti-IgE or anti-IL-5 use were examined using the Kaplan-Meier method. The hazard ratios (HRs) for AE-free time were examined using the Cox proportional hazard model. Results: The optimal cutoff values for prediction of sputum eosinophilia were defined as ≥2.7% wherein for FeNO as ≥27 ppb and B-EOS as ≥265/µL were considered. The high-FeNO subgroups showed significant high total IgE, compared with the low FeNO. The high-FeNO/high-B-EOS and the high-FeNO/low-B-EOS subgroups showed the largest prevalence of mepolizumab and benralizumab use among the other FeNO/B-EOS, respectively. The high-FeNO/low-B-EOS showed the largest frequency of AEs, high HR, and the shortest AE-free time, among the other FeNO/B-EOS. The sputum eosinophil-predominant subtype was the great majority in the high FeNO/high B-EOS. A diverse distribution of sputum leukocyte-predominant subtype was observed in the other FeNO/B-EOS. The subsequent AE-free time and its HR were comparable among the biologics use groups. Conclusion: The strategy of classifying severe asthma based on the combination of FeNO and B-EOS proposes particular refractory type 2 severe asthma and underlying airway inflammation as a feasible trait for optimal biologics use.

Japanese cedar pollen upregulates the effector functions of eosinophils.

BACKGROUND: Symptoms of rhinitis and asthma can be exacerbated during Japanese cedar pollen (JCP)-scattering season, even in subjects who are not sensitized to JCP, suggesting that innate immune responses may contribute to this process. We previously reported that house dust mite directly activates the effector functions of eosinophils. Similar mechanisms may play roles in the JCP-related aggravation of allergic diseases. OBJECTIVE: To investigate whether JCP or Cry j 1, a major allergen of JCP, can modify the effector functions of eosinophils. METHODS: Eosinophils isolated from the peripheral blood of healthy donors were stimulated with either JCP or Cry j 1, and their adhesion to human intercellular adhesion molecule-1 was measured using eosinophil peroxidase assays. The generation of eosinophil superoxide anion (O2 -) was measured based on the superoxide dismutase-inhibitable reduction of cytochrome C. Concentrations of eosinophil-derived neurotoxin in the cell media were measured by enzyme-linked immunosorbent assay as a marker of degranulation. RESULTS: Both JCP and Cry j 1 directly induced eosinophil adhesiveness, generation of O2 -, and release of eosinophil-derived neurotoxin. Both anti-αM and anti-ß2 integrin antibodies blocked all of these eosinophil functions induced by JCP and Cry j 1. Similarly, PAR-2 antagonists also partially suppressed all of these effector functions induced by JCP and Cry j 1. CONCLUSION: JCP and Cry j 1 directly activate the functions of eosinophils, and both αMß2 integrin and partly PAR-2 are contributed to this activation. Therefore, JCP-induced eosinophil activation may play a role in the aggravation of allergic airway diseases in nonsensitized patients as well as in JCP-sensitized patients.

Clinical evaluation of rush immunotherapy using house dust mite allergen in Japanese asthmatics.

BACKGROUND: Allergen immunotherapy (AIT) is a specific treatment of administering clinically important allergens to patients who have allergic diseases. In Japan, the standardized house dust mite (HDM) allergen for subcutaneous immunotherapy (SCIT) was approved in 2015, and we then introduced rush-immunotherapy (rush-IT) using the standardized HDM allergen for HDM-sensitive asthmatics. However, little data are available on the safety and effectiveness of rush-HDM-IT, especially for Japanese asthmatics. OBJECTIVE: The objective of this study was to examine the safety and clinical effectiveness of rush-IT using the standardized HDM for HDM-sensitive Japanese asthmatics. METHODS: Thirteen HDM-sensitive asthmatics who received rush-HDM-IT and 12 HDM-sensitive asthmatic controls were enrolled. To evaluate the safety, the number of systemic reaction (SR) events, including anaphylaxis, was assessed. To evaluate the effectiveness, changes in the treatment step, dose of inhaled corticosteroid, and asthma control after rush-HDM-IT and the subsequent maintenance SCIT were assessed. Changes in the HDM-induced production of type 2 cytokines from peripheral blood mononuclear cells were also evaluated. RESULTS: Among the 12 patients who received rush-IT, 4 (30.7%) experienced a SR and 3 (23.1%) experienced anaphylaxis. However, the anaphylaxis was not severe (grade 3) in all cases, and they recovered in a short time. The treatment step of asthma was better and the dose of inhaled corticosteroid was lower in the rush-HDM-IT group than in the control group. The HDM-induced production of both interleukin (IL)-5 and IL-13 from peripheral blood mononuclear cells was significantly lower in the rush-HDM-IT group than in the control group. CONCLUSION: Rush-HDM-IT can be performed relatively safely in Japanese asthmatics. Furthermore, rush-HDM-IT and the subsequent maintenance SCIT provided clinical improvement in asthma patients, and was accompanied by the suppression of HDM-specific Th2-mediated systemic immune responses.

[BRONCHIAL ASTHMA WITH VOCAL CORD DYSFUNCTION DIFFERENTIATED FROM SEVERE ASTHMA BY BRONCHOSCOPY].

Although an important cause of vocal cord dysfunction (VCD) is psychogenic reaction, VCD may be associated with severe asthma and must be distinguished from the disease. A 30-years-old woman was admitted to our hospital with dyspnea despite treatment for asthma. Inspiratory stridor and expiratory wheezes were noted, and neck and chest computed tomography showed normal airways and lungs. Fractional exhaled nitric oxide levels were also normal. Pulmonary function test with a flow-volume loop curve showed normal expiratory loop with flattening of the inspiratory loop after methacholine inhalation. During the attack, bronchoscopy revealed the vocal cord closing with stridor during the inspiratory phase. Therefore, the patient was diagnosed with VCD. The dyspnea improved with respiratory rehabilitation and pursed-lip breathing. VCD should be considered in the differential diagnosis of intractable severe asthma. In this case, bronchoscopy and bronchial inhalation challenge with methacholine helped in the diagnosis.

Predictors of adherence to sublingual immunotherapy for Japanese cedar pollinosis: a prospective analysis.

BACKGROUND: Sublingual immunotherapy (SLIT) often has low adherence rates. OBJECTIVE: To provide effective support for SLIT continuation, we investigated potential predictors of SLIT adherence through a prospective analysis of patient characteristics. We excluded evaluation of treatment effect and symptoms during treatment, aiming instead to identify predictors of later dropout or insufficient adherence due to indolence or forgetfulness using only information obtained at initial examination. METHODS: We provided patients with a questionnaire and monitored self-reported adherence once every 6 months. Cases of dropout for clear reasons were excluded, but cases of dropout or insufficient adherence to SLIT for indolence or forgetfulness were included. RESULTS: Fifty-three patients receiving SLIT were assessed. Nine patients dropped out after providing a clear reason. Thirty-four patients maintained good adherence. Seven patients continued SLIT but with insufficient adherence, while three patients discontinued SLIT for unclear reasons (indolence or forgetfulness) and these ten individuals were classified as the poor-adherence group. Univariate analysis and multivariate logistic regression analysis of the good-adherence and poor-adherence groups showed age to be a significant predictor of SLIT adherence. Based on analysis of a receiver operating characteristic curve, age < 40.5 years was selected as the optimal cutoff value for predicting poor adherence to SLIT. CONCLUSIONS: To prevent treatment SLIT discontinuation on account of indolence or forgetfulness, the necessity of longterm treatment continuity should be communicated clearly prior to commencing treatment, especially for patients under 40 years of age.

Eicosanoids seasonally impact pulmonary function in asthmatic patients with Japanese cedar pollinosis.

BACKGROUND: Condition of asthma in patients with asthma and concomitant seasonal allergic rhinitis (SAR) deteriorates during the Japanese cedar pollen (JCP) season. However, the underlying mechanisms remain unclear. METHODS: We analyzed seasonal variations in eicosanoid levels in the airways of patients with asthma and concomitant SAR sensitized to JCP (N = 29, BA-SAR-JCP group) and those not sensitized (N = 13, BA-AR-non-JCP group) during the JCP season. The association between changes in eicosanoid concentrations and pulmonary function was assessed. Exhaled breath condensate (EBC) was collected, and pulmonary function tests were performed during the JCP and non-JCP seasons. The cysteinyl leukotriene (CysLT), thromboxane B2 (TXB2), prostaglandin D2-methoxime (PGD2-MOX), and leukotriene B4 (LTB4) levels in the collected EBC were measured via enzyme-linked immunosorbent immunoassays. RESULTS: The log CysLT levels significantly increased in the BA-SAR-JCP group during the JCP season compared with the non-JCP season (1.78 ± 0.55, 1.39 ± 0.63 pg/mL, mean ± standard deviation, respectively, p = 0.01) and those in the BA-AR-non-JCP group during the JCP season (1.39 ± 0.38 pg/mL, p = 0.04). Moreover, the log TXB2 levels seemed to increase. However, the log LTB4 and log PGD2-MOX levels did not increase. The changes in the log CysLT levels during the two seasons were negatively correlated to forced expiratory volume in one second (FEV1) in the BA-SAR-JCP group (r = -0.52, p < 0.01). CONCLUSIONS: In the BA-SAR-JCP group, seasonal increases in eicosanoid levels in the airway likely promoted deterioration in pulmonary function despite optimal maintenance treatment.

Mechanisms of eosinophilic inflammation.

Eosinophils play roles in the pathogenesis of various diseases. In order to accumulate within sites of inflammation, eosinophils must adhere to, and migrate across the microvasculature. These processes are largely controlled by type 2-immune responses; interleukin (IL)-4 and IL-13 induce the expression of endothelial adhesion molecule vascular cell adhesion molecule-1 (VCAM-1), a representative adhesive ligand for eosinophils, while also stimulating generations of CC chemokines from structural cells, including epithelial cells. VCAM-1 and CC chemokines synergistically induce transmigration of eosinophils to the tissue inflammation site. Another type 2 cytokine, IL-5, prolongs survival, and enhances the effector functions of eosinophils. Recently, accumulating evidence has established that corticosteroid-resistant group 2 innate lymphoid cells are cellular sources for IL-5. Another immunological mechanism that may be contributing to eosinophilic inflammation involves type 1 immune system-associated molecules such as interferons and IP-10. In addition to these immune pathways, lipid mediators, such as cysteinyl leukotrienes, directly provoke the infiltration and activation of eosinophils. Extracellular matrix proteins including periostin also induce the adhesion and activation of eosinophils. Finally, activated neutrophils can also induce eosinophil transmigration. In summary, various mechanisms are involved within eosinophilic inflammation, and effective therapeutic strategies targeting these pathways should be established.

Effects of ß2-adrenergic agonists on house dust mite-induced adhesion, superoxide anion generation, and degranulation of human eosinophils.

BACKGROUND: Even in subjects who are not sensitized to house dust mite (HDM), allergic symptoms can be clinically aggravated by exposure to dust. We previously reported that Dermatophagoides farinae (Df), an important HDM, or Der f 1, a major allergen of Df, induced the effector functions of eosinophils, which may be an important mechanism for HDM-induced symptoms in nonsensitized patients. In a clinical setting, ß2-adrenergic agonists, such as salbutamol and formoterol, are used for the treatment of asthma attacks or exacerbation to release the airway obstruction. Several reports have suggested that some ß2-adrenergic agonists have an anti-inflammatory capacity. OBJECTIVE: In this study, we investigated whether ß2-adrenergic agonist could modify the Df- or Der f 1-induced activation of eosinophils. METHODS: Blood eosinophils obtained from healthy donors were preincubated with either formoterol (1 µM), salbutamol (1 µM), or buffer control and then stimulated with Df extract (1 µg/mL) or Der f 1 (100 pg/mL). Eosinophil adhesion to intercellular adhesion molecule (ICAM)-1 was measured using eosinophil peroxidase assays. Generation of superoxide anion (O2 -) was examined based on the superoxide dismutase-inhibitable reduction of cytochrome C. Eosinophil-derived neurotoxin (EDN) concentrations in cell media were measured by enzyme-linked immunosorbent assay. RESULTS: Formoterol, but not salbutamol, suppressed the Df- or Der f 1-induced eosinophil adhesion to ICAM-1. Furthermore, formoterol, but not salbutamol, suppressed Df-induced O2 - generation or EDN release. Neither formoterol nor salbutamol suppressed spontaneous eosinophil adhesion, O2 - generation, or EDN release. CONCLUSION: These findings suggested that formoterol, but not salbutamol, suppressed Df- or Der f 1-induced eosinophil activation when used at the same concentration. Therefore, formoterol could potentially be used for the treatment of bronchial asthma via both bronchodilation and anti-inflammatory effect.

Relationship between airway inflammation and airflow limitation in elderly asthmatics.

BACKGROUND: The prevalence of asthma in elderly population has been increasing. Previous studies have demonstrated clinical characteristics of elderly asthmatics (EA). However, little is known regarding the influence of immunological change on the physiological status of EA. OBJECTIVE: We investigated the relationship between inflammatory mediators and the pulmonary function (PF) of EA. METHODS: Eligible adult asthmatics recruited from the Allergy Center of Saitama Medical University Hospital were classified into a non-EA group (<40 years old, n = 15) and an EA group (≥60 years old, n = 43). Sputum induction and PF tests were performed. Concentrations of an eosinophil-derived neurotoxin (EDN) and neutrophil elastase (NE) in sputum supernatants were measured by enzyme-linked immunosorbent assay and a fluorometric assay using a commercial assay kit, respectively. Cell counts and EDN and NE concentrations in sputum were compared between the 2 groups. The association among those parameters and PF were analyzed in each group. RESULTS: The EA group had a significantly higher severe asthmatics proportion (p = 0.01), a lower current smokers proportion (p = 0.002), lower sensitization rate to aeroallergens (p = 0.012), several PFs deterioration (p < 0.0001) and lower total IgE levels (p = 0.001) than the non-EA group. Sputum neutrophil counts and NE concentrations were significantly higher in the EA group than those in the non-EA group (median neutrophil: 4.11 vs. 2.74 ×105/mL, p = 0.03; NE: 2.0 vs.1.6 µg/mL, p < 0.05, respectively), whereas sputum eosinophil counts and EDN concentrations were not. Sputum EDN concentrations were significantly positively correlated with sputum neutrophil counts (r = 0.39, p = 0.031) and NE concentrations (r = 0.57, p < 0.0001) only in the EA group. Eosinophil-related parameters were negatively correlated with several PFs in the 2 groups. Neutrophil-related parameters were negatively correlated with PFs only in the non-EA group. CONCLUSION: This study determines that in EA, persistent active eosinophilic airway inflammation is accompanied by advanced neutrophilic inflammation, which may contribute to deteriorated PF. This distinct airway inflammation may increase the severity of asthma in EA.

Implications of prostaglandin D2 and leukotrienes in exhaled breath condensates of asthma.

BACKGROUND: Various inflammatory eicosanoid levels in biomaterials from airways of asthma and their associations with clinical parameters remain uncertain. We hypothesized that prostaglandin and leukotriene levels differ between in exhaled breath condensates (EBCs) and in sputum in mild, moderate, and severe levels of asthma and that EBC and sputum eicosanoid levels are associated with indexes of pulmonary function and inflammation. OBJECTIVE: To determine the differences between EBC and sputum eicosanoid levels in healthy participants and patients with asthma with different asthma severity levels. METHODS: Collected EBC and sputum, as well as pulmonary function, were examined in adult patients with asthma and healthy participants. Exhaled breath condensate prostaglandin D2-methoxime (PGD2-MOX), cysteinyl leukotrienes (CysLTs), leukotriene B4 (LTB4), and thromboxane B2 levels, and some sputum eicosanoid and tryptase levels were measured. Differences in eicosanoid levels among participants and their associations with pulmonary function and tryptase and granulocyte levels in sputum were then evaluated. RESULTS: Analysis of 94 EBCs and 43 sputa revealed that EBC and sputum PGD2-MOX and CysLT levels were significantly higher in patients with asthma than in healthy participants. Exhaled breath condensate PGD2-MOX, CysLT, and LTB4 levels were significantly higher in patients with severe asthma. Exhaled breath condensate PGD2-MOX level was also significantly correlated with sputum tryptase levels and lower pulmonary function in patients with asthma. Sputum PGD2-MOX and CysLT levels were significantly correlated with the proportion of eosinophils among all cells in sputum in patients with asthma. CONCLUSION: The results suggest that EBC PGD2 levels are associated with impairment of pulmonary function in adults with asthma who have undergone guideline treatment. Exhaled breath condensate or sputum PGD2 and CysLTs may represent severity or airway inflammation in asthma.