APPaRENT 3: Asthma Patients' and Physicians' Perspectives on the Burden and Management of Asthma in Seven Countries.

INTRODUCTION: Asthma management is strongly dependent on physician and patient beliefs and perceptions about the disease and its long-term treatment. The APPaRENT 3 study was conducted to explore factors influencing treatment choice and to understand patients' and physicians' attitudes and perspectives on the use of controller inhalers in regular versus flexible dosing for asthma management. METHODS: This cross-sectional survey of patients with asthma and treating physicians was conducted in seven countries: Indonesia, Malaysia, Philippines, Thailand, Vietnam (patient survey only), Saudi Arabia, and the United Arab Emirates. Assessment was carried out through an online/face-to-face questionnaire, where patients' viewpoints were focused on their attitudes and beliefs about asthma and treatment adherence, whereas physicians' viewpoints were gathered on their attitudes and beliefs about asthma management, knowledge of and adherence to asthma treatment guidelines, and asthma treatment regimens. RESULTS: Overall, 1400 patients (mean age, 34 years) and 599 physicians (mean age, 43 years) were included in the survey. Physicians similarly prioritised symptom control (39%) and exacerbation reduction (40%) in moderate asthma, whereas patients prioritised symptom control (41%) over exacerbation reduction (22%). Although both groups (physicians, 86%; patients, 84%) perceived asthma as well-controlled, poor management was evident based on Asthma Control Test (ACT) scores (mean, 15.7; standard deviation, 4.14; 82% had an ACT score < 20) and high symptom burden (39% reported nighttime awakenings or early mornings ≥ 2 nights/week). Most patients (76%) with moderate asthma were prescribed regular dosing, with the most common treatment being inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA) with as-needed inhaled short-acting ß2-agonist (SABA; 20%). Among patients on maintenance and reliever therapy, 93% of patients received a separate inhaled reliever. CONCLUSIONS: Despite high symptom burden, patients overestimated their level of asthma control. Physicians prioritised controlling symptoms and reducing exacerbations as treatment goals for moderate asthma, often prescribing regular dosing with ICS/LABA with as-needed inhaled SABA.

Managing asthma depends a lot on what doctors and patients think about the illness and its long-term treatment. This study looked into what influences treatment decisions and what patients and doctors think about using inhalers regularly or on an as-needed basis to manage asthma across seven countries (Indonesia, Malaysia, Philippines, Thailand, Vietnam [patient survey only], Saudi Arabia, and the United Arab Emirates). In this study, patients with asthma and doctors managing asthma completed an online/face-to-face questionnaire. The study aimed to understand what patients think about asthma and their treatment plan. Meanwhile, the doctors were asked what they think about managing asthma and how much they apply clinical guidelines for treating patients with asthma. Doctors believed it is equally important to control symptoms and prevent worsening of symptoms in patients with moderate asthma, while patients cared more about controlling symptoms than preventing worsening of symptoms. While doctors and patients both regarded asthma as well-controlled, many patients had low Asthma Control Test scores and experienced a lot of symptoms, suggesting that they are poor perceivers of asthma control. Most patients with moderate asthma were given regular treatment, usually with inhaled corticosteroid combined with long-acting ß₂-agonist along with as-needed short-acting ß₂-agonist as a reliever. Most patients who were prescribed the same inhaler for regular use and as a reliever also had a separate inhaler for quick relief of symptoms. This study shows the need for patients and doctors to have better conversations about asthma, its treatments, and what to expect from them.

Umbilical cord mesenchymal stromal cells as critical COVID-19 adjuvant therapy: A randomized controlled trial.

One of the main causes of acute respiratory distress syndrome in coronavirus disease 2019 (COVID-19) is cytokine storm, although the exact cause is still unknown. Umbilical cord mesenchymal stromal cells (UC-MSCs) influence proinflammatory T-helper 2 (Th2 ) cells to shift to an anti-inflammatory agent. To investigate efficacy of UC-MSC administration as adjuvant therapy in critically ill patients with COVID-19, we conducted a double-blind, multicentered, randomized controlled trial at four COVID-19 referral hospitals in Jakarta, Indonesia. This study included 40 randomly allocated critically ill patients with COVID-19; 20 patients received an intravenous infusion of 1 × 106 /kg body weight UC-MSCs in 100 ml saline (0.9%) solution (SS) and 20 patients received 100 ml 0.9% SS as the control group. All patients received standard therapy. The primary outcome was measured by survival rate and/or length of ventilator usage. The secondary outcome was measured by clinical and laboratory improvement, with serious adverse events. Our study showed the survival rate in the UC-MSCs group was 2.5 times higher than that in the control group (P = .047), which is 10 patients and 4 patients in the UC-MSCs and control groups, respectively. In patients with comorbidities, UC-MSC administration increased the survival rate by 4.5 times compared with controls. The length of stay in the intensive care unit and ventilator usage were not statistically significant, and no adverse events were reported. The application of infusion UC-MSCs significantly decreased interleukin 6 in the recovered patients (P = .023). Therefore, application of intravenous UC-MSCs as adjuvant treatment for critically ill patients with COVID-19 increases the survival rate by modulating the immune system toward an anti-inflammatory state.

Rate of Forced Expiratory Volume in One Second and Forced Expiratory Volume in One Second/Forced Vital Capacity Decline among Indonesian Patients with Chronic Obstructive Pulmonary Disease after a Year of Treatment.

BACKGROUND: The rate of decline in lung function in chronic obstructive pulmonary disease (COPD) patients showed more profound decline than normal individuals. However, a 1-year lung function among Indonesian patients with COPD has not been elucidated. AIM: This study attempted to determine the rate of lung function decline in terms of obstruction variable among COPD patients after a 1-year of treatment. MATERIALS AND METHODS: This retrospective cohort study measures the rate of decline in forced expiratory volume in 1 s (FEV1) and ratio of FEV1 to forced vital capacity (FEV1/FVC) in COPD patients at COPD Outpatient Clinic Persahabatan Hospital after 1-year of treatment. RESULTS: There were 31 COPD patients with the prevalence of 1-year declined FEV1 and FEV1/FVC which were 83.9% and 51.6%, respectively. Among 1-year declined lung function group, there were significant (P < 0.05) decline in FEV1 (121.53 ± 120 ml/year) and in FEV1/FVC (2.75 ± 0.47%). The rate of decline in FEV1 was more prevalent in Group D, while the rate of decline in FEV1/FVC was more prevalent in Group B. No significant associations were found between sex, age, respiratory complaints, smoking history, Brinkman index, type of cigarette, comorbid, educational level, diagnosed age, body mass index, symptoms-based COPD classification, and risk-based COPD classification, with the rate of decline in FEV1 and FEV1/FVC. CONCLUSIONS: Most patients had statistically significant rate of decline in FEV1 and FEV1/FVC within 1-year of COPD treatment. This study recognized an unfavorable prognosis in terms of irreversible deteriorating lung function of COPD patients despite therapeutic management.

Comparison of lung function values of trained divers in 1.5 ATA hyperbaric chamber after inhaling 100% oxygen and regular air: a crossover study.

INTRODUCTION: Diving is an activity performed in more than 1 atmosphere absolute pressure (ATA) either underwater or in a hyperbaric chamber. We aimed to compare lung function values of trained divers in 1.5 ATA hyperbaric chambers after inhaling 100% oxygen and regular air. METHODS: This experimental study with crossover design involved 18 trained divers in 1.5 ATA hyperbaric room, which is equivalents to a 5-meter depth. The eighteen subjects as the supplementation group, using oro-nasal mask, inhaled 100% oxygen for 30 minutes followed by a one-day washout period. The subjects were then crossed-over into control group inhaling only regular air for 30 minutes. Lung function test was performed before and after supplementation. RESULTS: In eighteen subjects inhaling regular air, there was a significant difference (p < 0.05) in FEV1/FVC, PEF, FEF25, FEF50, and FEF75. Whereas in eighteen subjects inhaling 100% oxygen, significant difference (p < 0.05) was observed not only in FEV1/FVC, PEF, FEF25, FEF50 and FEF75, but also in FEV1. CONCLUSIONS: There were significant differences in lung function, especially in dynamic volume of trained divers in 1.5 ATA hyperbaric chamber after inhaling 100% oxygen and regular air for 30 minutes; while there were no significant differences in lung capacity (VC and FVC) in the both groups. Lung function returned to normal following supplementation with a 1-day washout period.

The Role of Innate and Adaptive Immune Cells in the Immunopathogenesis of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a chronic and progressive inflammatory disease of the airways and lungs that results in limitations of continuous airflow and is caused by exposure to noxious gasses and particles. A major cause of morbidity and mortality in adults, COPD is a complex disease pathologically mediated by many inflammatory pathways. Macrophages, neutrophils, dendritic cells, and CD8+ T-lymphocytes are the key inflammatory cells involved in COPD. Recently, the non-coding small RNA, micro-RNA, have also been intensively investigated and evidence suggest that it plays a role in the pathogenesis of COPD. Here, we discuss the accumulated evidence that has since revealed the role of each inflammatory cell and their involvement in the immunopathogenesis of COPD. Mechanisms of steroid resistance in COPD will also be briefly discussed.

Syndecan 4 Mediates Nrf2-dependent Expansion of Bronchiolar Progenitors That Protect Against Lung Inflammation.

The use of lung progenitors for regenerative medicine appears promising, but their biology is not fully understood. Here, we found anti-inflammatory attributes in bronchiolar progenitors that were sorted as a multipotent subset of mouse club cells and found to express secretory leukocyte protease inhibitor (SLPI). Notably, the impaired expression of SLPI in mice increased the number of bronchiolar progenitors and decreased the lung inflammation. We determined a transcriptional profile for the bronchiolar progenitors of Slpi-deficient mice and identified syndecan 4, whose expression was markedly elevated as compared to that of wild-type mice. Systemic administration of recombinant syndecan 4 protein caused a substantial increase in the number of bronchiolar progenitors with concomitant attenuation of both airway and alveolar inflammation. The syndecan 4 administration also resulted in activation of the Keap1-Nrf2 antioxidant pathway in lung cells, which is critically involved in the therapeutic responses to the syndecan 4 treatment. Moreover, in 3D culture, the presence of syndecan 4 induced differentiated club cells to undergo Nrf2-dependent transition into bronchiolar progenitors. Our observations reveal that differentiative switches between bronchiolar progenitors and club cells are under the Nrf2-mediated control of SLPI and syndecan 4, suggesting the possibility of new therapeutic approaches in inflammatory lung diseases.

The prevalence and patient characteristics of chronic obstructive pulmonary disease in non-smokers in Vietnam and Indonesia: An observational survey.

BACKGROUND AND OBJECTIVE: An estimated 25-40% of patients with chronic obstructive pulmonary disease (COPD) have never smoked. We investigated the prevalence and patient characteristics of COPD in non-smokers from Vietnam and Indonesia. METHODS: This population-based cross-sectional survey of participants from urban and rural Vietnam and Indonesia used a stratified multistage cluster sampling design, with sample and population weights applied to ensure representativeness. Participants were female or male (recruited in the ratio 2:1) non-smokers, 40 years or older and able to perform a spirometry test. Spirometry was performed at a single study visit. Other clinical information was collected via standardized questionnaires. RESULTS: The 1506 evaluable participants were approximately equally distributed between Vietnam and Indonesia, and rural and urban areas. Overall prevalence of COPD was found to be 6.9% (95% confidence interval (CI): 5.7-8.3), with almost three times higher prevalence in men than women (12.9% (95% CI: 9.1-18.0) vs 4.4% (95% CI: 3.0-6.5)). We found higher rates of COPD in Vietnam than Indonesia (8.1% (95% CI: 5.8-11.3) vs 6.3% (95% CI: 4.8-8.3)), with a particularly high prevalence in urban Vietnam (11.1% (95% CI: 8.1-15.1)). Very few participants (6%) diagnosed to have COPD during the study had been previously diagnosed with COPD. Respiratory symptoms and lower health-related quality of life were more common in participants with COPD. CONCLUSIONS: The prevalence of COPD in non-smoking individuals from rural and urban Vietnam and Indonesia was 6.9%, of which a significant proportion (94%) were previously undiagnosed.

Serial OX40 engagement on CD4+ T cells and natural killer T cells causes allergic airway inflammation.

RATIONALE: OX40-OX40 ligand (OX40L) interactions have been proposed to support induction of allergic airway inflammation, which may be attributable to OX40 signaling in CD4(+) helper T cells for adaptive immune responses. However, a possible involvement of natural killer T (NKT) cells in the pathogenesis suggests that the underlying mechanisms are not yet fully elucidated. OBJECTIVES: We aimed to characterize the OX40-modulated cellular contribution to allergic airway inflammation in a mouse model of house dust mite (HDM) allergen exposure. METHODS: Mice were sensitized to HDM and, 3 weeks later, challenged with HDM on three consecutive days through the airways. Two days after the last exposure, bronchoalveolar lavage fluids and blood samples and lung tissues were evaluated for the airway inflammation. MEASUREMENTS AND MAIN RESULTS: The development of HDM-induced eosinophilic airway inflammation was dependent on OX40 of both CD4(+) T cells and NKT cells; OX40 engagement on CD4(+) T cells in the sensitization led to pulmonary OX40L augmentation after the allergen challenge, which stimulated pulmonary NKT cells through OX40 to provide the pathogenic cytokine milieu. This was ablated by OX40L blockade by inhalation of the neutralizing antibody during the challenge, suggesting the therapeutic potential of targeting pulmonary OX40-OX40L interactions. Moreover, OX40 expression in CD4(+) T cells, but not in NKT cells, was reciprocally regulated by the helper T cell type 1-skewing transcription factor Runx3. CONCLUSIONS: OX40 on not only CD4(+) T cells but also NKT cells is involved in allergic airway inflammation. Notably, pulmonary blockade of OX40 ligation on NKT cells has therapeutic implications.