Effect of budesonide formoterol combined with tiotropium bromide on pulmonary function and inflammatory factors in patients with asthma-COPD overlap syndrome.

OBJECTIVE: To investigate the clinical efficacy of combining budesonide formoterol with tiotropium bromide for treating asthma-chronic obstructive pulmonary disease overlap syndrome (AOCS). METHODS: The data of 104 patients with AOCS admitted to our hospital from December 2019 to December 2020 were assessed, randomly and divided into an experimental group (comprising 52 patients, receiving drug combination therapy) and a conventional group (comprising 52 patients, receiving drug therapy alone). Patients' clinical efficacy, pulmonary function, fractioned exhaled nitric oxide (FeNO), immune function, endothelial function, serum lipid peroxidation injury indexes, adverse reactions, and quality of life scores were compared. RESULTS: Prior to treatment, no significant differences were observed in various pulmonary function indicators, FeNO, immune function, endothelial function, and lipid peroxidation injury indexes between the two groups (P > 0.05). However, after treatment, all observation indexes in both groups improved to different levels, with the experimental group -demonstrating -significantly superior improvement, compared to the conventional group (P < 0.05). We also observed that adverse reactions in the experimental group were significantly lower than in the conventional group (P < 0.05). CONCLUSION: The combination of budesonide formoterol to tiotropium bromide in treating asthma-COPD overlap syndrome may significantly improve pulmonary function, endothelial function, and immune status of patients and encourage the recovery of serum lipid peroxidation injury; therefore, this may deserve widespread adoption and application.

ß-Agonist exposure preferentially impacts lung macrophage cyclic AMP-related gene expression in asthma and asthma COPD overlap syndrome.

Bronchoalveolar lavage (BAL) samples from Severe Asthma Research Program (SARP) patients display suppression of a module of genes involved in cAMP-signaling pathways (BALcAMP) correlating with severity, therapy, and macrophage constituency. We sought to establish if gene expression changes were specific to macrophages and compared gene expression trends from multiple sources. Datasets included single-cell RNA sequencing (scRNA-seq) from lung specimens including a fatal exacerbation of severe Asthma COPD Overlap Syndrome (ACOS) after intense therapy and controls without lung disease, bulk RNA sequencing from cultured macrophage (THP-1) cells after acute or prolonged ß-agonist exposure, SARP datasets, and data from the Immune Modulators of Severe Asthma (IMSA) cohort. THP monocytes suppressed BALcAMP network gene expression after prolonged relative to acute ß-agonist exposure, corroborating SARP observations. scRNA-seq from healthy and diseased lung tissue revealed 13 cell populations enriched for macrophages. In severe ACOS, BALcAMP gene network expression scores were decreased in many cell populations, most significantly for macrophage populations (P < 3.9e-111). Natural killer (NK) cells and type II alveolar epithelial cells displayed less robust network suppression (P < 9.2e-8). Alveolar macrophages displayed the most numerous individual genes affected and the highest amplitude of modulation. Key BALcAMP genes demonstrate significantly decreased expression in severe asthmatics in the IMSA cohort. We conclude that suppression of the BALcAMP gene module identified from SARP BAL samples is validated in the IMSA patient cohort with physiological parallels observed in a monocytic cell line and in a severe ACOS patient sample with effects preferentially localizing to macrophages.

Asthma-chronic obstructive pulmonary disease overlap syndrome.

Overlap of asthma and chronic obstructive lung disease (ACO) in patients with obstructive lung disease is growing in recognition, though there is no consistent agreement on the diagnostic criteria for the disease process. Patients with ACO have distinct clinical characteristics and trajectories, which are representative of a heterogenous, multifactorial, and incompletely understood inflammatory pathophysiology. Current treatment strategies are focused on titration of inhaled therapies such as long-acting bronchodilators, with increasing interest in the use of targeted biologic therapies aimed at the underlying inflammatory mechanisms. Future directions for research will focus on elucidating the varied inflammatory signatures leading to ACO, the development of consistent diagnostic criteria and biomarkers of disease, and improving the clinical management with an eye toward targeted therapies.

A COVID-19 patient with intense burning pain.

A woman in her forties with asthma and COPD was admitted to a general medical floor with respiratory symptoms, body aches, and anosmia. Reverse transcription polymerase chain reaction detected severe acute respiratory syndrome coronavirus-2. Admission labs, including biomarkers of the systemic immunological dysfunction seen in many cases of coronavirus disease 2019 (COVID-19), were within normal ranges. On the second day of admission, she developed neck and back pain that was constant, burning in quality, and exacerbated by light touch and heat. Wearing clothing caused pain and interfered with her sleep. The area was tender to light finger stroke. The patient was given acetaminophen, NSAIDs, and opioids with no relief of pain. However, gabapentin was effective. At follow-up 1 month later, her symptoms were improved and still relieved by gabapentin. Neuropathic pain was seen in over 2% of COVID-19 patients in one observational study. The pain seen in our case was bilateral, involved an area innervated by multiple levels of spinal nerves, and was limited to the back. While it is rare, a significant number of COVID-19 patients are afflicted by neuropathic pain, and our case illustrates that gabapentin may be effective.

Pharmacotherapeutic management of asthma in the elderly patient.

INTRODUCTION: Asthma is a heterogeneous syndrome with variable phenotypes. Reversible airway obstruction and airway hyper-responsiveness often with an atopic or eosinophilic component is common in the elderly asthmatic. Asthma chronic obstructive pulmonary disease overlap syndrome (ACOS), a combination of atopy-mediated airway hyper-responsiveness and a history of smoking or other environmental noxious exposures, can lead to some fixed airway obstruction and is also common in elderly patients. Little specific data exist for the treating the elderly asthmatic, thus requiring the clinician to extrapolate from general adult data and asthma treatment guidelines. AREAS COVERED: A stepwise approach to pharmacotherapy of the elderly patient with asthma and ACOS is offered and the literature supporting the use of each class of drugs reviewed. EXPERT OPINION: Inhaled, long-acting bronchodilators in combination with inhaled corticosteroids represent the backbone of treatment for the elderly patient with asthma or ACOS . Beyond these medications used as direct bronchodilators and topical anti-inflammatory agents, a stepwise approach to escalation of therapy includes multiple options such as oral leukotriene receptor antagonist or 5-lipoxygense inhibitor therapy, oral phosphodiesterase inhibitors, systemic corticosteroids, oral macrolide antibiotics and if evidence of eosinophilic/atopic component disease exists then modifying monoclonal antibody therapies.

Triple Therapy with Budesonide/Glycopyrrolate/Formoterol Fumarate Improves Inspiratory Capacity in Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap.

Purpose: Asthma-chronic obstructive pulmonary disease overlap (ACO), characterized by airway limitation, is an important condition with high incidence and mortality. Although some guidelines recommend triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting ß2 agonists, this treatment approach is based on the extrapolation of data from studies of asthma or chronic obstructive pulmonary disease (COPD) alone. Methods: A 12-week, randomized, open-label cross-over pilot study was conducted in 19 patients with ACO to investigate the effect of triple therapy with glycopyrrolate (GLY) 50 µg/day on budesonide/formoterol fumarate (BUD/FORM) 640/18 µg/day. The study period included a 4-week wash-out, 4-week run-in, and 4-week treatment period. Respiratory function tests, fractional exhaled nitric oxide (FeNO), a COPD assessment test (CAT) and an asthma control questionnaire (ACQ) were carried out 0, 4, and 8 weeks after randomization. Results: A total of 19 patients with stable ACO (19 males and no females) with a mean age of 70.7 ± 7.6 years (± standard deviation, SD; range 55-83 years) participated in this study. All patients were ex-smokers with a smoking history of 63.1 ± 41.1 pack-years (± SD). Mean values for inspiratory capacity (IC), an index of hyperinflation of the lung that causes exertional dyspnea and reduced exercise, were 1.93 L (± 0.47 L) after the run-in, 1.85 L (± 0.51 L) after the BUD/FORM dual therapy period and 2.11 L (± 0.58 L) after the BUD/GLY/FORM triple therapy period. IC values after the BUD/GLY/FORM triple therapy were significantly higher than those after the run-in (p < 0.02). FeNO values, ACQ, and CAT scores were not significantly different among the run-in, wash-out, and triple-therapy periods. Conclusion: The present pilot study showed that triple therapy with BUD/GLY/FORM results in an improvement in lung function parameters including IC, indicating the potential value of triple therapy as standard treatment for ACO.

The pharmacological management of asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS).

Introduction: Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) is a disease phenotype that shares T helper lymphocyte cell Th1/neutrophilic/non-Type-2 Inflammation pathways thought to be key in COPD and Th2/eosinophilic/Type-2 inflammatory pathways of asthma. The pharmacology of treating ACOS is challenging in severe circumstances.Areas covered: This review evaluates the stepwise treatment of ACOS using pharmacological treatments used in both COPD and asthma. The most common medications involve the same inhalers used to treat COPD and asthma patients. Advanced stepwise therapies for ACOS patients are based on patient characteristics and biomarkers. Very few clinical trials exist that focus specifically on ACOS patients.Expert opinion: After inhalers, advanced therapies including phosphodiesterase inhibitors, macrolides, N-acetylcysteine and statin therapy for those ACOS patients with a COPD appearance and exacerbations are available. In atopic ACOS patients with exacerbations, advanced asthma therapies (leukotriene receptor antagonists and synthesis blocking agents.) are used. ACOS patients with elevated blood eosinophil/IgE levels are considered for immunotherapy or therapeutic monoclonal antibodies blocking specific Th2/Type-2 interleukins or IgE. Symptom control, stabilization/improvement in pulmonary function and reduced exacerbations are the metrics of success. More pharmacological trials of ACOS patients are needed to better understand which patients benefit from specific treatments.Abbreviations: 5-LOi: 5-lipoxygenase inhibitor; ACOS: asthma - COPD overlap syndrome; B2AR: Beta2 adrenergic receptors; cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; CI: confidence interval; COPD: chronic obstructive pulmonary disease; CRS : chronic rhinosinusitis; cys-LT: cysteinyl leukotrienes; DPI: dry powder inhaler; EMA: European Medicines Agency; FDA: US Food and Drug Administration; FDC: fixed-dose combination; FeNO: exhaled nitric oxide; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; GM-CSF: granulocyte-macrophage colony-stimulating factor; ICS : inhaled corticosteroids; IL: interleukin; ILC2: Type 2 innate lymphoid cells; IP3: Inositol triphosphate; IRR: incidence rate ratio; KOLD: Korean Obstructive Lung Disease; LABA: long-acting B2 adrenergic receptor agonist; LAMA: long-acting muscarinic receptor antagonist; LRA: leukotriene receptor antagonist; LT: leukotrienes; MDI: metered-dose inhalers; MN: M-subtype muscarinic receptors; MRA: muscarinic receptor antagonist; NAC: N-acetylcysteine; NEB: nebulization; OR: odds ratio; PDE: phosphodiesterase; PEFR: peak expiratory flow rate; PGD2: prostaglandin D2; PRN: as needed; RR: risk ratio; SABA: short-acting B2 adrenergic receptor agonist; SAMA: short-acting muscarinic receptor antagonist; SDMI: spring-driven mist inhaler; Th1: T helper cell 1 lymphocyte; Th2: T helper cell 2 lymphocytes; TNF-α: tumor necrosis factor alpha; US : United States.

Identification of Asthma-COPD Overlap, Asthma, and Chronic Obstructive Pulmonary Disease Phenotypes in Patients with Airway Obstruction: Influence on Treatment Approach.

BACKGROUND: Many studies have described asthma-COPD overlap (ACO) among patients diagnosed with asthma or chronic obstructive pulmonary disease (COPD), but less so in broad populations of patients with chronic airway obstruction. OBJECTIVE: This study aimed to (i) examine the prevalence of ACO, asthma, and COPD phenotypes among subjects referred for pulmonary function testing (PFT), who had airway obstruction in spirometry (forced expiratory volume in 1 s [FEV1]/forced vital capacity [FVC] <0.7); and (ii) delineate the therapeutic approach of each group. METHODS: Cross-sectional study of patients who were referred for PFT at the Rokach Institute, in Jerusalem. Working definitions were as follows: (a) COPD: post-bronchodilator (BD) FEV1/FVC <0.70; (b) asthma: physician-diagnosed asthma before age 40 and/or minimum post-BD increase in FEV1 or FVC of 12% and 200 mL; and (c) ACO: the combination of the 2. Demographics, smoking habits, episodes of exacerbation, health-related quality of life (HRQL), and respiratory medication utilization were analyzed. RESULTS: Of 3,669 referrals from January 1 to April 30, 2017, 1,220 had airway obstruction of which 215 were included. Of these, 82 (38.1%) had ACO, 49 (22.8%) asthma, and 84 (39.1%) COPD. ACO subjects tended to (a) be predominantly female; (b) be older than asthmatics, (c) be smokers; (d) have worse HRQL in the activity domain; and (d) have more exacerbations. Treatment of ACO and COPD patients differed from that of asthmatics, but not from each other, in the proportion of subjects on maintenance treatment, use of LABA, LAMA, and ICS, alone or in combination, and in the number of inhaler devices used by patients. CONCLUSION: ACO represented >1/3 of patients referred for PFT. Despite a clearly identifiable phenotype, ACO patients received treatment similar to COPD patients, suggesting poor ACO identification. Our data emphasize the need to raise the awareness of ACO among clinicians, in order to guide better recognition and appropriate treatment in individual patients.

Management of asthma COPD overlap.

OBJECTIVE: To review the latest literature on management approaches to patients with asthma chronic obstructive pulmonary disease (COPD) overlap (ACO). DATA SOURCES: Studies and reports were identified from the databases of PubMed/Medline and ClinicalTrials.gov from the US National Institutes of Health and the Cochrane Register of Controlled Trials. STUDY SELECTIONS: Studies on the management of asthma, COPD, and ACO were included in this review. RESULTS: Patients with asthma COPD overlap tend to have greater morbidity than those with asthma or COPD alone, but the information on the best therapeutic approach to this group of patients is still limited. Current treatment recommendations rely on expert opinions, roundtable discussions, and strategy documents, because most clinical studies in asthma and COPD have excluded patients with ACO. Because of the potential risk described in patients with asthma with the use of long-acting 2 agonist monotherapy, initial therapy for patients with ACO is recommended to include a long-acting bronchodilator in conjunction with inhaled corticosteroids. Long-acting muscarinic antagonists are effective in both asthma and COPD and should be considered in ACO as an add-on treatment. If inhaler therapy is not effective, advanced therapies based on phenotyping and identification of treatable traits may be considered. CONCLUSION: Few studies have evaluated prospectively therapies in the ACO population, and future studies need to determine best strategies for the treatment of these patients, focusing on targeting its different phenotypes and its treatable traits.

Effects of statins on anxiety and depression in patients with asthma-chronic obstructive pulmonary disease overlap syndrome.

BACKGROUND: The effects of statins on anxiety and depression in patients with asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) have not been reported. This population-based study investigated these effects. METHODS: Taiwan's National Health Insurance Research Database between 2000 and 2010. We enrolled two ACOS cohorts, one of statin users (n = 1252) and one of nonstatin users matched by age, sex, and index date (n = 7887). The cumulative incidence of anxiety and depression was analyzed using time-dependent Cox proportional regression analysis. RESULTS: After adjustment for multiple confounding factors, including age, sex, comorbidities, and medications-statins, inhaled corticosteroids (ICSs), and oral steroids (OSs)-the ACOS cohort with statin use had significantly lower risks of anxiety and depression (anxiety: adjusted hazard ratio [aHR] = 0.34, 95% confidence interval [CI] = 0.28-0.42; depression: aHR = 0.36, 95% CI = 0.25-0.53). The aHRs (95% CIs) for statin use with ICSs or OSs were 0.32 (0.13-0.78) and 0.37 (0.24-0.57), respectively. CONCLUSION: The ACOS cohort with statin use had lower risks of anxiety and depression, regardless of age, sex, commodities, or ICSs and OSs. The incidences of anxiety and depression were relatively low among users of statins with ICSs or OSs in the ACOS cohort.

Practical Guide to the Identification and Diagnosis of Asthma-COPD Overlap (ACO).

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality around the world. COPD is characterised by a heterogeneous clinical presentation and prognosis which may vary according to the clinical phenotype. One of the phenotypes of COPD most frequently studied is the asthma-COPD overlap (ACO), however, there are no universally accepted diagnostic criteria for ACO. It is recognised that the term ACO includes patients with clinical features of both asthma and COPD, such as more intense eosinophilic bronchial inflammation, more severe respiratory symptoms and more frequent exacerbations, but in contrast, it is associated with a better prognosis compared to COPD. More importantly, ACO patients show better response to inhaled corticosteroid treatment than other COPD phenotypes. The diagnosis of ACO can be difficult in clinical practice, and the identification of these patients can be a challenge for non-specialized physicians. We describe how to recognise and diagnose ACO based on a recently proposed Spanish algorithm and by the analysis of three clinical cases of patients with COPD. The diagnosis of ACO is based on the diagnosis of COPD (chronic airflow obstruction in an adult with significant smoking exposure), in addition to a current diagnosis of asthma and/or signficant eosinophilia.

Inhaled Corticosteroid-Related Tuberculosis in the Real World Among Patients with Asthma and COPD: A 10-Year Nationwide Population-Based Study.

BACKGROUND: There have been concerns about the risk of inhaled corticosteroid (ICS)-related tuberculosis (TB) development. OBJECTIVE: We investigated the occurrence of TB among ICS users according to underlying respiratory diseases and type of ICS. METHODS: A 12-year population cohort comprising approximately 1 million subjects collected from the Korean claims database were used. Adult ICS users (budesonide or fluticasone) were enrolled. The temporal relationship between TB development and the last ICS prescription before TB development was evaluated. A nested case-control study was performed with 1:4 matching for age, sex, and the initiation date of the ICS. RESULTS: There were 17,991 ICS users, and 175 developed TB during the study period. Approximately 80% (140/175) of patients who developed TB were diagnosed within 3 years after the last ICS prescription. In the nested case-control study, the occurrence of TB was not related to the type of ICS, but was related to a higher annual admission rate and a higher comorbidity score. The risk of TB was higher in patients with chronic obstructive pulmonary disease (COPD) than in those with asthma (odds ratio: 2.31; CI 95%: 1.39-3.38; P = .0011) after adjusting for covariates. The subgroup analysis revealed no difference between budesonide and fluticasone with respect to the risk of developing TB in patients with asthma, COPD, or asthma-COPD overlap syndrome. CONCLUSION: An increased risk of TB development may persist for 3 years after stopping the ICS and the risk is higher in patients with COPD regardless of the type of ICS used.