Involvement of Muscarinic M3 Receptor in the Development of M2 Macrophages in Allergic Inflammation.

INTRODUCTION: The muscarinic M3 receptor antagonist, tiotropium, has a bronchodilatory effect on asthma patients. Additionally, tiotropium inhibits allergic airway inflammation and remodeling in a murine asthma model. However, the underlying mechanisms of this M3 receptor antagonist remain unclear. Therefore, we investigated the effect of muscarinic M3 receptor blockage on M2 macrophage development during allergic airway inflammation. METHODS: BALB/c mice were sensitized and challenged with ovalbumin to develop a murine model of allergic airway inflammation mimicking human atopic asthma. During the challenge phase, mice were treated with or without tiotropium. Lung cells were isolated 24 h after the last treatment and gated using CD68-positive cells. Relm-α and Arginase-1 (Arg1) (M2 macrophage markers) expression was determined by flow cytometry. Mouse bone marrow mononuclear cell-derived macrophages (mBMMacs) and human peripheral blood mononuclear cells (PBMCs)-derived macrophages were stimulated with IL-4 and treated with a muscarinic M3 receptor antagonist in vitro. RESULTS: The total cells, eosinophils, and IL-5 and IL-13 levels in BAL fluids were markedly decreased in the asthma group treated with tiotropium compared to that in the untreated asthma group. The Relm-α and Arg1 expression in macrophages was reduced considerably in the asthma group treated with tiotropium compared to that in the untreated asthma group, suggesting that the development of M2 macrophages was inhibited by muscarinic M3 receptor blockage. Additionally, muscarinic M3 receptor blockage in vitro significantly inhibited M2 macrophage development in both mBMMacs- and PBMCs-derived macrophages. CONCLUSIONS: Muscarinic M3 receptor blockage inhibits M2 macrophage development and prevents allergic airway inflammation. Moreover, muscarinic M3 receptors might be involved in the differentiation of immature macrophages into M2 macrophages.

Impact of dupilumab across seasons in patients with type 2, uncontrolled, moderate-to-severe asthma.

BACKGROUND: Seasonal variability could influence asthma exacerbations. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4/IL-13, key and central drivers of type 2 inflammation. In the 52-week QUEST study (NCT02414854), add-on dupilumab every 2 weeks vs placebo significantly reduced exacerbations and improved prebronchodilator forced expiratory volume in 1 second in patients with uncontrolled, moderate-to-severe asthma. TRAVERSE (NCT02134028), the open-label QUEST extension study, enrolled patients with moderate-to-severe asthma to investigate long-term safety and efficacy of dupilumab, including patients who previously received placebo that initiated dupilumab therapy. OBJECTIVE: To investigate long-term dupilumab efficacy in reducing exacerbations across yearly seasons in patients with type 2 inflammatory asthma with and without clinical evidence of allergic asthma. METHODS: Unadjusted annualized exacerbation rate and proportions of patients experiencing severe asthma exacerbations are reported by month and season and for both hemispheres. RESULTS: The proportion of patients with type 2 asthma experiencing 1 or more severe asthma exacerbations during QUEST was 20.8% vs 10.0% in spring, 18.2% vs 7.3% in summer, 22.2% vs 12.6% in autumn, and 26.4% vs 12.0% in winter, for placebo- vs dupilumab-treated patients, respectively; P was less than .001 for placebo vs dupilumab in all seasons. Reductions in the proportion of patients experiencing severe exacerbations across seasons in subgroups with and without evidence of allergic asthma were similar to the overall type 2 population. Reductions in severe exacerbations observed during QUEST were sustained during TRAVERSE, up to 96 weeks across both hemispheres. CONCLUSION: Dupilumab reduced asthma exacerbations, with no difference in the reduction between seasons, in patients with type 2 inflammation, with and without evidence of allergic asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02414854, NCT02134028.

Eosinophils and tissue remodeling: Relevance to airway disease.

The ability of human tissue to reorganize and restore its existing structure underlies tissue homeostasis in the healthy airways, but in disease can persist without normal resolution, leading to an altered airway structure. Eosinophils play a cardinal role in airway remodeling both in health and disease, driving epithelial homeostasis and extracellular matrix turnover. Physiological consequences associated with eosinophil-driven remodeling include impaired lung function and reduced bronchodilator reversibility in asthma, and obstructed airflow in chronic rhinosinusitis with nasal polyps. Given the contribution of airway remodeling to the development and persistence of symptoms in airways disease, targeting remodeling is an important therapeutic consideration. Indeed, there is early evidence that eosinophil attenuation may reduce remodeling and disease progression in asthma. This review provides an overview of tissue remodeling in both health and airway disease with a particular focus on eosinophilic asthma and chronic rhinosinusitis with nasal polyps, as well as the role of eosinophils in these processes and the implications for therapeutic interventions. Areas for future research are also noted, to help improve our understanding of the homeostatic and pathological roles of eosinophils in tissue remodeling, which should aid the development of targeted and effective treatments for eosinophilic diseases of the airways.

[EPIPEN INSTRUCTIONS FOR ANAPHYLAXIS PATIENTS DURING DISPENSING: FACTORS RELATED TO THE QUALITY OF PHARMACISTS' INSTRUCTIONS].

BACKGROUND AND AIM: We previously reported that pharmacists working in pharmacies don't have enough knowledge and enough experience teaching anaphylaxis (An) and EpiPen use. We administered a questionnaire survey to pharmacists with experience handling EpiPen prescriptions. We investigated the relationship between the questionnaire results and the factors in the pharmacists' background regarding the explanation and guidance to patients. RESULTS: The percentage of pharmacists working in pharmacies who provided guidance using visual information and demonstrations was insufficient. Moreover, this figure decreased after the second guidance session. Objective confirmation of patient understanding was also insufficient. The results indicated that self-examination and participation in drug information sessions were important background factors for pharmacists who provided detailed guidance to patients. DISCUSSION: For appropriate long-term management of their condition, An patients must master the EpiPen technique. Pharmacists' guidance plays a critical role in this regard. A support system should be established for proper instruction of pharmacy patients by improving pharmacists' self-education and other educational opportunities.

Population Pharmacokinetic Model and Dosing Simulation of Meropenem Using Measured Creatinine Clearance for Patients with Sepsis.

PURPOSE: Creatinine clearance (CCr) and pharmacokinetic parameters are markedly affected by pathophysiological changes in patients with sepsis. However, only a few reports have assessed renal function in patients with sepsis using the measured CCr. Furthermore, the administration regimen has not been sufficiently evaluated using a population PK (PPK) model across renal function broad ranges. Therefore, this study was performed to construct a meropenem PPK model for patients with sepsis using the measured CCr and evaluate the optimized meropenem dosing regimen based on the CCr. METHODS: Patients with sepsis who received intravenous meropenem at the Showa University Hospital were enrolled in this prospective observational study. The PPK model was constructed using blood samples and clinical information of patients. The probability of target attainment (PTA) indicates the likelihood of achieving 50% time above the minimum inhibitory concentration (% T > MIC) based on 10,000 virtual patients using Monte Carlo simulations. The PTA for each meropenem regimen was 50% T > MIC based on different renal functions using the Monte Carlo simulation. RESULTS: One hundred samples were collected from 31 patients. The final PPK model incorporating the measured CCr as a covariate in CL displayed the best fit. The recommended dosing regimen to achieve a PTA of 50% T > MIC of 4 mcg/mL was 1 g every 8 hours as a 3-hour prolonged infusion for patients with CCr 85-130 mL/min and 1 g every 8 hours as an 8-hour continuous infusion for patients with CCr ≥ 130 mL/min. CONCLUSIONS: This model precisely predicted meropenem concentrations in patients with sepsis by accurately evaluating renal function using the measured CCr. Extended dosing was demonstrated to be necessary to achieve a PTA of 50% T > MIC for patients with CCr ≥ 85 mL/min. Meropenem effectiveness can be maximized in patients with sepsis by selecting the appropriate dosing regimen based on renal function and the MIC.

Long-term safety of once-daily indacaterol acetate/glycopyrronium bromide/mometasone furoate high-dose, and indacaterol acetate/mometasone furoate high-dose, in Japanese patients with inadequately controlled asthma: Results from two open-label, 52-week studies.

INTRODUCTION: The 52-week long-term safety of once-daily indacaterol acetate/glycopyrronium bromide/mometasone furoate (IND/GLY/MF) high-dose (150/50/160 µg) and IND/MF high-dose (150/320 µg) was evaluated in two studies enrolling Japanese patients with inadequately controlled asthma. METHODS: Study 1 (IND/GLY/MF) and Study 2 (IND/MF) were 52-week, phase III, open-label, single-arm, multicenter studies conducted in Japanese adult patients with inadequately controlled asthma. The primary endpoint was incidence and severity of treatment-emergent adverse events (AEs) over 52-weeks. RESULTS: In Study 1, 94 patients received IND/GLY/MF high-dose and 84 (89.4%) patients completed the 52-week study treatment; in Study 2, 51 patients received IND/MF high-dose and 48 (94.1%) patients completed the 52-week study treatment. In Study 1, 68.1% and 6.4% of 94 patients reported ≥1 AE and ≥1 serious AE (SAE) respectively. In Study 2, 78.4% of 51 patients reported ≥1 AE; no patients reported SAEs. The most commonly reported AEs were asthma (exacerbation; 30.9% and 54.9%) and nasopharyngitis (18.1% and 29.4%) in Study 1 and Study 2, respectively. Severe AEs including asthma (exacerbation) were reported in 13.8% and 13.7% of patients in Study 1 and Study 2, respectively. In Study 1, 10 patients (10.6%) reported treatment-related AEs, of which dysphonia (9 patients [9.6%]) was the most commonly reported; no treatment-related AEs were reported in Study 2. In Study 1, one death (not study drug-related) was reported after study discontinuation (92 days after last dose of study medication). CONCLUSIONS: Once-daily IND/GLY/MF and IND/MF high-dose were well-tolerated in Japanese patients with inadequately controlled asthma. No unexpected safety findings were observed.Supplemental data for this article is available online at.

Consensus on mild asthma management: results of a modified Delphi study.

OBJECTIVE: In order to understand the role of regular controller inhaled corticosteroids (ICS) versus as-needed ICS-formoterol in managing mild asthma, we performed a modified Delphi procedure. METHODS: Opinions from 16 respiratory experts to three surveys and during a virtual scientific workshop helped to develop final consensus statements (pre-defined as 70% agreement). RESULTS: Thirteen participants completed all rounds (response rate 81%). At the end of the procedure, there was final consensus on: regular daily ICS being the recommended treatment approach in mild persistent asthma, with better symptom control and robust long-term clinical data compared with as-needed ICS-formoterol (85%); to avoid noncompliance, frequently seen in mild asthma patients, regular ICS dosing should be accompanied by ongoing education on treatment adherence (100%); treatment aims should be targeting asthma control (92%) and reduction of exacerbation risk (85%). No consensus was reached on whether GINA or national guidelines most influence prescribing decisions. CONCLUSIONS: It is important to encourage patients to be adherent and to target both asthma control and exacerbation risk reduction. There is robust clinical evidence to support proactive regular dosing with ICS controller therapy plus as-needed short-acting beta-agonists for the management of patients with mild asthma.

Comparative Efficacy of ALK Inhibitors for Treatment-Naïve ALK-Positive Advanced Non-Small Cell Lung Cancer with Central Nervous System Metastasis: A Network Meta-Analysis.

Central nervous system (CNS) metastases and acquired resistance complicate the treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC). Thus, this review aimed to provide a comprehensive overview of brain metastasis, acquired resistance, and prospects for overcoming these challenges. A network meta-analysis of relevant phase III randomized controlled trials was performed to compare the efficacies of multiple ALK inhibitors by drug and generation in overall patients with ALK-p untreated advanced NSCLC and a subgroup of patients with CNS metastases. The primary endpoint was progression-free survival (PFS). Generation-specific comparison results showed that third-generation ALK inhibitors were significantly more effective than second-generation ALK inhibitors in prolonging the PFS of the subgroup of patients with CNS metastases. Drug-specific comparison results demonstrated that lorlatinib was the most effective in prolonging PFS, followed by brigatinib, alectinib, ensartinib, ceritinib, crizotinib, and chemotherapy. While lorlatinib was superior to brigatinib for PFS in the overall patient population, no significant difference between the two was found in the subgroup of patients with CNS metastases. These results can serve as a foundation for basic, clinical, and translational research and guide clinical oncologists in developing individualized treatment strategies for patients with ALK-p, ALK inhibitor-naive advanced NSCLC.

[SURVEY OF KNOWLEDGE ABOUT ANAPHYLAXIS AND GUIDANCE WHEN DISPENSING EPIPEN FOR PHARMACISTS WORKING IN PHARMACIES].

BACKGROUND/PURPOSE: Anaphylactic shock is a serious and life-threatening condition, and affected patients should be quickly and effectively treated with an EpiPen. Although the correct use of an EpiPen is greatly affected by a user's proficiency level and the instructions accompanying the EpiPen, there has been almost no investigation into the knowledge of the EpiPen and the actual situation of the accompanying instructions for use. Therefore, we conducted this nationwide survey to elucidate these issues. METHODS: A questionnaire survey was conducted among pharmacists registered as members of the system of a research company outside the university and working at pharmacies with experience in handling EpiPen prescriptions. RESULTS: Many of the pharmacists surveyed knew that the EpiPen is the first-line treatment for anaphylactic shock. However, they did not have sufficient knowledge of administration routes and candidates for second-line treatment. Both their occasions and experiences of dealing of EpiPen were found to be low. CONSIDERATION: It is desirable to learn at conferences regarding allergology/clinical allergy and seminars for medical professionals including pharmacists in order to acquire the skills and knowledge to consult with patients with allergic diseases, including action plans presented by doctors in preparation for recurrence of anaphylaxis.

Fetal Lung Cells Transfer Improves Emphysematous Change in a Mouse Model of Neutrophil Elastase-Induced Lung Emphysema.

Recently, several studies for lung regeneration have been reported. However, regenerating the lung tissue by the transfer of any cells directly to the lung has been hardly successful. The aim of this study was to evaluate the effect of fetal lung cells (FLCs) in a mouse model of lung emphysema. C57BL/6 mice were stimulated with neutrophil elastase (NE) intra-tracheally (i.t.) to generate lung emphysema. To collect fetal lung cells, C57BL/6-Tg (CAG-EGFP) mice were bred for 14 days. Before delivery, the bred mice were euthanized, and fetal lungs were harvested from the fetal mice and the cells were collected. The FLCs were transferred i.t. 24 h after the NE instillation. Four weeks after the NE instillation, mice were euthanized, and the samples were collected. The mean linear intercept (MLI) was significantly prolonged in the NE instillation group compared to the control group. However, in the FLCs transfer group stimulated with NE, the MLI became shorter than the NE-stimulated group without an FLCs transfer. This result shows that an FLCs transfer inhibited the progression of lung emphysema. Additionally, motility of the mice was also improved by the FLCs transfer. These results indicate that transfer of the FLCs, which were presumed to be progenitor cells for lung tissue, may improve the emphysematous change.

The environmental impact of inhaled therapy: making informed treatment choices.

When selecting the best inhaler and drug combination for a patient with respiratory disease, a number of factors should be considered. While efficacy and safety of medical treatments are always a priority, in recent years the environmental impacts of all aspects of life have become an increasingly necessary consideration and inhaled therapies are no exception. The carbon footprint of an item, individual or organisation is one of the most important and quantifiable environmental impacts, assessed by the amount of greenhouse gases (often expressed in terms of carbon dioxide equivalents) generated throughout the life cycle. The two most commonly prescribed and manufactured inhaler types worldwide are pressurised metered-dose inhalers (pMDIs) containing hydrofluorocarbon (HFC) propellants and dry powder inhalers (DPIs). Most of the carbon footprint of current pMDIs is a result of the propellants that they contain (HFC-134a and HFC-227ea, which are potent greenhouse gases). In comparison, the powder in DPIs is dispersed by the patient's own inhalation, meaning DPIs do not contain a propellant and have a lower carbon footprint than most pMDIs currently available. Soft mist inhalers are another propellant-free option: the device contains a spring, which provides the energy to disperse the aqueous medication. In this review, we examine the published data on carbon footprint data for inhalers, providing an analysis of potential implications for treatment decision making and industry initiatives.

Comprehensive Gene Expression Signature Using RNA-Seq in Airways of Mouse Model of Severe Asthma with Fungal Sensitization.

INTRODUCTION: Inhalation of fungal allergens induces airway epithelial damage following airway inflammation and excessive mucus secretion, which can lead to severe asthma with fungal sensitization (SAFS). Comprehensive gene expression analysis in Alternaria-exposed mouse airways, a model of SAFS, has not been conducted. METHODS: BALB/c mice received intranasal administration of Alternaria extract or phosphate-buffered saline twice a week for 6 weeks. Lung sections and bronchoalveolar lavage fluid were obtained to assess airway inflammation. RNA-Seq in the central airway was performed, and gene ontology (GO) analysis and gene set enrichment analysis (GSEA) were conducted for pathway analyses. An in vitro experiment using human airway epithelial cell 16HBE14o- was performed to validate the RNA-Seq findings. RESULTS: Eosinophilic airway inflammation with mucus overproduction and airway remodeling was observed in mice exposed to Alternaria. RNA-Seq analysis revealed 403 upregulated and 108 downregulated genes in airways of Alternaria-exposed mice. In GO analysis, the functions of immunoglobulin (Ig) receptor binding, Ig production, inflammatory response, and T-cell activation were upregulated, while those of keratinization and defense response to other organisms were downregulated. GSEA revealed positive enrichment in T-cell receptor complex, immunological synapse, antigen binding, mast cell activation, and Ig receptor binding, and negative enrichment in keratinization and cornification in Alternaria-exposed mice relative to control. Alternaria exposure to 16HBE14o- cells validated the downregulation of epithelial keratinization-related genes, including SPRR1A, SPRR1B, and KRT6B. CONCLUSION: RNA-Seq analysis showed that Alternaria exposure induced inflammatory response and impaired defense mechanisms in mice airway epithelium, which might be therapeutic targets for SAFS.

A phase 3, randomized, double-blind, clinical study to evaluate the long-term safety and efficacy of gefapixant in Japanese adult participants with refractory or unexplained chronic cough.

BACKGROUND: In two phase 3, global clinical trials (COUGH-1 and COUGH-2), the P2X3-receptor antagonist gefapixant significantly reduced objective 24-h cough frequency in participants with refractory or unexplained chronic cough (RCC or UCC) at a dosage of 45 mg twice daily (BID), with an acceptable safety profile. The primary objective of this phase 3, randomized, double-blind, parallel-group study was to assess the safety and tolerability of gefapixant in Japanese participants with RCC or UCC (ClinicalTrials.gov, NCT03696108; JAPIC-CTI, 184154). METHODS: Participants aged ≥20 years with chronic cough lasting ≥4 months and a diagnosis of RCC or UCC despite treatment in accordance with Japanese Respiratory Society guidelines were randomized 1:1 to receive gefapixant 15 or 45 mg BID for 52 weeks. The primary objective was to evaluate the safety and tolerability of gefapixant, including adverse events (AEs) and discontinuations due to AEs. Cough-specific quality of life was assessed using the Leicester Cough Questionnaire as a secondary objective. RESULTS: Of 169 randomized and treated participants, 63% were female and mean age was 58 years. Adverse events were reported by 79 (94%) and 82 (96%) participants in the 15- and 45-mg BID groups, respectively. Most treatment-related AEs were taste related. Discontinuations due to AEs occurred in 6 (7%) and 17 (20%) participants receiving gefapixant 15 or 45 mg BID, respectively. There were no serious treatment-related AEs or deaths. Leicester Cough Questionnaire total scores improved from baseline through Week 52. CONCLUSIONS: Gefapixant had an acceptable safety profile, with no serious treatment-related AEs in Japanese participants.

Downregulation of type III interferons in patients with severe COVID-19.

Coronavirus disease 2019 (COVID-19) is globally rampant, and to curb the growing burden of this disease, in-depth knowledge about its pathophysiology is needed. This was an observational study conducted at a single center to investigate serum cytokine and chemokine levels of COVID-19 patients, based on disease severity. We included 72 consecutive COVID-19 patients admitted to our hospital from March 21 to August 31, 2020. Patients were divided into Mild-Moderate I (mild) and Moderate II-Severe (severe) groups based on the COVID-19 severity classification developed by the Ministry of Health, Labor and Welfare (MHLW) of Japan. We compared the patient characteristics as well as the serum cytokine and chemokine levels on the day of admission between the two groups. Our findings indicated that the severe group had significantly higher levels of serum fibrinogen, d-dimer, lactate dehydrogenase, C-reactive protein, ferritin, Krebs von den Lungen-6, surfactant protein (SP)-D, and SP-A than the mild group. Strikingly, the levels of interleukin (IL)-28A/interferon (IFN)-λ2 were significantly lower in the severe group than in the mild group. We believe that reduced levels of type III interferons (IFN-λs) and alterations in the levels of other cytokines and chemokines may impact the severity of the disease.

Spontaneous sputum discriminates inflammatory phenotypes in patients with asthma.

BACKGROUND: Eosinophils in induced sputum are not only a useful biomarker for diagnosing asthma but are also associated with severe asthma. However, little is known about the association between eosinophils in spontaneous sputum and asthma severity. OBJECTIVE: To investigate whether spontaneous sputum eosinophils are related to severe asthma in adult patients with asthma. METHODS: We conducted a retrospective cross-sectional study on 86 people with asthma whose spontaneous sputa were successfully collected. Patients were classified into 4 phenotypes according to the eosinophil and neutrophil levels in spontaneous sputum. We determined the association between inflammatory phenotypes and severe asthma. Moreover, we also compared asthma severity among the phenotypes classified according to blood eosinophils and spontaneous sputum eosinophils. RESULTS: Asthma phenotypes were as follows: paucigranulocytic, 30.2%; neutrophilic, 18.6%; eosinophilic, 32.6%; and mixed, 18.6%. People with eosinophilic asthma had the highest blood eosinophils, total immunoglobulin E (IgE), and fractional exhaled nitric oxide among the 4 phenotypes. Significant differences were observed in asthma severity between the phenotypes (P = .019). In particular, 57.2% and 56.2% of patients had severe eosinophilic asthma and mixed asthma, respectively. The logistic regression analysis revealed that spontaneous sputum eosinophilia represented the strongest association with severe asthma among the inflammatory variables. Finally, more patients with severe asthma were included in the phenotype with spontaneous sputum eosinophils greater than 3% and blood eosinophils less than or equal to 300/µL and in the phenotype with spontaneous sputum eosinophils greater than 3% and blood eosinophils greater than 300/µL. CONCLUSION: Spontaneous sputum can provide helpful information on airway inflammatory phenotyping in patients with asthma.

Investigating Patient and Family Satisfaction with the Respiratory Status in Patients with Chronic Obstructive Pulmonary Disease.

The current chronic obstructive pulmonary disease (COPD) management aims to improve the patients' quality of life and healthy life expectancy; however, few studies have evaluated the level of satisfaction with the patients' current respiratory status in COPD patients and their families. This study aimed to examine the level of patient and family satisfaction with the patients' current respiratory status and to identify the clinical factors closely linked to dissatisfaction.This multicenter, cross-sectional study included 454 outpatients with COPD and 296 family members. Patients and families were allocated to the satisfied and dissatisfied groups based on their satisfaction with the patients' current respiratory status. Patients' health status, dyspnoea, appetite, respiratory function, and mood disorders were assessed.Among the participants of this study, 67% of patients and 60% of their families were dissatisfied with the patients' current respiratory status. The COPD assessment test (CAT) was the most sensitive marker of dissatisfaction compared to other clinical factors (p < 0.01). The statistical cut-off value of CAT for predicting patient dissatisfaction was 11. CAT reflected patient dissatisfaction independent of age, sex, dyspnoea, appetite, mood disorders, body mass index, and respiratory function (odds ratio: CAT; 1.12 (1.07-1.19): p < 0.01).Many patients and families are dissatisfied with the patients' respiratory status, and the patients' CAT score is useful to predict dissatisfaction. Our findings are consistent with the Global Initiative for Chronic Obstructive Lung Disease indicating that treatment should be enhanced in patients with a CAT score ≥10. Furthermore, treatment strategies targeting CAT may contribute to an improved patient satisfaction.

Molecular and Clinical Features of EGFR-TKI-Associated Lung Injury.

The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and obtained survival benefits had somatic EGFR mutations. EGFR-TKI-related adverse events (AEs) are usually tolerable and manageable, although serious AEs, including lung injury (specifically, interstitial lung disease (ILD), causing 58% of EGFR-TKI treatment-related deaths), occur infrequently. The etiopathogenesis of EGFR-TKI-induced ILD remains unknown. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, chronic obstructive pulmonary disease, and poor performance status, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries. There is limited evidence from preclinical and clinical studies of the mechanisms underlying EGFR-TKI-induced ILD in the available literature. Herein, we evaluated the relationship between EGFR-TKIs and AEs, especially ILD. Recent reports on mechanisms inducing lung injury or resistance in cytokine-rich circumstances were reviewed. We discussed the relevance of cytotoxic agents or immunotherapeutic agents in combination with EGFR-TKIs as a potential mechanism of EGFR-TKI-related lung injury and reviewed recent developments in diagnostics and therapeutics that facilitate recovery from lung injury or overcoming resistance to anti-EGFR treatment.

Mepolizumab improved airway hyperresponsiveness in a patient with allergic bronchopulmonary aspergillosis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a severe type of asthma characterized by hypersensitivity to Aspergillus fumigatus and lung infiltration with eosinophilia. The central pathogenesis of asthma is airway hyperresponsiveness (AHR), with eosinophils playing a critical role. Anti-interleukin (IL)-5 antibody therapy has been recently introduced to treat severe asthma, which reportedly inactivates and reduces eosinophil count. A recent case series highlighted the improvement in asthmatic symptoms associated with ABPA, but previous reports failed to demonstrate any improvement in AHR. OBJECTIVE: Herein, we aimed to elucidate the efficacy of mepolizumab in a patient with ABPA who showed improvement in AHR. METHODS: Case report. RESULTS: A 63-year-old Asian woman with ABPA showed improvement in asthmatic symptoms and AHR following mepolizumab therapy. CONCLUSIONS: Our results suggest that IL-5 may serve in the pathogenesis of ABPA.

Extracorporeal Membrane Oxygenation for Secondary Organizing Pneumonia after Severe SARS-CoV-2 Infection: A Case Report.

(Background) COVID-19 is caused by SARS-CoV-2 infection and may result in unfavorable outcomes. A recent large-scale study showed that treatment with dexamethasone leads to favorable outcomes in patients with severe COVID-19, and the use of extracorporeal membrane oxygenation (ECMO) has also been shown to improve outcomes. Recently, secondary organizing pneumonia (SOP) has been reported after SARS-CoV-2 infection, but the diagnostic and treatment strategies are still unclear. (Case presentation) Here, we report a patient with severe COVID-19 who developed SOP even after the use of dexamethasone, for whom the introduction of ECMO on the 19th day after hospitalization led to a favorable outcome. (Conclusions) Life-threatening SOP may evolve even after the use of dexamethasone, and the late-phase introduction of ECMO may save such patients with COVID-19.

Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype may benefit from treatment with mepolizumab, a monoclonal antibody directed against interleukin-5. METHODS: We performed two phase 3, randomized, placebo-controlled, double-blind, parallel-group trials comparing mepolizumab (100 mg in METREX, 100 or 300 mg in METREO) with placebo, given as a subcutaneous injection every 4 weeks for 52 weeks in patients with COPD who had a history of moderate or severe exacerbations while taking inhaled glucocorticoid-based triple maintenance therapy. In METREX, unselected patients in the modified intention-to-treat population with an eosinophilic phenotype were stratified according to blood eosinophil count (≥150 per cubic millimeter at screening or ≥300 per cubic millimeter during the previous year). In METREO, all patients had a blood eosinophil count of at least 150 per cubic millimeter at screening or at least 300 per cubic millimeter during the previous year. The primary end point was the annual rate of moderate or severe exacerbations. Safety was also assessed. RESULTS: In METREX, the mean annual rate of moderate or severe exacerbations in the modified intention-to-treat population with an eosinophilic phenotype (462 patients) was 1.40 per year in the mepolizumab group versus 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 to 0.98; adjusted P=0.04); no significant between-group differences were found in the overall modified intention-to-treat population (836 patients) (rate ratio, 0.98; 95% CI, 0.85 to 1.12; adjusted P>0.99). In METREO, the mean annual rate of moderate or severe exacerbations was 1.19 per year in the 100-mg mepolizumab group, 1.27 per year in the 300-mg mepolizumab group, and 1.49 per year in the placebo group. The rate ratios for exacerbations in the 100-mg and 300-mg mepolizumab groups versus the placebo group were 0.80 (95% CI, 0.65 to 0.98; adjusted P=0.07) and 0.86 (95% CI, 0.70 to 1.05; adjusted P=0.14), respectively. A greater effect of mepolizumab, as compared with placebo, on the annual rate of moderate or severe exacerbations was found among patients with higher blood eosinophil counts at screening. The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: Mepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype. This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations. (Funded by GlaxoSmithKline; METREX and METREO ClinicalTrials.gov numbers, NCT02105948 and NCT02105961 .).