Prophylactic and therapeutic alternatives for respiratory diseases: technological innovations obtained in natural products

Chronic respiratory diseases affect both the upper and lower airways. The main components of the respiratory system are the rib cage, airways, and the pulmonary interstitium. The airway originates in the trachea, a structure located in the mediastinum, which splits into two parts to form the main bronchus (right and left bronchi). The bronchi gradually divide into secondary bronchi, bronchioles, alveolar ducts, and alveoli. Acute or chronic respiratory diseases are present in all age groups, with many different forms of clinical presentation. In general, the most common diseases are asthma, chronic obstructive pulmonary disease, respiratory allergies, occupational lung diseases, pulmonary hypertension, sinusitis, pharyngitis, bronchitis, tuberculosis, cold, and influenza (flu). Among the acute illnesses, infections of the upper respiratory tract, flu, and pneumonia are particularly prominent, and since 2019, we could include in this group the COVID-19 with the beginning of the pandemic of this disease. For chronic diseases, diseases of the lower respiratory tract are the most common, such as bronchitis, emphysema, and asthma. © 2023 Elsevier B.V.

Key Role of Mesenchymal Stromal Cell Interaction with Macrophages in Promoting Repair of Lung Injury.

Lung macrophages (Mφs) are essential for pulmonary innate immunity and host defense due to their dynamic polarization and phenotype shifts. Mesenchymal stromal cells (MSCs) have secretory, immunomodulatory, and tissue-reparative properties and have shown promise in acute and chronic inflammatory lung diseases and in COVID-19. Many beneficial effects of MSCs are mediated through their interaction with resident alveolar and pulmonary interstitial Mφs. Bidirectional MSC-Mφ communication is achieved through direct contact, soluble factor secretion/activation, and organelle transfer. The lung microenvironment facilitates MSC secretion of factors that result in Mφ polarization towards an immunosuppressive M2-like phenotype for the restoration of tissue homeostasis. M2-like Mφ in turn can affect the MSC immune regulatory function in MSC engraftment and tissue reparatory effects. This review article highlights the mechanisms of crosstalk between MSCs and Mφs and the potential role of their interaction in lung repair in inflammatory lung diseases.

Observed and predicted premature mortality in Australia due to non-communicable diseases: a population-based study examining progress towards the WHO 25X25 goal.

BACKGROUND: The World Health Organization's (WHO) 25X25 goal aims for a 25% relative reduction in premature death due to four non-communicable diseases (NCD4)-cancer, cardiovascular disease, chronic respiratory diseases and diabetes-by 2025 compared to 2010. This study aimed to quantify the premature mortality in the Australian population due to NCD4, quantify the variation in mortality rates by age and sex, predict the premature mortality due to NCD4 in 2025 and evaluate the progress towards the WHO 25X25 goal. METHODS: A population-based study using cause-specific mortality data of all deaths which occurred in Australia from 2010 to 2016 and registered up to 2017, for adults aged 30-69 years, was conducted. Age-specific and age-standardised mortality rates (ASMR) and probability of death for NCD4 were calculated for each year. ASMRs in 2016 were calculated for men and women. Deaths and the probability of death in 2025 were predicted using Poisson regression based on data from 2006 to 2016. To assess the progress against the WHO 25X25 goal, the relative reduction in the probability of death from NCD4 conditions in 2025 compared to 2010 was calculated. RESULTS: ASMRs for NCD4 decreased from 2010 to 2016, except for diabetes which increased on average by 2.5% per year. Across sociodemographic factors, ASMRs were highest in males and increased with age. The projected probability of premature death in 2025 was 7.36%, equivalent to a relative reduction of 25.16% compared to 2010 levels. CONCLUSIONS: Premature mortality due to cancer, cardiovascular disease, respiratory diseases and diabetes declined in Australia from 2010 to 2016. This trend is consistent across age groups and by sex, and higher mortality rates were observed in males and at older ages. Nationally, if the current trends continue, we estimate that Australia will achieve a 25.16% relative reduction in premature deaths due to NCD4 in 2025 compared to 2010, signifying substantial progress towards the WHO 25X25 goal. Concerted efforts will need to continue to meet the 25X25 goal, especially in the context of the COVID-19 pandemic.

Targeting eosinophils in chronic respiratory diseases using nanotechnology-based drug delivery

Asthma, COPD, COVID-19, EGPA, Lung cancer, and Pneumonia are major chronic respiratory diseases (or CRDs) affecting millions worldwide and account for substantial morbidity and mortality. These CRDs are irreversible diseases that affect different parts of the respiratory system, imposing a considerable burden on different socioeconomic classes. All these CRDs have been linked to increased eosinophils in the lungs. Eosinophils are essential immune mediators that contribute to tissue homeostasis and the pathophysiology of various diseases. Interestingly, elevated eosinophil level is associated with cellular processes that regulate airway hyperresponsiveness, airway remodeling, mucus hypersecretion, and inflammation in the lung. Therefore, eosinophil is considered the therapeutic target in eosinophil-mediated lung diseases. Although, conventional medicines like antibiotics, antiinflammatory drugs, and bronchodilators are available to prevent CRDs. But the development of resistance to these therapeutic agents after long-term usage remains a challenge. However, progressive development in nanotechnology has unveiled the targeted nanocarrier approach that can significantly improve the pharmacokinetics of a therapeutic drug. The potential of the nanocarrier system can be specifically targeted on eosinophils and their associated components to obtain promising results in the pharmacotherapy of CRDs. This review intends to provide knowledge about eosinophils and their role in CRDs. Moreover, it also discusses nanocarrier drug delivery systems for the targeted treatment of CRDs.

Current status of prevention and treatment of respiratory diseases in primary care in China: a cross-sectional study.

BACKGROUND: China launched its new round of health care reform to develop primary care in 2009, establishing 954,390 primary care institutions that employed over 10 million staff by 2019. However, some studies have shown that the prevention and management of respiratory diseases is inadequate in these institutions. METHODS: We conducted a cross-sectional survey of grassroots institutions throughout China between September and December 2020 based on the standardized Prevention and Treatment System and Capacity Building Project of Respiratory Diseases in primary care settings. The operation of the respiratory department in primary health care institutions was evaluated in terms of facilities, drugs, personnel and management of chronic diseases by means of questionnaires. Descriptive analyses were performed to calculate percentages and frequencies of key parameters. RESULTS: A total of 144 primary health care institutions were surveyed, including 51 in the east, 82 in the west, 9 in the central and 2 in the northeast. Approximately 60% of institutions had spirometers and pulse oximeters. The majority had short-acting bronchodilators, theophylline, systemic corticosteroids, antibiotics, and traditional Chinese medicine. More than half had at least one respiratory physician and operator for spirometry. Half of the institutions carried out screening of chronic obstructive pulmonary disease within the jurisdiction. The institutions in the east were superior to those in the west regarding the equipment, common drugs, medical staff, and management of respiratory diseases. CONCLUSIONS: The study reveals that the overall operation of the respiratory department in primary care settings needs to be further strengthened. It is crucial to provide adequate essential equipment, medical professionals, and medicines for proper diagnosis and treatment of chronic respiratory diseases, as well as improving the management of diseases.

Targeting eosinophils in chronic respiratory diseases using nanotechnology-based drug delivery.

Asthma, COPD, COVID-19, EGPA, Lung cancer, and Pneumonia are major chronic respiratory diseases (or CRDs) affecting millions worldwide and account for substantial morbidity and mortality. These CRDs are irreversible diseases that affect different parts of the respiratory system, imposing a considerable burden on different socio-economic classes. All these CRDs have been linked to increased eosinophils in the lungs. Eosinophils are essential immune mediators that contribute to tissue homeostasis and the pathophysiology of various diseases. Interestingly, elevated eosinophil level is associated with cellular processes that regulate airway hyperresponsiveness, airway remodeling, mucus hypersecretion, and inflammation in the lung. Therefore, eosinophil is considered the therapeutic target in eosinophil-mediated lung diseases. Although, conventional medicines like antibiotics, anti-inflammatory drugs, and bronchodilators are available to prevent CRDs. But the development of resistance to these therapeutic agents after long-term usage remains a challenge. However, progressive development in nanotechnology has unveiled the targeted nanocarrier approach that can significantly improve the pharmacokinetics of a therapeutic drug. The potential of the nanocarrier system can be specifically targeted on eosinophils and their associated components to obtain promising results in the pharmacotherapy of CRDs. This review intends to provide knowledge about eosinophils and their role in CRDs. Moreover, it also discusses nanocarrier drug delivery systems for the targeted treatment of CRDs.

Barriers and Enablers to Pulmonary Rehabilitation in Low- and Middle-Income Countries: A Qualitative Study of Healthcare Professionals.

Introduction: Low- and middle-income countries bear a disproportionately high burden of global morbidity and mortality caused by chronic respiratory diseases. Pulmonary rehabilitation is recommended as a core intervention in the management of people with chronic respiratory diseases. However, the intervention remains poorly accessed/utilised globally, especially in low- and middle-income countries. Aim: This qualitative study explored barriers and enablers to pulmonary rehabilitation in low- and middle-income countries from the perspective of healthcare professionals with pulmonary rehabilitation experience in these settings. Methods: Online-based semi-structured in-depth interviews with healthcare professionals were undertaken to data saturation, exploring lived barriers and enablers to pulmonary rehabilitation in their low- or middle-income country. Anonymised interviews were audio-recorded, transcribed verbatim, and analysed using thematic analysis. Results: A total of seven healthcare professionals from seven low- and middle-income countries representing Africa, Asia, and South America were interviewed. They included five physiotherapists (four females), one family physician (male), and one pulmonologist (female). Themes for barriers to pulmonary rehabilitation included limited resources, low awareness, coronavirus disease 2019, and patient access-related costs. Themes for enablers included local adaptation, motivated patients, coronavirus disease 2019 (which spanned both enablers and barriers), better awareness/recognition, provision of PR training, and resource support. Conclusion: Barriers to pulmonary rehabilitation in low- and middle-income countries include limited resources, low awareness, coronavirus disease 2019, and patient access-related costs. Enablers include local adaptation, motivated patients, coronavirus disease 2019 (which spanned both enablers and barriers), better awareness/recognition, provision of PR training, and resource support. Successful implementation of these enablers will require engagement with multiple stakeholders. The findings of this study are a necessary step towards developing strategies that can overcome the existing pulmonary rehabilitation evidence-practice gap in low- and middle-income countries and alleviating the burden of chronic respiratory diseases in these countries.

Issue 1 - "Update on adverse respiratory effects of outdoor air pollution". Part 1): Outdoor air pollution and respiratory diseases: A general update and an Italian perspective.

OBJECTIVE: to summarize the main updated evidence about the health effects of air pollution and to focus on Italian epidemiological experiences on the respiratory effects. RESULTS: the recent literature indicates that there is strong evidence for causal relationships between PM2.5 air pollution exposure and all-cause mortality as well as mortality from acute lower respiratory infections, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lung cancer. A growing body of evidence also suggests causal relationships with type II diabetes and impacts on neonatal mortality from low birth weight and short gestation as well as neurologic effects in both children and adults. Italy, a Southern European country, faces a more threatening air pollution challenge because of the effects of both anthropogenic pollutants and natural dust (particulate matter, PM). The 2020 Report of the European Environment Agency highlighted the number of premature deaths in Italy attributable to main pollutants: 52,300 for PM2.5, 10,400 for NO2 and 3,000 for O3 in 2018. In Italy, original time series and analytical epidemiological studies showed increased cardio-respiratory hospital admissions and mortality and increased risk of respiratory diseases in people living in urban areas. CONCLUSIONS: adverse health effects of air pollutants, even at low levels, have been confirmed by recent epidemiological studies. Further studies should focus on the potential link between air pollution exposure and respiratory infections. This topic has become particularly important in the current SARS-COV-2 pandemic. Based on strong scientific evidence, the Italian government, which hosts the Global Alliance against Chronic Respiratory Diseases (GARD)-Italy at the Ministry of Health, the scientific respiratory societies and the patients' associations, as well as others in the health sector and civil society, must increase their engagement in advocacy for clean air policies, especially in light of the new Air Quality Guidelines of the World Health Organization.

Association between Inhaled Corticosteroid Use and SARS-CoV-2 Infection: A Nationwide Population-Based Study in South Korea.

BACKGROUND: Although it is known that inhaled corticosteroid (ICS) use may increase the risk of respiratory infection, its influence on the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unknown. Thus, the aim of this study was to investigate the association between ICS use and the positivity of SARS-CoV-2 infection among patients with chronic respiratory diseases. METHODS: Nationwide data of 44,968 individuals with chronic respiratory diseases tested for SARS-CoV-2 until May 15, 2021 were obtained from the Ministry of Health and Welfare and Health Insurance Review and Assessment Service in Korea. The positivity of SARS-CoV-2 infection was retrospectively analysed according to the prescription, type, and dose of ICS taken one year before SARS-CoV-2 test. RESULTS: Among 44,968 individuals tested, 931 (2.1%) were positive for SARS-CoV-2. A total of 7,019 patients (15.6%) were prescribed ICS one year prior to being tested for SARS-CoV-2. Low, medium, and high doses of ICS were prescribed in 7.5%, 1.6%, and 6.5% of total cases, respectively. Among types of ICS, budesonide, fluticasone, beclomethasone, and ciclesonide were prescribed in 3.7%, 8.9%, 2.3%, and 0.6% of total cases, respectively. A multivariate analysis showed no significant increase in infection with ICS use (odds ratio, 0.84; 95% confidence interval, 0.66-1.03). Moreover, there were no associations between the positivity of infection and the dose or type of ICS prescribed. CONCLUSION: Prior ICS use did not increase the positivity for SARS-CoV-2 infection. Moreover, different doses or types of ICS did not affect this positivity.

Impact of COVID-19 on (Non-COVID) chronic respiratory disease outcome survey in India (CCROS study).

BACKGROUND: India has high prevalence of chronic respiratory diseases, especially bronchial asthma and chronic obstructive pulmonary disease (COPD). Both of these are also recognized as risk factors for severity and poor outcome of COVID-19 disease. It is assumed that COVID-19 outbreak as well as an effective lockdown might have affected the incidence and outcome of some of these. METHODS: To substantiate above hypothesis, an online survey was mailed to 547 pulmonologists across the country; 314 (54.7%) responses were recorded in the given period. The survey included observations on incidence and outcome of common chronic respiratory diseases such as asthma, COPD and interstitial lung diseases (ILD) in predefined pre-COVID and during COVID period in a total of 24 questions. RESULTS: It was observed that the reduction in incidence of outpatient department cases, acute exacerbations and hospitalization for asthma, COPD and ILD was statistically significant. The outcome of acute exacerbations of these chronic respiratory diseases was analyzed in terms of discharges from hospitals after satisfactory recovery and/ or mortalities. For COPD and ILD, it was not significantly affected during the COVID period. At the same time, a relatively higher proportion of acute asthma mortality was reported. A wide variation in nebulization practices was reported during this period. The doses of inhaled corticosteroids in asthma management were not affected. A wide variety of factors including effective lockdown, better quality of air and regular use of masks were probably responsible for reduced incidence of exacerbations of these chronic respiratory diseases. CONCLUSION: We conclude that while outpatient department visits, acute exacerbations and hospitalizations were significantly reduced during COVID-19 period, outcome of asthmatics was relatively unfavorable as compared to that of COPD and ILDs.

Interleukin-13: A pivotal target against influenza-induced exacerbation of chronic lung diseases.

Non-communicable, chronic respiratory diseases (CRDs) affect millions of individuals worldwide. The course of these CRDs (asthma, chronic obstructive pulmonary disease, and cystic fibrosis) are often punctuated by microbial infections that may result in hospitalization and are associated with increased risk of morbidity and mortality, as well as reduced quality of life. Interleukin-13 (IL-13) is a key protein that regulates airway inflammation and mucus hypersecretion. There has been much interest in IL-13 from the last two decades. This cytokine is believed to play a decisive role in the exacerbation of inflammation during the course of viral infections, especially, in those with pre-existing CRDs. Here, we discuss the common viral infections in CRDs, as well as the potential role that IL-13 plays in the virus-induced disease pathogenesis of CRDs. We also discuss, in detail, the immune-modulation potential of IL-13 that could be translated to in-depth studies to develop IL-13-based therapeutic entities.

Impact of the COVID-19 pandemic on the management of chronic noninfectious respiratory diseases.

Introduction: The COVID-19 pandemic has challenged health care across the world, not just by the severity of the disease and the high mortality rate but also by the consequences on the management of the patients with chronic diseases.Areas covered: This review summarizes the most up-to-date published data regarding the impact of COVID-19 on the management and outcomes of patients with chronic noninfectious respiratory illnesses including obstructive sleep apnea, asthma, chronic obstructive pulmonary disease, bronchiectasis, interstitial and pulmonary vascular diseases, and lung cancer.Expert opinion: Most of chronic respiratory diseases (except asthma and cystic fibrosis) are associated with more severe COVID-19 and poor outcomes but the mechanisms involved are not yet identified. The therapeutic management of the patients with chronic respiratory diseases and COVID-19 is similar to the other patients but the post-recovery course could be worse in this population and followed by the development of pulmonary fibrosis, bronchiectasis, and pulmonary hypertension. The pandemic highly impacted our usual medical activities by limiting the access to several diagnosis procedures, the necessity to develop new methods for the monitoring of the disease and adapt the therapeutic strategies. The long-term consequences of all these changes are still unknown.

Eosinophils and Chronic Respiratory Diseases in Hospitalized COVID-19 Patients.

BACKGROUND: Studies on the role of eosinophils in coronavirus disease 2019 (COVID-19) are scarce, though available findings suggest a possible association with disease severity. Our study analyzes the relationship between eosinophils and COVID-19, with a focus on disease severity and patients with underlying chronic respiratory diseases. METHODS: We performed a retrospective analysis of 3018 subjects attended at two public hospitals in Madrid (Spain) with PCR-confirmed SARS-CoV-2 infection from January 31 to April 17, 2020. Patients with eosinophil counts less than 0.02×109/L were considered to have eosinopenia. Individuals with chronic respiratory diseases (n=384) were classified according to their particular underlying condition, i.e., asthma, chronic pulmonary obstructive disease, or obstructive sleep apnea. RESULTS: Of the 3018 patients enrolled, 479 were excluded because of lack of information at the time of admission. Of 2539 subjects assessed, 1396 patients presented an eosinophil count performed on admission, revealing eosinopenia in 376 cases (26.93%). Eosinopenia on admission was associated with a higher risk of intensive care unit (ICU) or respiratory intensive care unit (RICU) admission (OR:2.21; 95%CI:1.42-3.45; p<0.001) but no increased risk of mortality (p>0.05). CONCLUSIONS: Eosinopenia on admission conferred a higher risk of severe disease (requiring ICU/RICU care), but was not associated with increased mortality. In patients with chronic respiratory diseases who develop COVID-19, age seems to be the main risk factor for progression to severe disease or death.

The impact of COVID-19 on tuberculosis: challenges and opportunities.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a seafood market in Wuhan, China, has ushered in a new era. It transformed into a pandemic, seized global attention, and was the biggest highlight of the year 2020. The SARS-CoV-2 outbreak has jeopardized health systems and greatly affected socioeconomic parameters. With global focus on fighting this unpredictable fight with this new virus, the biggest chronic infectious killer, mycobacterium tuberculosis (M. tb), was hugely affected from this shift in attention. Due to certain similarities in the behavior of the two infectious agents, there have been inevitable consequences. On one hand, administrative measures to contain SARS-CoV-2 have simultaneously led to a breaking in the chain of tuberculosis (TB) management. Consequently, a regression occurred in the milestones achieved in the battle against TB. On the other hand, the same measures and heightened hygiene awareness has helped to decrease the spread of the TB bacilli. With an improved understanding of the interrelations and the outcomes noticed in 2020, we can better gear ourselves to develop a more sophisticated and robust strategy to tilt the balance against TB. Keeping this in mind, in this review we aim to discuss in detail the implications of SARS-CoV-2 on an already unwavering health hazard: TB.

Three-Dimensional Cell Cultures as a Research Platform in Lung Diseases and COVID-19.

BACKGROUND: Chronic respiratory diseases (CRD) are a major public health problem worldwide. In the current epidemiological context, CRD have received much interest when considering their correlation with greater susceptibility to SARS-Cov-2 and severe disease (COVID-19). Increasingly more studies have investigated pathophysiological interactions between CRD and COVID-19. AREA COVERED: Animal experimentation has decisively contributed to advancing our knowledge of CRD. Considering the increase in ethical restrictions in animal experimentation, researchers must focus on new experimental alternatives. Two-dimensional (2D) cell cultures have complemented animal models and significantly contributed to advancing research in the life sciences. However, 2D cell cultures have several limitations in studies of cellular interactions. Three-dimensional (3D) cell cultures represent a new and robust platform for studying complex biological processes and are a promising alternative in regenerative and translational medicine. EXPERT OPINION: Three-dimensional cell cultures are obtained by combining several types of cells in integrated and self-organized systems in a 3D structure. These 3D cell culture systems represent an efficient methodological approach in studies of pathophysiology and lung therapy. More recently, complex 3D culture systems, such as lung-on-a-chip, seek to mimic the physiology of a lung in vivo through a microsystem that simulates alveolar-capillary interactions and exposure to air. The present review introduces and discusses 3D lung cultures as robust platforms for studies of the pathophysiology of CRD and COVID-19 and the mechanisms that underlie interactions between CRD and COVID-19.

Are Patients with Asthma and Chronic Obstructive Pulmonary Disease Preferred Targets of COVID-19?

The coronavirus pandemic, known as coronavirus disease 2019 (COVID-19), is an infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus first identified in patients from Wuhan, China. Since December 2019, SARS-CoV-2 has spread swiftly around the world, infected more than 25 million people, and caused more than 800,000 deaths in 188 countries. Chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) appear to be risk factors for COVID-19, however, their prevalence remains controversial. In fact, studies in China reported lower rates of chronic respiratory conditions in patients with COVID-19 than in the general population, while the trend is reversed in the United States and Europe. Although the underlying molecular mechanisms of a possible interaction between COVID-19 and chronic respiratory diseases remain unknown, some observations can help to elucidate them. Indeed, physiological changes, immune response, or medications used against SARS-CoV-2 may have a greater impact on patients with chronic respiratory conditions already debilitated by chronic inflammation, dyspnea, and the use of immunosuppressant drugs like corticosteroids. In this review, we discuss importance and the impact of COVID-19 on asthma and COPD patients, the possible available treatments, and patient management during the pandemic.