Lung inflammation can be caused by exposure to airborne toxins or irritants, respiratory infections, and lung diseases like asthma or chronic bronchitis. Symptoms may include wheezing, shortness of breath, chest pain, and coughing.

Lung inflammation can be acute (rapidly occurring and severe) or chronic (persistent or recurrent). The diagnosis may involve a physical exam, blood tests, imaging tests, and other procedures. Treatment is typically focused on treating the underlying cause, but anti-inflammatory or immunosuppressant drugs may be prescribed to directly treat the inflammation. Sometimes surgery is needed.

This article explains some common symptoms and causes of different types of lung inflammation. It also discusses how inflammation in the lungs is diagnosed and treated.

Verywell / Nez Riaz

Lung Inflammation Symptoms

Symptoms of lung inflammation can develop very suddenly or gradually over time. The symptoms vary based on the underlying cause, the extent of the inflammation, and your general health.

Symptoms of lung inflammation may include:

  • Fatigue
  • Wheezing
  • Shortness of breath
  • Productive (wet) or non-productive (wet) cough
  • Easy exhaustion with physical exertion
  • Chest discomfort, pain, or tightness

With chronic lung inflammation, a loss of appetite and unintended weight loss are common.


When severe, lung inflammation can limit airflow or lower your ability to absorb oxygen. This can cause hypoxemia (low blood oxygen) or hypoxia (low oxygen in tissues), leading to symptoms like:

  • Extreme restlessness
  • Slow heart rate (bradycardia)
  • Blueish skin (cyanosis)
  • Dizziness or fainting

Over time, chronic lung inflammation can change the thickness, composition, or volume of the airways, leading to a condition known as bronchiectasis. Bronchiectasis is a long-term, progressive condition in which the airways become permanently widened, leading to a build-up of mucus in the lungs and an increased risk of infection.

These changes can also result in hypercapnia in which it is harder to get carbon dioxide out of the lungs. In cases like this, a mechanical ventilator may be needed to help you breathe.

What Causes Lung Inflammation?

Inflammation is the body's natural response to injury or infection. There are many different reasons why this might occur in the lungs. While inflammation is a means for the body to heal itself, persistent inflammation can cause damage to airways and lung tissues.

Common causes of lung inflammation include:

Respiratory Irritants

When airborne toxins or irritants enter the lungs, the body responds with inflammation. This causes the airways to swell and produce a gooey substance called mucus that surrounds the particles and protects the wall of the airways. Mucus can then be dislodged with coughing.

Some common irritants include:

  • Cigarette smoke
  • Air pollution
  • Industrial aerosols
  • Household ammonia or chlorine
  • Solvents
  • Smoke

You can also have hypersensitivity pneumonitis in which your immune system overreacts to an inhaled irritant and triggers an extreme allergic response with lung inflammation. Dust mites, pollen, and pet dander are common triggers.

Lung Infections

There are many different pathogens (disease-causing agents) that cause lung infections. These include viruses that tend to cause acute infection, bacteria that can cause acute and chronic lung infections, and fungi that tend to cause severe infections in people with compromised immune systems.

Examples include:

Severe lung infections may cause acute respiratory distress syndrome (ARDS), a potentially life-threatening condition in which you cannot get enough oxygen in your blood.


Asthma is a condition in which your airways narrow and swell in response to different airborne triggers or health conditions. It causes episodes of bronchospasm in which the airways spasm violently, causing wheezing and coughing. Mucus might also be produced.

People with poorly managed asthma have a higher risk of pneumonia as a result of persistent lung inflammation.

Chronic Obstructive Pulmonary Disease (COPD)

Chronic obstructive pulmonary disease (COPD) is associated with chronic lung inflammation and an increased risk of bronchiectasis and pneumonia. Cigarette smoking is strongly linked to COPD. The disease progresses from chronic bronchitis (inflammation of the major airways) to emphysema (in which the lungs are heavily pitted).

People with advanced COPD often require inhaled corticosteroids (steroids) to reduce and control lung inflammation.


A chest injury or infection can lead to a condition called costochondritis in which the cartilage that joins your rib bone to your breastbone becomes inflamed. Costochondritis causes sharp or stinging pain and pressure on the chest wall.

Autoimmune Diseases

Lupus, rheumatoid arthritis, sarcoidosis, and scleroderma are all autoimmune diseases in which the body's own immune systems attacks healthy cells and tissues. Each of these diseases can directly or indirectly affect the lung and trigger lung inflammation. All autoimmune diseases are inflammatory.

Autoimmune diseases affecting the lungs can lead to interstitial lung disease (ILD). ILD affects tissues around the airways, causing progressive scarring (pulmonary fibrosis). The scarring causes the lungs to stiffen and makes it harder to breathe. Lung damage from ILD is often irreversible and gets worse over time.


Any type of trauma to the lungs or chest wall can cause acute lung inflammation. These include injuries like a rib fracture, a puncture wound, or a collapsed lung (pneumothorax) following a car accident.

People who suffer severe chest or lung trauma are vulnerable to pneumonia due to the build-up of fluid in or around the lungs. Penetrating wounds also allow bacteria to enter the chest wall, leading to a potentially severe infection.

Cystic Fibrosis

Cystic fibrosis (CF) is a progressive genetic disease that affects the lungs, pancreas, and other organs. CF causes the excess build-up of mucus in the lungs, making it harder to breathe.

While CF isn't primarily an inflammatory disease, the blockage of the airways can trigger severe inflammation, particularly as the disease worsens.


Pericarditis is an inflammation of the sac (pericardium) that surrounds the heart. Pericarditis can be caused by an infection, heart attack, certain diseases, and even some medical treatments.

While pericarditis directly affects the lining of the heart, the inflammation can spread to the lungs, particularly if the underlying cause is severe or chronic.

Pulmonary Embolism

Pulmonary embolism (PE) occurs when a blood clot (embolus) gets stuck in the artery of the lung. The clot often develops in the lower extremities due to a condition called deep vein thrombosis (DVT). When a clot in the artery of the leg is dislodged, it can travel to the lungs and cause PE.

Large clots can cause severe chest pain and other overt symptoms. Smaller clots may be less noticeable at first but still cause significant damage due to the loss of oxygen in the surrounding tissues. The damage can be worsened by high levels of inflammation at the site of the obstruction.

Lung Cancer

Lung cancer is characterized by chronic lung inflammation as the immune system launches an assault again the cancerous tumor.

Lung inflammation is also a common side effect of cancer treatments, including radiation, chemotherapy, and newer targeted drugs and immunotherapies. All of these treatments trigger an inflammatory response as they target cancer cells for destruction.

How Is Lung Inflammation Diagnosed?

The causes of lung inflammation are many and require no less than a physical exam (including a check of breath sounds) and a review of your medical and family. Based on the findings, other tests and procedures may be ordered.

These include lab tests like:

Procedures your healthcare provider may order include:

  • Pulse oximeter: A device placed on the finger that can tell how saturated oxygen is in your blood
  • Pulmonary function tests (PFTs): A battery of tests involving devices you breathe into that measure the volume and strength of your lungs
  • Electrocardiogram (ECG): A non-invasive test that measures the electrical activity of the heart
  • Bronchoscopy: A procedure in which a narrow scope is passed through your nose or mouth and into your lungs to view the airways
  • Lung biopsy: A procedure in which a sample of lung tissue is removed with a needle or scalpel to view the airways

Imaging tests may include:

  • Chest X-ray: An imaging test that creates black-and-white images with low-dose ionizing radiation
  • Computed tomography (CT): An imaging test that composites multiple X-ray images to create three-dimensional "slices" of the lungs
  • Magnetic resonance imaging (MRI): An imaging test that used powerful magnetic and radio waves to create highly detailed images of soft tissues
  • Echocardiogram: An imaging test that evaluates how well the heart's chambers and valves are working using reflected sound waves
  • Ventilation-perfusion scan: An imaging test traces the flow of air and blood through your lungs

How Is Lung Inflammation Treated?

Treating lung inflammation depends on the cause. For lung inflammation due to viral infections, such as the cold or flu, time and supportive care are all that is really involved. Lung inflammation due to other types of infection, such as Tb, will usually resolve once the underlying infection is treated.

Other causes may need treatments specific to lung inflammation to bring the inflammation under control.

Urgent Care

If you're having a breathing emergency, you may need oxygen therapy to bring your arterial blood gasses back to normal. In severe care, respiratory support may be needed to help you breathe. This support could include mechanical ventilation with intubation. This is when a tube is fed into the mouth and down the throat to deliver oxygen under controlled pressure.


Different medications may be used to alleviate lung inflammation either directly or indirectly. These include:

  • Antibiotics: Used to treat bacterial lung infections
  • Antivirals: Sometimes used to treat viral infections (like Paxlovid for COVID-19)
  • Antifungals: Given by mouth or intravenously (into a vein) to treat fungal lung infections
  • Antihistamines: Used to relieve inflammation due to allergy or atopic diseases
  • Inhaled corticosteroids (steroids): Often used to control lung inflammation in people with asthma or COPD
  • Oral corticosteroids: Including drugs like prednisone intended for short-term use of acute inflammation
  • Biologic drugs: Including drugs like Humira (adalimumab) that suppress parts of the immune system to treat different types of autoimmune diseases

Procedures and Surgery

Home oxygen therapy may be indicated for chronic lung conditions that severely restrict oxygen blood saturation. It involves a portable oxygen tank and thin tubing (called a cannula) that delivers oxygen into your nostrils.

Surgery may sometimes be needed to remove an area of the lung that has been damaged by disease. Generally, lung cancer surgery involves removing a lobe of a lung or sometimes an entire lung to ensure the tumor and any cancer cells are extracted. Surgery for COPD entails removing damaged areas of the lung to improve airflow.


Lung inflammation may be due to infection, disease, injury, or exposure to environmental toxins or irritants. Lung inflammation can make it harder to breathe. Over time, if the inflammation doesn't improve, it can damage your lungs.

Diagnosing lung inflammation may involve a review of your medical history, a physical exam, blood test, imaging tests, and procedures to measure how well your lungs and heart are working. Treatment is typically focused on treating the underlying cause. If needed, oral or inhaled steroids can help temper the inflammation, while oxygen therapy can help if you have trouble breathing. Surgery is needed in some cases.

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Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory condition that represents the third leading cause of death worldwide.1,2 According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 definition, COPD is a

Heterogeneous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, expectoration, and/or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction.2

People with HIV (PWH) are particularly vulnerable to the development and progression of COPD, with both higher rates of COPD and an earlier and more rapid decline in lung function than in the general population, even after accounting for cigarette smoking and other known risk factors, such as intravenous drug use.3–7 The exact mechanisms that underlie HIV-associated COPD are incompletely known, but environmental exposures, heightened immune activation and systemic inflammation, accelerated aging, a predilection for the development of pneumonia, and alterations in the lung microbiome likely play important roles (Figure 1).8–11 The purpose of this review is to describe what is currently understood about the epidemiology and pathobiology of COPD among PWH, to indicate selected areas of active investigation, and to outline screening, diagnostic, prevention, and treatment strategies.

Figure 1 Drivers of COPD in PWH.



As survival among PWH has improved with the use of antiretroviral therapy (ART), COPD has become an increasingly important comorbidity. PWH develop an earlier and more rapid decline in lung function, even after adjustment for traditional risk factors.3,5–7,12–15 A recent retrospective study evaluating comorbidities in PWH based on hospital discharge data found that COPD was the most common comorbidity across the 10-year study period and that COPD prevalence was higher among PWH than among those without HIV (23.5% versus 14.0%).16 Prevalence estimates of COPD among PWH have ranged from 3.4% to over 40% in prior studies; notably, most of these have been conducted in Europe and North America.17,18 Part of this heterogeneity is due to differences in COPD classification methods, such as self-report, International Classification of Diseases (ICD) diagnostic codes, use of CT scans, and spirometry.17,19 For example, a systematic review and meta-analysis by Bigna et al evaluating the global prevalence of COPD among PWH found that the prevalence varied from 5.6% to 10.6% depending on the diagnostic criteria used, with a higher prevalence when using spirometric criteria instead of self-report or ICD diagnostic codes.4


COPD in PWH occurs anywhere PWH reside. However, the risk factors for the development of COPD in PWH vary regionally due to differences in age, rates and duration of tobacco smoking, exposure to biomass fuels, and prevalence of tuberculosis, all of which have been implicated in COPD development.2,20–22 While the majority of studies on COPD in PWH have been conducted in the US and Europe, most PWH live in sub-Saharan Africa, where there is a high prevalence of both tuberculosis (TB) and exposure to biomass fuels, and where patients are typically younger and less likely to smoke tobacco. While earlier studies suggested that ART itself may be a risk factor for worsening lung function,23,24 Kunisaki et al conducted a multinational randomized controlled trial (RCT) in the modern ART era and did not find a difference in lung function based on timing of ART initiation.25

Biologic Sex

Biologic sex may also contribute to differences in COPD trajectories among PWH. In one study of longitudinal lung function changes in PWH, female sex was associated with distinct lung function trajectories, including baseline low diffusing capacity for carbon monoxide (DLco).26 In a study by McNeil et al of virally suppressed adults with HIV and their seronegative counterparts in Uganda, women with HIV demonstrated an accelerated FEV1 decline as compared to women without HIV, a finding that was not seen among men with and without HIV.27 Interestingly, in a large US-based cross-sectional analysis comparing women with and without HIV, women with HIV had a lower DLco than women without HIV, but there were no differences in spirometric outcomes by HIV status.28,29 In another study including the same cohort of women, baseline COPD prevalence was similar among men with and without HIV and women with and without HIV, but COPD incidence was higher among men with HIV when compared to men without HIV.30 In contrast, Abelman et al found in a post-pneumonia Ugandan cohort that women with HIV had over three-fold higher odds of COPD on spirometry compared to men with HIV, a sex-based difference not found in women and men without HIV.31 Further work is currently underway to investigate whether these reported HIV-associated sex-specific differences in COPD rates are driven by immunologic, hormonal, or environmental factors.

Risk Factors for COPD in PWH

There are many risk factors for the development of COPD in PWH including HIV itself,5,32 cigarette smoking and other inhalational exposures, air pollution, opportunistic infections and pneumonia, microbiome alterations,33,34 accelerated aging,35–38 and socioeconomic factors.39 This section focuses on the major drivers, such as smoking, as well as potential risk factors under investigation, such as chronic cytomegalovirus (CMV) coinfection.


Smoking is the key risk factor for COPD in PWH. Smoking is more prevalent among PWH compared to their seronegative counterparts.40–42 However, studies of co-exposure to HIV and tobacco smoke suggest that PWH who smoke may also be more susceptible to smoking-induced lung damage than HIV-uninfected people who smoke. For example, Diaz et al found emphysema to be more prevalent among smokers with HIV as compared to smokers without HIV.43 Further, in a longitudinal multi-center cohort of 13,687 veterans with and without HIV, Crothers et al found that the prevalence and incidence of both COPD and lung cancer were higher among those with HIV compared to those without HIV despite similar levels of smoking.5 Importantly, among PWH on ART, smoking may reduce life expectancy more than HIV itself.44–46 While the pathophysiologic mechanism driving this HIV-associated difference is incompletely known, recent work suggests that, among PWH, tobacco smoke suppresses alveolar macrophage production of T-cell recruiting chemokines. This impairs the migration of cytotoxic T cells from the airway mucosa into the alveolar space, leading to localized airway mucosa inflammation and tissue destruction.47

Air Pollution

Air pollution – the leading environmental cause of death globally48 – is now the greatest threat to human health,49 and COPD is a leading cause of the nearly 7 million annual deaths attributed to air pollution.48,50 Air pollution results from a variety of human-related activities and natural events that include emissions from vehicles, factories, and power plants; traffic-related products; biomass fuel burning (ie, charcoal, firewood, animal dung, crop residues) for cooking and heating; dust storms; forest fires; and volcanic eruptions. The dominant pollution sources vary by region. Traffic- and industry-related sources drive exposure in high-income countries and urban settings, while biomass-related sources drive exposure in low- and middle-income countries and rural settings.51 Air pollution causes acute and chronic lung dysfunction, structural lung abnormalities, submaximal lung growth in childhood and adolescence, and augments lung disease risk in vulnerable populations.52–63 Even small acute increases in fine particulate matter (PM2.5) exposure worsen mortality,64 and there is no “safe” level of exposure.65 Biomass-associated COPD, compared to tobacco-associated COPD, is characterized by more small airways disease and fibrosis, less emphysema, higher DLco, and less airflow obstruction – in effect, a more fibrotic and less emphysematous phenotype.66–69 Exposure to biomass fuel smoke has also been associated with defective bacterial phagocytosis.70 In addition, PM2.5 exposure may also potentiate TB risk,21,71,72 which by itself is a risk factor for COPD and an important consideration in TB-endemic regions.

Similar to the influence of tobacco smoke, PWH may be more susceptible to air pollution-associated lung damage. For example, among PWH living in San Francisco, exposure to higher levels of outdoor air pollution was associated with increased susceptibility to Pneumocystis infection.73–75 Using ambulatory carbon monoxide (CO) sensors to measure personal air pollution exposure among 260 adults with and without HIV in rural Uganda, North et al found that exposure to short-term CO levels that exceed WHO air quality guidelines was associated with self-reported respiratory symptoms among PWH but not among HIV-uninfected comparators.76 Characterizing air pollution exposure among PWH and exploring the potentially outsized influence of air pollution exposure on lung health in this population is an area of ongoing investigation. As global smoking prevalence continues to decline and rapid industrialization and urbanization progresses, air pollution is poised to replace tobacco as the leading cause of chronic lung disease,77–79 and a multifaceted approach that also focuses on this often overlooked risk factor for lung disease among PWH is critical.

Opportunistic Infections and Pneumonia

PWH have historically had higher rates of pneumonia, and while incidence of bacterial pneumonia has decreased with the advent of ART,80,81 it remains common in this population.82–84 In the current era, PWH have similar rates of acute respiratory infections as people without HIV, but PWH experience more severe disease.85 Pneumonia has been associated with higher rates of COPD and lung function abnormalities in PWH.86–89 For example, Drummond et al conducted a US-based multi-center study evaluating spirometry in adults with and without HIV and found that participants with airflow obstruction were more likely to have a history of bacterial pneumonia and Pneumocystis jirovecii (PJP) infection.90 Specifically, PJP, an opportunistic infection that occurs in PWH with CD4 counts <200 cells/mm,3 elevated HIV RNA, and colonization by Pneumocystis have each been associated with higher risk of COPD among PWH.88,91,92 There are numerous contributors to the increased risk of pneumonia in PWH, including alterations in immunity, which lead to persistently elevated markers of immune activation and inflammation, as well as environmental and behavioral risk factors, and a higher prevalence of COPD, which is both a consequence of and a risk factor for pneumonia.9,93–96

Globally, tuberculosis is the leading infectious cause of death among PWH;97 PWH are 19 times more likely to develop TB disease than their seronegative counterparts.98,99 Pulmonary TB has been found to cause permanent scarring, bronchiectasis, pleural fibrosis, damage to small and large airways, as well as lung parenchymal damage, all of which may contribute to permanent lung function impairment.20,100 Whereas during the treatment phase of TB this impairment is typically restrictive, there is increasing evidence of a relationship between prior pulmonary TB infection and the subsequent development of obstruction and COPD.20,87 Rates differ significantly by the population under study, but pulmonary TB has been found to lead to airway obstruction in 18.4–86% of people in the general population.100 HIV is now recognized as a risk factor for post-TB lung disease, although the extent of this relationship is currently under study.87,100–104 There is some evidence to suggest that HIV may be associated with reduced severity of post-TB lung disease, but this is an area that merits further evaluation.100,105,106

Chronic CMV Infection

CMV is an important and omnipresent coinfection in HIV that has been associated with cardiovascular and cerebrovascular disease, other non-AIDS events, and increased mortality.107–112 Given the high rates of CMV antibody seropositivity among PWH, CMV IgG titers are commonly used as markers of CMV activity and have been shown to correlate with adverse outcomes.112,113 However, studies of CMV’s effect on lung function and COPD in PWH are limited. While chronic CMV infection in children with perinatally acquired HIV on ART has been associated with an abnormal FEV1,114 CMV’s association with COPD and other chronic lung diseases in adults with HIV has not been evaluated. Emerging data from the general population, however, suggest that chronic CMV infection is associated with COPD,115 and that higher CMV IgG titers are associated with COPD-related mortality.113 CMV is also associated with abnormal DLco in solid organ transplant recipients, although this has not been studied in PWH.116–118

There are several proposed mechanisms for CMV-mediated systemic immune effects, including persistent immune activation, endothelial dysfunction, and alterations in the gut microbiome.17,119–121 Similar biomarker activation patterns are noted in PWH with CMV and those with COPD. For example, sCD163, sCD14, and IL-6 are increased in both CMV IgG-positive PWH122–124 and PWH with lung function abnormalities, including both abnormal spirometry and abnormal DLco.10,121 These data suggest that there may be a shared mechanistic pathway between chronic CMV infection and chronic lung disease in PWH, but further work is needed to understand and characterize this relationship.

HIV-Specific Influences on COPD Pathogenesis

Several HIV-specific mechanisms may contribute to the increased incidence and accelerated development of COPD in PWH. Chronic HIV infection and the direct effects of HIV-related proteins on lung cells, altered lung and systemic immune responses (both immunosuppressive and pro-inflammatory), altered airway and gut microbial communities, impaired response to pathogens, and toxicity from antiretroviral therapies may all contribute to COPD pathogenesis in this population.23,24,125–132

HIV Infection

As the lung acts as a reservoir for HIV even after viral suppression, chronic HIV infection may directly contribute to COPD pathogenesis in various ways.132–134 Newly replicated viral particles released slowly over time bind to and interact with many cell types within the lung, which can lead to direct injury, oxidative stress, low-level chronic inflammation, and impaired response to pathogens.128,135 Although other cell types in the lung may be infected, alveolar macrophages are the best studied reservoir of HIV in the lung.132 HIV infection impairs macrophage phagocytic activity, thus hindering response to pathogens.127,132 HIV also skews the macrophage phenotype towards a pro-inflammatory and protease-producing phenotype through the release of a host of cytokines, chemokines, oxidants, and proteases, all of which contribute to COPD pathology. Cytokine and chemokine signaling in HIV-infected macrophages trigger a pro-inflammatory response including neutrophil and lymphocyte infiltration. Kaner et al found that alveolar macrophage expression of proteases such as matrix metalloproteinases 9 and 12 (MMP-9, MMP-12) is higher in PWH who smoke with emphysema than their seronegative counterparts.131 In murine models, MMPs degrade the extracellular matrix, directly contributing to emphysematous tissue destruction.136

Altered Adaptive Immune Responses

COPD development is not only mediated by HIV direct effects, but also by the altered cell-mediated adaptive immune responses in PWH, in particular, altered CD4+ T-cell responses. Numerous studies have shown a relationship between low CD4+ T cell counts and COPD or accelerated lung function decline, although conflicting data also exists.23,125,126,137 T cell exhaustion is typically seen in response to chronic antigen stimulation, such as chronic viral infection, and results in decreased functionality. In PWH, CD4+ T cells show signs of exhaustion even in the presence of ART, with an increased expression of programmed cell death protein-1 (PD-1), as well as impaired proliferative capacity.130,138,139 Furthermore, in PWH with COPD, airway mucosal CD4+ T cell numbers are depleted and poorly responsive to pathogens.130 These findings suggest that dysfunctional CD4+ T cell responses may uniquely contribute to COPD pathogenesis in PWH.

Activated and dysfunctional CD8+ T cells also appear to contribute to the disordered adaptive immune response in chronic HIV infection, and thus could contribute to COPD pathogenesis.138,139 PWH show persistent expansion of CD8+ T cells in blood and alveolar compartments, and the decreased CD4+/CD8+ ratio is associated with lung abnormalities even in PWH on ART.140,141 These expanded CD8+ T cell populations also show dysfunction, which is typically indicative of an accelerated aging or “immunosenescent” response. Like CD4+ T cells, CD8+ T cells display exhaustion markers, including PD-1, and a low proliferative capacity.138,139 The expanded population skews towards memory T cell and terminally differentiated CD8+ T cell populations unable to respond to new insults. Despite their impaired function, these exhausted T-cells produce a low-grade inflammatory response at mucosal surfaces, which is considered central to COPD pathology.

Changes to the Airway Epithelium

Alterations to the airway epithelium, the main barrier protecting the lungs from outside insults, such as cigarette smoke, air pollution, and inhaled toxins, can also play a major role in COPD pathogenesis. HIV has both direct and indirect effects on the airway epithelium, contributing to disordered barrier function, decreased mucociliary clearance, and generation of pro-inflammatory mediators. For example, HIV enters epithelial cells and disrupts cell–cell adhesion.129 HIV-associated proteins released from other infected cells disrupt epithelial tight junctions and induce oxidative stress.142 HIV and cigarette smoke synergistically disrupt mucociliary clearance, additively suppressing CFTR expression to decrease mucus hydration in cell culture models and inducing goblet cell metaplasia/hyperplasia to increase mucus production in simian models.143,144 Finally, when HIV binds specifically to basal cells, epithelial progenitor cells release proteases such as MMP-9 and pro-inflammatory mediators that induce migration and proliferation of macrophages and neutrophils.145

Changes in the Lung and Gut Microbiome

Lastly, shifts in both the lung and the gut microbiome can also contribute to chronic inflammatory responses in the lung and, hence, COPD pathogenesis. Data are conflicting on whether lung microbial communities differ in PWH based on 16S sequencing.146–148 However, subtle differences in the microbiome at the species or strain level or at a functional level cannot be discerned via these sequencing methods. It is plausible that at least a subset of PWH experience pathologic microbial alterations in the airways because of a more hospitable environment for pathogen growth. If present in PWH, microbiome perturbations could contribute to chronic airway inflammation. Furthermore, microbial translocation from a compromised gut mucosa, stimulating a chronic systemic inflammatory response, may contribute to lung disease in PWH as has been seen in asthma and pulmonary infections.149

Diagnosis and Clinical Findings of COPD in PWH

Screening and Diagnosis

COPD remains both underdiagnosed and misdiagnosed in people with HIV.150,151 While currently the US Preventative Services Task Force does not recommend screening for COPD in the general population,152 higher COPD prevalence among PWH raises the question whether screening should be done in this subpopulation. Currently, there are no screening and diagnostic criteria specific to PWH. While several studies have evaluated different screening approaches, no conclusive recommendations can be made regarding COPD screening and diagnosis in PWH at this time.150,153–156 For example, a group in Canada offered screening spirometry to all patients in an HIV clinic;156 notably, less than a third of the invited participants agreed to participate, and only 11% had airflow obstruction.

Recruitment and retention throughout the screening-to-diagnosis cascade have been major challenges in all studies. For example, a group in Italy implemented a three-step case-finding program, involving a 5-question screening questionnaire (which included questions about age, smoking history, cough and sputum production, shortness of breath, and exercise limitation), portable spirometry, and diagnostic spirometry.150 They found that 282 participants (19.6%) had a positive screening questionnaire, defined as having a positive answer to at least three questions, but only 33 participants ultimately completed diagnostic spirometry, of whom 22 met criteria for COPD. High participant dropout at each step of the screening process has been similarly reported elsewhere,153–155 even when the authors bypassed the screening spirometry and had a shorter questionnaire.155 Even within these limitations, COPD prevalence based on the screening outcomes has been consistently higher than the known COPD prevalence in each respective clinic,154 further underscoring the underappreciated burden of chronic lung disease in this population. Additional challenges with screening this high-risk population include lack of a high-performing, validated screening questionnaire in PWH and poor correlation between respiratory symptoms and obstruction on pulmonary function tests (PFTs).155 To our knowledge, qualitative studies focused on identifying patient, provider, or systems-level issues contributing to high dropout rates in screening studies among PWH have not been conducted. Having diagnostic spirometry available at the time of a positive screening questionnaire may help reduce high dropout rates.

Any PWH suspected of having COPD should undergo diagnostic testing with, at a minimum, portable spirometry and, in our opinion, full PFTs with pre- and post-bronchodilator spirometry, total lung capacity and lung volumes if spirometry is abnormal, and DLco measurement. Chest radiography demonstrates classic findings (Figure 2) mostly in individuals with advanced disease but is useful in ruling out alternative etiologies that also present with respiratory symptoms similar to those of COPD. Occasionally, additional testing such as chest computed tomography (CT) scans may be warranted to characterize the observed PFT abnormalities, and certain CT findings such as the presence of large bulla (Figure 3) may lead to consideration of additional therapies (eg, bullectomy).

Figure 2 Chest radiograph from person with HIV and COPD demonstrating hyperinflation, flattened diaphragms, and bilateral bullous lung disease (Courtesy of Laurence Huang, MD).

Figure 3 Chest computed tomography from the same person with HIV and COPD demonstrating large, bilateral bullae. This individual eventually underwent bullectomy with dramatic improvement in his respiratory status (Courtesy of Laurence Huang, MD).

Longitudinal Lung Function Trajectories of COPD in PWH

While there is a paucity of data on the natural history of COPD in PWH, lung function declines faster in PWH compared to HIV-negative controls, even when HIV is well-controlled and smoking rates are comparable.6,7,157 Notably, findings from the Pittsburgh HIV Lung Cohort suggested that there may be distinct lung function trajectories among PWH, in which differences in the rate of decline are associated with specific symptoms and distinct profiles of elevated immune activation biomarkers.26 Importantly, this study did not exclusively enroll individuals with COPD. In the general population, COPD studies have shown that lung function decline accelerates as COPD severity increases,158 but whether similar trajectories are seen in PWH is an area currently under study. In a study evaluating factors associated with lung function decline among PWH by Li et al, the authors found that lung function decline occurred more rapidly in older individuals and those with GOLD stage 1 than those with GOLD stage 0 COPD.126 Taken together, these studies suggest that PWH with COPD may demonstrate distinct lung function trajectories when compared to their seronegative counterparts, although additional study is needed in this area.

Lung Function Trajectories in People with Perinatally Acquired HIV

While this review is focused on COPD in adults with HIV, the growing number of individuals with perinatally acquired HIV and their lung function trajectory should also be considered. Children and adolescents with HIV have a higher risk of pulmonary infections, including TB, and even with early ART initiation they remain more vulnerable to small airways dysfunction and risk of obstructive lung disease and other pulmonary abnormalities on spirometry and imaging.159–166 Even children who were exposed to but not infected with HIV remain at risk for abnormal lung function.167 Further, lung function in children seems to be affected by the timing of maternal ART initiation (pre-pregnancy versus during pregnancy).167 In addition, lung development and the ability to reach maximal lung function is impaired by HIV, repeat infections, smoking, pollution, and poverty, which in turn increases the risk for the development of chronic lung disease in adulthood.168,169 As this vulnerable population ages, we are likely to see an increased burden of chronic obstructive disease earlier in life. As most of our understanding of lung function trajectories in PWH with COPD comes from adult PWH from higher income settings, focused efforts for early screening, diagnosis, and management of this condition are needed in areas with high prevalence of adolescents and adults with perinatally acquired HIV.

Diffusing Capacity for Carbon Monoxide

Abnormal diffusing capacity for carbon monoxide is the most prevalent finding on PFTs in PWH, even when spirometry is normal.29,170 DLco impairment is non-specific and can be attributed to emphysema, fibrosis, pulmonary hypertension, or anemia. In PWH, it is also often associated with prior respiratory infections such as PJP, TB, or bacterial pneumonia, and the DLco abnormality may persist long after clinical and radiographic resolution of infection.89,126 Other risk factors for abnormal DLco include HIV infection, CD4 < 200 cells/mm,3 intravenous drug use, and hepatitis C infection.29,101,170–172

DLco abnormalities can predict the development, symptoms, and outcomes of COPD. Among people who smoke, DLco can become abnormal before spirometric criteria for COPD are met; DLco may also be a marker of early emphysema prior to the development of spirometric obstruction, small airways disease, or early vascular abnormalities.173–175 While there are additional and unique risk factors for abnormal DLco in PWH compared to the general population, perhaps suggestive of an HIV-specific lung function abnormality,10,176 it is also plausible that isolated DLco abnormalities may serve as a marker for early COPD in some patients. Among PWH, abnormal DLco, like abnormal FEV1, is an independent predictor of worse respiratory symptoms (such as dyspnea, cough, and mucus production),170 as well as a worse 6-minute walk test.177,178 Finally, abnormal DLco is an independent predictor of mortality in PWH with COPD.179,180

Imaging Findings in PWH with COPD

New techniques for quantitative imaging assessment have allowed in-depth characterization of imaging abnormalities in people with COPD. As current GOLD criteria define COPD based on chronic respiratory symptoms,2 chest imaging findings such as emphysema describe the structural abnormalities that drive this clinical entity. In the general population of people who smoke, studies have found that evidence of small airways disease and air trapping on imaging could predict COPD development and faster spirometry decline.181,182 Importantly, multiple imaging findings such as early interstitial lung abnormalities,183 pulmonary artery to aorta ratio >1,184 pulmonary arterial vascular pruning,185 progression186 and homogeneity of emphysema,187 airway wall thickness,188,189 and air trapping have all been associated with disease severity and adverse outcomes in COPD.181

Studies in PWH have shown a high prevalence of emphysema even in individuals without overt respiratory disease.190 In addition, Leung et al found that people with low DLco and a combination of centrilobular and paraseptal emphysema were more likely to have progression of emphysema,191 and significant emphysema burden was associated with increased mortality.192 Elevated TNFα and IL-1β, soluble CD14, nadir CD4, and low CD4/CD8 ratio are also independently associated with emphysema in PWH,140,193,194 although reports of a direct association of HIV with emphysema are contradictory.194,195 While the exact mechanisms are an area of active investigation, HIV-mediated chronic inflammation and immune dysregulation likely play an important role in emphysema formation.

Symptoms, Exacerbations, and Mortality

Compared to HIV-negative individuals, PWH with COPD have a higher respiratory symptom burden, worse quality of life, and an increased risk for COPD exacerbations.24,196–202 For example, PWH with emphysema have a worse chronic cough, increased mucus production, and decreased 6-minute walk distance compared to HIV-negative controls.198 In PWH who inject drugs, obstructive lung disease has been associated with more severe dyspnea than in their seronegative counterparts.203 In addition, PWH perform worse on six-minute walk testing.178 While COPD is associated with increased frailty in individuals with and without HIV, physical limitation scores are worse among PWH.204,205 Finally, COPD in PWH is not only often comorbid with cardiovascular disease, but also a risk factor for myocardial infarction206 and has been associated with increased mortality.180,192

Management of COPD in PWH

PWH have historically been excluded from large randomized controlled trials of COPD treatments. Therefore, there are very few HIV-specific data on COPD management, and instead general COPD guidelines for both chronic disease management and COPD exacerbations are applied to PWH.207 These management strategies include guideline-driven inhaler therapy, pulmonary rehabilitation, routine vaccinations, surgical or bronchoscopic lung volume reduction in qualifying patients, and management of other medical comorbidities.2 Here, we will focus on a few HIV-specific considerations.

Smoking Cessation

Given the high smoking prevalence among PWH and the excess morbidity and mortality associated with smoking in this population, smoking cessation remains a fundamental aspect of COPD care in PWH. Unfortunately, prescribing rates for smoking cessation therapies have been low for PWH with tobacco use disorder for many reasons, including competing clinical priorities, lack of time, low rates of provider training in smoking cessation interventions, and limited knowledge of nicotine replacement therapies and varenicline.208,209 In addition, PWH face additional challenges on the path to sustained smoking cessation that are due to HIV-related stigma, high rates of comorbid substance use, anxiety and depression, financial instability, lack of insurance, low level of education, and racial biases.210–213 Tailoring smoking cessation therapies to this population is an active area of research.209,214–226 Increased awareness among HIV care providers of the importance of smoking cessation, financial support for smoking cessation initiatives, and intervention studies inclusive of PWH are needed to identify the best ways to support smokers with HIV on their path to quitting.

Choice of Inhalers

Special attention should be paid in the treatment of COPD to PWH who are taking ritonavir or other boosted ART regimens. Ritonavir and cobicistat block the CYP3A4 isozyme and can increase the concentration of most corticosteroids. As a result, use of inhaled corticosteroids (ICS) in patients on these medications has been reported to cause Cushing’s syndrome.227–230 Beclomethasone is the ICS drug with the best side effect profile and can be used in PWH treated with ritonavir or cobicistat.230 In PWH who are receiving ritonavir or cobicistat, an added consequence is the inability to use any combination medication for COPD that includes an ICS as fluticasone- and budesonide-containing combination inhaler therapies are contraindicated and beclomethasone is only available as a single, standalone inhaler. Given the already elevated risk of pulmonary tuberculosis and other pneumonias in this population, additional caution should be applied when using ICS, as they can increase the risk of lung infections in this already vulnerable population.231,232

Modulation of Chronic Inflammation

While no HIV-specific COPD therapies exist, there is an interest in the role of modulating chronic inflammation to improve lung function and clinical outcomes. For example, in a small double-blind pilot clinical RCT of rosuvastatin taken daily for the management of COPD in PWH, Morris et al showed that after 24 weeks of daily rosuvastatin therapy, FEV1 stabilized and DLco improved significantly.233 Another trial studied the role of weekly azithromycin in HIV-related chronic lung disease, defined as an irreversible obstructive defect with minimal radiographic abnormalities, in children and adolescents.234 While the authors found no improvement in lung function parameters after 72 weeks of treatment, they noted an increased time to and fewer total exacerbations. Furthermore, data in the general population have shown benefit of using angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) in slowing down the progression of emphysema on chest CT in COPD, albeit with no effect on longitudinal lung function on spirometry.235 A randomized controlled trial by MacDonald et al measured pneumoprotein levels as a proxy for lung function decline in PWH with COPD randomized to placebo or losartan treatment, but did not see any significant changes in the pneumoprotein plasma concentrations after 12 months of follow-up.236 Finally, an NHLBI-funded multi-site randomized controlled trial evaluating the influence of twice daily doxycycline on change in DLco among PWH who smoke is currently underway.237 In sum, findings from prior studies suggest that targeting chronic inflammation has the potential to improve lung function of PWH with COPD, but currently there are no definitive data to support any single drug’s use.

Prevention of COPD in PWH

Smoking Cessation

Smoking is perhaps the single most important modifiable risk factor for COPD among PWH. Evidence suggests that PWH may metabolize nicotine more rapidly than HIV-uninfected smokers,238 which could have important implications for the effectiveness of smoking cessation interventions among this population. A growing body of literature is focused on identifying effective smoking cessation interventions among PWH; Table 1 summarizes the randomized controlled trials that have been conducted or have recently completed enrollment on smoking cessation in PWH.218,220,225,226,239–262 For example, O’Cleirigh et al found that among 41 PWH who smoke and reported motivation to quit, those who were randomized to receive cognitive behavioral therapy for smoking cessation and anxiety/depression treatment in addition to nicotine replacement therapy were more likely to quit smoking compared to those who received nicotine replacement therapy alone,225 highlighting the importance of focusing concomitantly on smoking cessation and mental health in this population. A Cochrane review summarizing 14 randomized controlled trials of smoking cessation interventions among PWH in the United States found that pairing behavioral interventions with medications may facilitate short-term abstinence in comparison to medications alone but did not appear to facilitate long-term abstinence.263 Further, a systematic review of smoking cessation interventions among PWH found that successful smoking cessation was most likely when the intervention included cellphone-based technology.264 Although long-term smoking cessation is the goal, any reduction in exposure to tobacco products is likely to have significant health impacts. Using a Monte Carlo microsimulation model, Reddy et al demonstrated that sustained smoking cessation among PWH could result in over 260,000 expected years of life gained.44 This per-person survival gain is more than the life expectancy gained with early ART initiation or improved ART adherence, and among the general population is more than the life expectancy gained by initiating statins for primary cardiovascular disease prevention or clopidogrel for secondary cardiovascular disease prevention. Therefore, encouraging and supporting smoking cessation must remain a priority in the care for PWH.

Table 1 Summary of Randomized Controlled Trials of Smoking Cessation in People with HIV

Air Pollution Mitigation

Interventions aimed at reducing personal air pollution exposure can be categorized into policy-level approaches (regional, national, international) and personal-level approaches. Overall, there is no level of air pollution exposure below which there are no negative health impacts. In fact, evidence suggests that the greatest gains in health per unit reduction in air pollution exposure may occur at the lowest end of the exposure spectrum.265 While attention is being paid to regional and national air quality guidelines, individuals with HIV can adopt behavioral changes that may reduce their personal exposure. Evidence to guide these decisions is still an area of active research. In 2019, Carlsten et al published a summary of 10 key approaches to reduce personal exposure to outdoor and indoor pollution sources, including: using close-fitting face masks when exposure is unavoidable; preferential use of active transport (walking or cycling) rather than motorized transport; choosing travel routes that minimize near-road air pollution exposure; optimizing driving style and vehicle settings when in polluted conditions; moderating outdoor physical activity when and where air pollution levels are high; monitoring air pollution levels to inform when individuals should act to minimize exposure; minimizing exposure to household air pollution by using clean fuels, optimizing household ventilation, and adopting efficient cookstoves where possible; and using portable indoor air cleaners.266 Unfortunately, the data supporting these strategies are not of high quality, which highlights the importance of future work focused on carefully designed studies leveraging implementation science methodology to characterize the feasibility, acceptability, and effectiveness of behavioral interventions focused on improving air pollution-associated lung disease.

Infection Prevention

As pulmonary infections, many of which are preventable, have been implicated in the development of COPD among PWH, infection prevention is important for mitigating COPD risk. First, early ART initiation is imperative, as many pulmonary infections such as PJP are opportunistic infections and develop in the setting of high HIV viral loads and low CD4 counts. Primary prophylaxis for PJP prevention is recommended in PWH with CD4 counts <200 cells/mm3 and considered in those with CD4% <14%.267 Given the high morbidity and mortality associated with pneumococcal infection in PWH, pneumococcal immunization has been recommended in all adults with HIV.268 Consistent with general population recommendations, PWH should also receive annual flu vaccination, as well as the full COVID-19 vaccination series. Given the increased risk of TB disease and its associated mortality among PWH, screening for TB is recommended for all PWH at the time of HIV diagnosis and once a CD4 count ≥200 cells/mm3.269 PWH should be tested annually only if they have a history of a negative test for latent TB infection and are at high-risk for repeated or ongoing exposure to people with active TB disease.269 Among PWH diagnosed with latent TB, TB preventive treatment reduces both mortality and progression to active TB and thus should be offered to all PWH with a positive TB screening test without evidence of active TB disease.269,270

Future Directions

Although progress has been made in understanding the underlying mechanisms of COPD among PWH, significant knowledge gaps remain. For example, there are many cross-sectional studies evaluating the prevalence of COPD among PWH but only limited data on the natural disease course of COPD in PWH and whether it differs from the general population. Additionally, while studies suggest that PWH demonstrate a higher risk of COPD and a higher symptom burden, there are no HIV-specific screening guidelines for COPD in PWH. Further research is also needed on the interplay between risk factors such as mode of HIV transmission, biologic sex, aging, CMV infection, air pollution, and TB, as well as a deeper understanding of the epidemiology, development, and progression of chronic lung disease in PWH. Management strategies designed specifically for PWH with COPD are also warranted. Lastly, while much progress has been made in understanding the mechanistic pathways that render PWH particularly vulnerable to developing COPD, we remain limited in our ability to counteract these pathways and prevent COPD development. These are only a few examples highlighting the multiple avenues for future research, all of which have the potential to substantially improve both our scientific understanding of COPD among PWH and our ability to effectively prevent and treat this deadly, irreversible condition.


COPD is highly prevalent among PWH. With an aging global population of PWH, high rates of cigarette smoking, and air pollution, COPD is a growing health challenge, and improved diagnosis and treatment of COPD in PWH will become increasingly important. Further research is needed to understand the underlying mechanisms driving COPD in PWH, as well as HIV-specific screening and treatment modalities.


Katerina L Byanova and Rebecca Abelman are co-first authors for this study. Dr. Byanova was supported by NIH F32 HL166065. Dr. Abelman was supported by NIH T32 AI060530 and K12 HL143961. Dr. North was supported by NIH K23 HL154863. Dr. Christenson was supported by NIH R01 HL143998, she also reports personal fees from AstraZeneca, Sanofi, Regeneron, GlaxoSmithKline, Amgen, MJH Holdings LLC: Physicians’ Education Resource, Glenmark Pharmaceuticals, and Axon Advisors, outside the submitted work. Dr. Huang was supported by NIH R01 HL128156, R01 HL128156-07S2, and R01 HL143998.


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186. Ash SY, San Jose Estepar R, Fain SB, et al. Relationship between emphysema progression at CT and mortality in ever-smokers: results from the COPDGene and ECLIPSE cohorts. Radiology. 2021;299(1):222–231. doi:10.1148/radiol.2021203531

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190. Leader JK, Crothers K, Huang L, et al. Risk factors associated with quantitative evidence of lung emphysema and fibrosis in an HIV-infected cohort. J Acquir Immune Defic Syndr. 2016;71(4):420–427. doi:10.1097/QAI.0000000000000894

191. Leung JM, Malagoli A, Santoro A, et al. Emphysema distribution and diffusion capacity predict emphysema progression in human immunodeficiency virus infection. PLoS One. 2016;11(11):e0167247. doi:10.1371/journal.pone.0167247

192. Triplette M, Justice A, Attia EF, et al. Markers of chronic obstructive pulmonary disease are associated with mortality in people living with HIV. AIDS. 2018;32(4):487–493. doi:10.1097/QAD.0000000000001701

193. Thudium RF, Ringheim H, Ronit A, et al. Independent associations of tumor necrosis factor-alpha and interleukin-1 beta with radiographic emphysema in people living with HIV. Front Immunol. 2021;12:668113. doi:10.3389/fimmu.2021.668113

194. Attia EF, Akgun KM, Wongtrakool C, et al. Increased risk of radiographic emphysema in HIV is associated with elevated soluble CD14 and nadir CD4. Chest. 2014;146(6):1543–1553. doi:10.1378/chest.14-0543

195. Ronit A, Kristensen T, Hoseth VS, et al. Computed tomography quantification of emphysema in people living with HIV and uninfected controls. Eur Respir J. 2018;52(1):1800296. doi:10.1183/13993003.00296-2018

196. Lambert AA, Kirk GD, Astemborski J, Mehta SH, Wise RA, Drummond MB. HIV infection is associated with increased risk for acute exacerbation of COPD. J Acquir Immune Defic Syndr. 2015;69(1):68–74. doi:10.1097/QAI.0000000000000552

197. Sims Sanyahumbi AE, Hosseinipour MC, Guffey D, et al. HIV-infected Children in Malawi have decreased performance on the 6-minute walk test with preserved cardiac mechanics regardless of antiretroviral treatment status. Pediatr Infect Dis J. 2017;36(7):659–664. doi:10.1097/INF.0000000000001540

198. Triplette M, Attia E, Akgun K, et al. The differential impact of emphysema on respiratory symptoms and 6-minute walk distance in HIV infection. J Acquir Immune Defic Syndr. 2017;74(1):e23–e29. doi:10.1097/QAI.0000000000001133

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241. Gritz ER, Danysh HE, Fletcher FE, et al. Long-term outcomes of a cell phone-delivered intervention for smokers living with HIV/AIDS. Clin Infect Dis. 2013;57(4):608–615. doi:10.1093/cid/cit349

242. Vidrine DJ, Arduino RC, Gritz ER. Impact of a cell phone intervention on mediating mechanisms of smoking cessation in individuals living with HIV/AIDS. Nicotine Tob Res. 2006;8 Suppl 1(1):S103–108. doi:10.1080/14622200601039451

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245. Ingersoll KS, Cropsey KL, Heckman CJ. A test of motivational plus nicotine replacement interventions for HIV positive smokers. AIDS Behav. 2009;13(3):545–554. doi:10.1007/s10461-007-9334-4

246. Lloyd-Richardson EE, Stanton CA, Papandonatos GD, et al. Motivation and patch treatment for HIV+ smokers: a randomized controlled trial. Addiction. 2009;104(11):1891–1900. doi:10.1111/j.1360-0443.2009.02623.x

247. Moadel AB, Bernstein SL, Mermelstein RJ, Arnsten JH, Dolce EH, Shuter J. A randomized controlled trial of a tailored group smoking cessation intervention for HIV-infected smokers. J Acquir Immune Defic Syndr. 2012;61(2):208–215. doi:10.1097/QAI.0b013e3182645679

248. Cropsey KL, Hendricks PS, Jardin B, et al. A pilot study of screening, brief intervention, and referral for treatment (SBIRT) in non-treatment seeking smokers with HIV. Addict Behav. 2013;38(10):2541–2546. doi:10.1016/j.addbeh.2013.05.003

249. Cropsey KL, Jardin BF, Burkholder GA, Clark CB, Raper JL, Saag MS. An algorithm approach to determining smoking cessation treatment for persons living with HIV/AIDS: results of a pilot trial. J Acquir Immune Defic Syndr. 2015;69(3):291–298. doi:10.1097/QAI.0000000000000579

250. Humfleet GL, Hall SM, Delucchi KL, Dilley JW. A randomized clinical trial of smoking cessation treatments provided in HIV clinical care settings. Nicotine Tob Res. 2013;15(8):1436–1445. doi:10.1093/ntr/ntt005

251. Manuel JK, Lum PJ, Hengl NS, Sorensen JL. Smoking cessation interventions with female smokers living with HIV/AIDS: a randomized pilot study of motivational interviewing. AIDS Care. 2013;25(7):820–827. doi:10.1080/09540121.2012.733331

252. Pengpid S, Peltzer K, Puckpinyo A, et al. Screening and concurrent brief intervention of conjoint hazardous or harmful alcohol and tobacco use in hospital out-patients in Thailand: a randomized controlled trial. Subst Abuse Treat Prev Policy. 2015;10(1):22. doi:10.1186/s13011-015-0018-1

253. Mercie P, Arsandaux J, Katlama C, et al. Efficacy and safety of varenicline for smoking cessation in people living with HIV in France (ANRS 144 Inter-ACTIV): a randomised controlled phase 3 clinical trial. Lancet HIV. 2018;5(3):e126–e135. doi:10.1016/S2352-3018(18)30002-X

254. Mussulman LM, Faseru B, Fitzgerald S, Nazir N, Patel V, Richter KP. A randomized, controlled pilot study of warm handoff versus fax referral for hospital-initiated smoking cessation among people living with HIV/AIDS. Addict Behav. 2018;78:205–208. doi:10.1016/j.addbeh.2017.11.035

255. Ashare RL, Thompson M, Serrano K, et al. Placebo-controlled randomized clinical trial testing the efficacy and safety of varenicline for smokers with HIV. Drug Alcohol Depend. 2019;200:26–33. doi:10.1016/j.drugalcdep.2019.03.011

256. Ditre JW, LaRowe LR, Vanable PA, De Vita MJ, Zvolensky MJ. Computer-based personalized feedback intervention for cigarette smoking and prescription analgesic misuse among persons living with HIV (PLWH). Behav Res Ther. 2019;115:83–89. doi:10.1016/j.brat.2018.10.013

257. Gryaznov D, Chammartin F, Stoeckle M, et al. Smartphone app and carbon monoxide self-monitoring support for smoking cessation: a randomized controlled trial nested into the Swiss HIV cohort study. J Acquir Immune Defic Syndr. 2020;85(1):e8–e11. doi:10.1097/QAI.0000000000002396

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CHICAGO -- Chest CT images reveal that cigarette and marijuana smokers are at higher risk of developing emphysema, according to research presented November 28 at the RSNA annual meeting.

In her presentation, Jessie Kang, MD, from Dalhousie University in Halifax, Nova Scotia, Canada, showed findings suggesting that people who combine marijuana and cigarettes are 12 times more likely to develop centrilobular emphysema than non-smokers.

“With our study, we show that there are physical effects of marijuana smoking on the lungs and that cigarette smoking and marijuana smoking may have a combined damaging effect on the lungs,” Kang said in a statement.

While there is clear evidence that cigarette smoking causes harm to the lungs, little is known about smoking marijuana’s effects, as well as the combined effects of smoking both.

Kang also noted that marijuana is the most widely used illicit psychoactive substance in the world. Canada legalized nonmedical marijuana in 2018.

Kang and colleagues investigated the effects of marijuana smoking on the lungs and chest wall by evaluating CT chest images in regular marijuana smokers.

The team included people who have at least a two-year history of marijuana use, including use four times a month, and who have had a chest CT. The group excluded people who use marijuana as edibles or oral drops.

CT images show airway changes in a 66-year-old male marijuana and tobacco smoker with cylindrical bronchiectasis and bronchial wall thickening (arrowheads) in multiple lung lobes in a background of paraseptal and centrilobular emphysema. Image and caption courtesy of the RSNA.CT images show airway changes in a 66-year-old male marijuana and tobacco smoker with cylindrical bronchiectasis and bronchial wall thickening (arrowheads) in multiple lung lobes in a background of paraseptal and centrilobular emphysema. Image and caption courtesy of the RSNA.

The researchers found that the proportion of patients with paraseptal emphysema is higher in the cigarette smoker and combined smoker groups. They also found that marijuana smoking was tied to a five- to seven-times higher risk of developing paraseptal emphysema than nonsmokers.

Additionally, the researchers found that the combined smoking group was 12 times more likely to have centrilobular emphysema than nonsmokers. This is a type of pulmonary emphysema where the air sacs within the lungs are damaged, leading to breathing difficulties and other serious respiratory symptoms.

Finally, the team reported that the combined smoker group had a four times higher risk of developing bronchial wall thickening than nonsmokers. However, it also found no significant association between marijuana smokers and gynecomastia.

Kang said this study addressed misconceptions about smoking marijuana’s health effects on the lungs. However, she also called for more research to study the long-term effects, so that the public can make an informed decision on recreational usage of marijuana.

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Alpha-1 antitrypsin (AAT) is a glycoprotein serine protease inhibitor (coded by the SERPINA1 gene). AAT is mainly synthesized in the liver and released into serum. The main physiological function of AAT is to protect the lung from damage by inhibiting neutrophil elastase but also has anti-inflammatory, immunomodulatory, and anti-infective properties on a wide range of cell types.1,2 The allele coding for the normal AAT protein is designated as M and the homozygous Pi*MM genotype is present in 85–90% of individuals, which leads to the production of serum levels of functional AAT between 90 and 200 mg/dL.3

Alpha-1 antitrypsin deficiency (AATD) is a chronic, autosomal co-dominant hereditary condition characterized by decreased serum AAT levels, which may potentially lead to a loss of pulmonary function, emphysema, and development of liver disease, panniculitis, and vasculitis.4,5 So far, more than 150 mutations of the SERPINA1 gene have been identified, in which 40% of them are responsible for causing AATD.6 The risk for lung disease due to AATD depends on the AAT genotype, the AAT serum levels, and environmental exposures to hazardous agents.4,7 The two most common deficiency mutations are the S and Z alleles, which result in five deficiency genotypes: MS, SS, MZ, SZ, and ZZ.3 The homozygous Pi*ZZ genotype is characterized by a reduction in AAT levels below the protective threshold of 11 µM,8 and predisposes the carriers to develop lung disease (emphysema and premature onset of chronic obstructive pulmonary disease [COPD]) and liver disease (cirrhosis in children and adults, cholestasis, and hepatocarcinoma).9 The remaining deficient AAT genotypes are grouped as rare variants, such as Pi*I and Pi*M malton, and null variants, in which no serum AAT levels are detected.10

Clinical practice guidelines recommend that all symptomatic patients with COPD, emphysema, or asthma with airflow obstruction and relatives of someone with AATD or COPD should undergo specific testing for AATD.4,5,11,12 However, AATD is still a highly underdiagnosed disorder, with less than 10% of patients diagnosed.3 This is often due to the fact that a confirmatory testing needs to be conducted in specialized centers.13,14 Early identification of patients with AATD is recommended because delayed diagnosis worsens clinical status, including COPD-related symptoms.15

Overall, it is estimated that 3.4 million individuals worldwide have one of the deficient allele combinations. When reviewing the epidemiology of the disease, AATD frequency varies markedly among countries worldwide. Specifically, the mean prevalence of Pi*ZZ genotype in Europe is 1 in 35,702, being higher in north-western countries and decreasing gradually from west to east, and in America, the Pi*ZZ prevalence is 1 in 26,002 patients.3 Therefore, there are approximately 74,000 individuals in the European countries and 44,000 in North America with severe AATD of the Pi*ZZ genotype.3 In addition, differences in the risk for developing AATD have been reported depending on the ethnic of the individuals.2 Of note is that mutations rarely described in European patients may be predominantly detected in other countries.16 In some regions of the Mediterranean area, such as southern Italy and central Tunisia, the frequency of rare variant PI*M malton has been described over Pi*Z.16,17

In Turkey, there are limited data on the frequency of AATD and the presence of rare variants.18,19 Considering that prevalence data may differ greatly among countries, regions, and ethnicities, targeted screening programs are needed in countries such as Turkey to identify carriers of AATD variants. Therefore, the aims of the study were to identify AATD as a genetic underlying cause of lung disease in patients with COPD, bronchiectasis, or asthma and to report the frequency of AATD alleles in Turkey.

Materials and Methods

This was a non-interventional, multicenter, prospective study conducted at eight sites in Turkey between October 2021 and June 2022. The study was based on analysis of clinical data obtained under standard clinical practice conditions and enrolled patients with documented COPD or other reasons for AATD testing, such as a relative in whom AATD has been diagnosed.


Patients were selected on the basis of the following inclusion criteria: male or female adult (≥18) of any ethnic origin with documented respiratory symptoms, ie, COPD, bronchiectasis, or asthma, or another reason for wanting to exclude or confirm AATD (for example, liver symptoms or AATD in family members), and willingness to participate in the study. Patients were excluded if they had been previously tested for AATD. Screening of COPD patients in search of AATD was carried out following the ATS-ERS AATD Guidelines.4,5

The protocol was reviewed and approved by the independent ethics committee from the Aydin Adnan Menderes University Medical Faculty and submitted to the national regulatory health authorities (approval number E-66175679-514.05.04–443436) prior to patient enrollment. All patients signed a written informed consent form before the study was initiated, and all study procedures were compliant with the ICH standards for Good Clinical Practice (GCP). The study was conducted in full conformance with applicable local and national laws and regulations and the Declaration of Helsinki.


At screening, demographic and clinical characteristics of patients were recorded (age, sex, ethnicity, and family members with known AATD or COPD), liver disease history (neonatal hepatitis, or a diagnosis with any liver disease), diagnosis of pulmonary disease (COPD, emphysema, bronchiectasis, or asthma), pulmonary function tests (forced expiratory volume in 1 sec % [FEV1], forced vital capacity [FVC], FEV1/FVC), smoking history, respiratory symptoms (chronic cough, sputum production, or shortness of breath), number of COPD exacerbations during the last year, and the number hospitalizations due to exacerbations during the last 2 years. Data from patients were collected on a case report form (CRF).

AAT levels were measured by nephelometry.20 AAT levels should not be measured when patients have an infection since AAT levels would be increased as an acute-phase reaction. Adverse events (AEs) were recorded during the study visit including up to at least 30 minutes after the collection of blood samples. This study was conducted with an in vitro device with no direct contact with the patient except for the blood draw.

Genotyping Test

Whole blood samples were collected as dried blood spots (DBS) by finger stick capillary blood on filter paper for AATD genotyping testing. The diagnostic test also allowed sampling from oral mucosa with a buccal swab. However, that procedure was not approved by health authorities when the study was conducted. Genomic DNA was extracted from whole-blood sample and the allele-specific genotyping was carried out with the validated A1AT Genotyping Test (Progenika, a Grifols company, Derio, Spain). This was a qualitative, PCR, and hybridization-based in vitro diagnostic test (FDA cleared, and CE marked). It relies on allele-specific probes attached to color-coded microspheres, which hybridize specifically to the labelled PCR products. A subsequent fluorescent labelling step allows detection and quantification of the hybridization signal with the Luminex 200TM (Diasorin, Saluggia, Italy) instrument for the simultaneous detection and identification of 14 allelic variants and their associated alleles found in the AAT codifying gene SERPINA1: PI*F, PI*I, PI*S, PI*Z, PI*M procida, PI*M malton, PI*S iiyama, PI*Q0 granite falls, PI*Q0 west, PI*Q0 bellingham, PI*P lowell, PI*Q0 mattawa, PI*Q0 clayton, and PI*M heerlen. The absence of any of the 14 alleles included in the analysis was interpreted, with over 99% of probability, as an M/M genotype.

The AAT allelic variant genotypes and associated allele results, when used in conjunction with clinical findings and other laboratory tests, are intended as an aid in the diagnosis of individuals with AATD.

Statistical Analysis

A sample size of approximately 1000 patients was planned anticipating 10% AATD gene carriers and between three and five cases of severe AATD in that population.3,21 Continuous variables were summarized using the following standard descriptive statistics: number of observations, mean, standard deviation, or median and minimum and maximum ranges, as applicable. Categorical data are described using absolute and relative frequencies. All patients with genotyping analysis results were analyzed. Statistical analysis was descriptive by calculating the different percentages to obtain the frequencies of each AATD genotype. No inferential statistical analysis was conducted.


Study Patients’ Characteristics and Disease Activity

A total of 1090 patients were enrolled during the study period. Two of them (0.18%) did not meet eligibility criteria and were excluded from the analysis. Baseline patient characteristics were available for a total of 1087 patients. The majority were male (85.6%), with a mean age of 61.7 years, and current smokers (32.2%). Patients were diagnosed with COPD (92.7%), bronchiectasis (20.7%) or asthma (19.2%). Some patients had overlapping diagnoses with two or more conditions. The most frequent respiratory symptoms were shortness of breath in 855 (78.7%), sputum production in 683 (68.2%) and chronic cough in 628 (57.8%) patients (Table 1).

Table 1 Demographic and Clinical Data of Assessable Patients Included in the Study. Data Were Available for n=1087 Patients

When patients were stratified by the presence or absence of AATD mutation, no relevant differences between groups were observed in respirometry, smoking habits, or workplace exposure to dust, fumes, or gases. Likewise, no differences were observed in the percentage of patients diagnosed with COPD or emphysema. Liver disease was slightly more common in the group containing AATD mutation than in the non-AATD group (5.9% vs 2.1%). In the AATD group, 35% of the patients had exacerbations in the last year, compared with the 47% in the non-AATD group, although the mean number of exacerbations was the same (Table 1).

AAT serum levels were available for 168 (15%) of patients, with a mean (range) of 1.78 (0.2–20.1) g/L. As expected, AAT serum levels in AATD patients were lower (1 [0.2–1.94] g/L) than in patients without AATD (1.8 [1.3–20.1] g/L).

No adverse events (AEs) or any other safety signal were reported. This was an in vitro device with no direct contact of the device with the patient and no patient contact except for the blood draw.

AATD Genotyping results

The distribution of mutations is shown in Figure 1. Overall, there were 1037 patients (95%) carrying no mutations and 51 (5%) patients with a AATD mutation of any type. Of the patients with mutations, 15 (29.4%) showed the well-known mutations S or Z, whereas 36 patients (70.6%) carried rare alleles (Pi*M malton, Pi*I, Pi*P lowell, Pi*M heerlen, and Pi*S iiyama). The most frequent combinations reported were Pi*M/Z (n=12, 24%), followed by Pi*M/M malton (n=11, 22%). The percentage of patients carrying two deficiency alleles, was 19.6% (n=10 patients): two of them with Pi*Z/Z genotype, seven had a severe deficiency associated with the M malton allele (Pi*M malton/M malton and Pi*Z/M malton), and one had the genotype Pi*Z/M Heerlen (Figure 1).

Figure 1 Distribution of AATD mutations in the study cohort. Data are expressed as absolute values with percentages in parenthesis: the first percentage is referred to the total number of patients with mutations (n=51 patients); the second percentage is referred to the total number of patients in the study cohort (n=1088 patients).

Eighteen (35.3%) patients presented with the Pi*Z mutation. Most of them were former or current smokers (n=17) and had COPD (n=16). Moreover, evidence of advanced COPD (post-bronchodilator FEV1 of 60% or lower) was reported in 10 patients, with the following genotypes: Pi*Z/Z (n=2), Pi*Z/M malton (n=2), Pi*Z/M heerlen (n=1), and Pi*M/Z (n=5).

Rare Genotypes

In this study, AATD mutation Pi*M malton was observed in 18 patients (35.3% of the total mutations), achieving the same frequency as the Z allele. Of those patients with one or two M malton alleles, 11 (61%) had the diagnosis COPD, and all of them were former or current smokers. Three patients with genotypes Pi*M malton/M malton (n=2) and Pi*Z/M malton (n=1) had a post-bronchodilator FEV1 below 30%, indicating severe COPD and emphysema. Six patients were diagnosed with the M malton mutation without having major respiratory symptoms, and one patient was diagnosed with the severe genotype Pi*M malton/M malton who suffered from COPD and was a relative of an individual with AATD.

The heterozygous genotypes P*M/I and P*M/P lowell were identified in eight (16%) and seven (14%) patients, respectively. All of them were current or former smokers who suffered from COPD. The Pi*M heerlen mutation was detected in two (4%) patients. One had the combination with the Z allele (Pi*Z/M heerlen) and had severe AATD. The other was heterozygous with one normal allele (Pi*M/M heerlen). Both patients were former smokers and suffered from severe COPD (FEV1 of 36% and 22%, respectively) with AAT serum levels of 0.44 g/L and 1.03 g/L, respectively. The heterozygous genotypes Pi*M/S and Pi*M/S iiyama corresponded to former smokers with advanced COPD (post-bronchodilator FEV1% of 44%) and emphysema.

The geographic distribution of AATD alleles in Turkey is shown in Figure 2. Geographic data were available for 46 out of 51 patients (90.2%). Most of the AATD mutations (n=24, 52%) were documented in the Eastern Black Sea region of Turkey, whereas in the south (Mediterranean region), no AATD mutations were reported. Of note is that many of the patients diagnosed with an M malton allele came from the Black Sea region (Rize, n=8) and Eastern Anatolia (Erzurum, n=2).

Figure 2 Geographic distribution of AATD mutations among the seven geographical regions of Turkey: Black Sea, Marmara, Aegean, Central Anatolia, Eastern Anatolia, Southeastern Anatolia and Mediterranean. Out of n=51 patients with AATD mutations, data about their geographic origin was available for n=46 patients. Map obtained from

AAT Levels in Patients with AATD Mutation

AAT serum levels were available in 11 (21.1%) patients with AATD mutation and varied according to the mutation. The highest AAT level (1.94 g/L) corresponded to a patient with the Pi*M/I genotype and a FEV1 of 82%, whereas the lowest AAT level (0.21 g/L) was associated with a patient with two deficiency alleles, Pi*Z/M malton and a FEV1 of 60% (Table 2).

Table 2 Alpha-1 Antitrypsin (AAT) Serum Levels (g/L) and Clinical Phenotype Based on Each Genotype in Patients with AATD. AAT Levels Were Available for n=11 (21.6%) Patients with AATD Mutations


This prospective study conducted under standard clinical practice conditions described the frequency of each AATD genotype in a selected sample population of Turkish individuals with pulmonary disease. Specifically, this study was designed to identify patients who were previously diagnosed with COPD, bronchiectasis, or asthma that have a mutation in the SERPINA1 gene, a potential underlying genetic cause of lung disease.

Despite knowing that early diagnosis could help manage patients with AATD, this condition remains widely underdiagnosed.4,11 The present study evidenced that AATD was detected in 5% of patients with COPD, bronchiectasis, and asthma. Interestingly, this percentage was similar to two recent studies, which reported genetic AAT mutations in 7.1% and 3.5% of Turkish patients with COPD.18,19 Similarly, these results were aligned with previous studies that evaluated AATD distribution in patients with other pulmonary diseases,22,23 and reinforced the utility of routine screening for AATD in these patients. The percentage of male patients in our study (85.6%) was unusually high when compared with the COPD and AATD series from other countries, but it was similar to values reported in other Turkish studies (80.6%, 90.5%).18,19 It is possible that cultural reasons in Turkey keep women more hesitant to consult a doctor regarding pulmonary and other diseases.24

Family members of patients with AATD are expected to have more AATD mutations, and a targeted approach for this subgroup usually yields a higher AATD detection rate.25 We identified seven AATD patients with a family history of AATD, six of whom had no respiratory symptoms. This result emphasizes the importance of early testing for AATD in adults with first-degree relatives with severe AATD, regardless of respiratory symptoms, as an important test targeting strategy. Altogether, more extensive screening for AATD could prevent certain clinical consequences by allowing patients to receive early therapeutic intervention or at least smoking prevention or cessation counseling.

The prevalence of AATD mutations in European countries has been extensively evaluated, but there is limited evidence in Turkey. In Finland, the allele frequencies were 19.7 per 1000 habitants for Pi*Z and 10.2 cases per 1000 habitants for Pi*S.26 Similarly, Poland reported a frequency of 17.5 per 1000 for the Pi*S allele and 10.5 per 1000 habitants for the Pi*Z allele.27 The highest frequency of the S allele was observed in the Iberian Peninsula (100–200 cases per 1000 habitants).28

In the present study, we observed a considerably lower frequency for the Pi*S genotype (0.09%) compared with these studies. These differences between geographic areas are to be expected since the distribution of Pi*Z and Pi*S alleles is different among countries and even within different regions of the same country.28 Interestingly, the proportions of the Pi*Z and Pi*S mutations in our Turkish population (35.3% and 2%, respectively) were consistent with the percentages obtained in a feasibility study of the A1AT genotyping test that evaluated the percentage of these mutations in Turkey (36.4% and 5%, respectively).29

The use of AATD genotyping testing is also useful to analyze the most prevalent rare variants in each region. In Turkey, we identified a total of 36 patients who carried rare alleles (Pi*M malton, Pi*I, Pi*P lowell, Pi*M heerlen, and Pi*S iiyama). This high frequency of rare alleles has been previously detected in other countries, evidencing that the so-called rare AATD alleles may not be as rare as expected.10 In Italian patients with AATD, the prevalence of rare AAT genotypes was 11%.17 Similarly, in Switzerland, rare AAT alleles represented 7%,30 and in Japan, the most common deficient variant is the PI*S iiyama, a rare variant present in most patients with AATD.31

Regarding the worldwide geographic distribution of AATD, the highest frequency of Pi*ZZ is located in the Atlantic region of Europe. Then, it decreases gradually from west to east, and in the most remote regions of the south of the continent, until it almost disappears in Asia.28,32 Here, we observed a similar geographic distribution in the frequency of AATD variants since a higher percentage of mutations was observed in the north and decreasing gradually to the south of Turkey.

This study revealed the high frequency of rare AAT variants in Turkey, especially the Pi*M malton, being the most frequent mutation detected. Thirty-five percent of all AATD mutations were associated with the Pi*M malton rare allele, which has the same frequency as the most prevalent mutation (Z allele) in other regions. This finding is in agreement with previous research in which the rare variant Pi*M malton prevails over Z and S alleles in particular regions of the Mediterranean area, such as southern Italy,17 central Tunisia, and North Africa.16,33 Human migrations, commercial purposes, and ethnic relationships between these countries have been proposed to be responsible for spreading rare AATD variants in these regions.16,19,33 The Pi*M malton mutations and other rare AATD variants seem to be widespread in regions in which the frequency of Pi*ZZ is lower.16,17 In the current study, the geographic distribution of patients carrying the rare AATD variant Pi*M malton were mainly located in the Black Sea region in northern Turkey. More importantly, individuals with the Pi*M malton may develop pulmonary emphysema and polymeric intrahepatic inclusions like in AATD patients with Pi*ZZ genotype.10 Indeed, it has been shown that rare AATD mutations could be identified in up to 17% of clinical cases.34 In the present study, most of the reported Pi*M malton cases presented with pulmonary emphysema. Since rare AATD variants remain unexplored in many regions worldwide, targeted screening programs could be recommended even in countries in which a high prevalence of the disease has been reported.

One of the potential benefits of conducting extensive AATD genetic testing is to consider providing early lifestyle interventions, such as smoking prevention, and to prevent delayed introduction of augmentation therapy to preserve lung parenchyma in patients with emphysema. The S iiyama allele is another extremely rare variant mainly identified among Japanese patients that has very rarely been found outside of Japan.31 It was found in the study cohort in a heterozygous Pi*M/S iiyama variant patient who was a former smoker with advanced COPD. Altogether, more than 150 mutations of the SERPINA-1 gene have been described in the literature,34 and new mutations are currently being identified.35 Evidence is emerging that rare AATD mutations may play an important role in Turkey. For example, Pi*M malton was found to have the same frequency as Pi*Z and lead to comparable clinical symptoms.

AATD is characterized by a diverse clinical expression and prognosis. Augmentation therapy with AAT is indicated for patients with severe AATD, in which serum AAT levels are below the protective threshold of 11 µM (or 0.5 g/L),4 and who have evidence of advanced lung disease. Early identification of those patients with extremely low AAT levels is paramount since they are more prone to developing COPD and emphysema.8,36 In our analysis, only three patients were documented to have AAT serum levels below the protective threshold: 0.33 g/L (Pi*ZZ genotype), 0.21 g/L (Pi*Z/M malton) and 0.44 g/L (Pi*Z/M heerlen). AAT serum levels were not routinely available in the study centers. It would be important to better establish AAT serum-level testing in Turkey for the future.

One of the limitations of this study is that the real AATD prevalence was overestimated since this was a highly selected population in which patients with family members known to have AATD disease were included. This could have increased the probability of identifying a patient with AATD. AATD prevalence in a whole-population-based study is usually lower compared to a study conducted in a targeted population.37 Additional limitations are that AAT serum levels were only available for a small number of patients because it was not routinely collected and that female patients were underrepresented. The inclusion of these patients would have strengthened the generalizability of the study results.


In conclusion, our results confirm AATD as a genetic underlying cause of lung disease and determine the frequencies of different AATD alleles in a selected population of Turkish individuals.

Data Sharing Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.


Eugenio Rosado, PhD, and Jordi Bozzo, PhD CMPP (Grifols), are acknowledged for medical writing and editorial support in the preparation of this manuscript. The authors wish to thank all the patients who contributed to this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas and took part in drafting, revising, or critically reviewing the article. MP: conceptualization, study design, methodology, resources, data acquisition, data curation, investigation, writing – review and editing. STO, SA, NS, MÇ, DK, AŞ, BPY, NK, SAB, and SKC: study design, methodology, resources, data acquisition, data curation, validation, investigation, writing – review and editing. AN and BD: conceptualization, formal analysis, project administration, supervision, validation, visualization, writing – review and editing. All authors critically revised, edited, agreed, and approved the final version of the article before submission, and during the revision, of the manuscript. Authors agreed in the journal to which the article is submitted, take responsibility, and are accountable for the contents of the article.


This study was funded by Grifols, manufacturer of A1AT Genotyping Test and plasma-derived alpha-1 antitrypsin medicinal products.


AN and BD are full-time employees of Grifols. DK reports honoraria paid to her institution, as speaker, from AstraZeneca, Abdi İbrahim, Novartis and Grifols, outside the submitted work. The remaining authors have no conflicts of interest to declare for this work.


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Chronic obstructive pulmonary disease awareness month: Welcome back to “The Science Of Health”, ABP Live’s weekly science column. Last week, we explained how climate change and air pollution affect cardiovascular health, which communities are most vulnerable to the impacts of climate change, and what must be done to reduce the risk of heart diseases occurring as a result of climate change. This week, we discuss the latest advancements in the treatment of chronic obstructive pulmonary disease (COPD), and science advances that can serve as treatments in the future.

COPD is a group of diseases that results in airflow blockage due to damage to the airways or other parts of the lung, making it hard to breathe. COPD is primarily of two types: emphysema and chronic bronchitis. Emphysema involves damage to the lungs over time, while chronic bronchitis involves a long-term cough with mucus. 

Check ABP Live's stories explaining the science behind various health phenomena, and the articles appearing in the weekly health column here.

In emphysema, the air sacs in the lungs are affected. The elastic air sacs become filled with air when one breathes in, like small balloons, and deflate when one breathes out. The walls between many of the air sacs in the lungs become damaged when one suffers from emphysema. As a result, the air sacs lose shape and become floppy. 

Since the walls of the air sacs can also be damaged, there are fewer and larger air sacs instead of many tiny ones, making it harder for the lungs to move oxygen and carbon dioxide out of the body. 

In chronic bronchitis, there is inflammation and irritation of the bronchial tubes, which are airways carrying air to and from the air sacs in the lungs. When the bronchial tubes are irritated, mucus is produced. Due to the swelling of the tubes and mucus formation, the lungs find it hard to move oxygen in and carbon dioxide out of the body. 

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Current treatments for COPD

While there is no cure for COPD, it can be controlled, and one can take steps to ensure that the symptoms do not get worse. Since smoking is the main cause of COPD, people who smoke must quit this habit to slow lung damage. 

According to the US National Institutes of Health (NIH), medicines used to treat COPD are quick-relief drugs that help open the airways, anti-inflammatory drugs to reduce swelling in the airways, control drugs to reduce lung inflammation, and long-term antibiotics. 

When COPD is severe, one may need to receive steroids by mouth or intravenously, oxygen therapy, bronchodilators, and assistance from a machine to help breathing with the help of a mask or through an endotracheal tube. 

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Oxygen therapy may be required if one has a low level of oxygen in the blood.

Pulmonary rehabilitation is a medical programme aimed at making the lives of people with lung diseases better through exercise and education. This helps improve the physical function of patients, and reduces their symptoms. The patients are given exercise training, psychological counselling, and education. 

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Advanced treatments for COPD

Lung volume reduction surgery (LVRS) and bullectomy are some treatment options in which damaged, hyper-inflated, and non-functioning portions of the lungs are removed. This improves lung function because the remaining healthy portion of the lung can work better.

“Treatment options for some patients with severe COPD are lung volume reduction surgery (LVRS) and bullectomy which involves removing damaged, hyperinflated and non-functioning portions of the lung and improving lung function by allowing the remaining healthy lung parts to work better,” Dr Vikas Mittal, Associate Director, Pulmonology, Max Hospital, Shalimar Bagh. told ABP Live.

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Lung transplant

However, if one has advanced COPD, and their conditions keep worsening despite taking all precautions and undergoing all forms of treatment, they should opt for lung transplant.

“Lung transplant involves replacing the lungs affected by COPD with healthy lungs from an appropriate brain-dead donor. Lung transplantation requires meticulous patient selection and is a specialised procedure performed by a team of experts at select centres. It is a costly treatment option and needs long term immunosuppression treatment and follow ups,” said Dr Mittal.

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The reason why immunosuppression is needed is that the immune system may reject the newly replaced lungs.

Lung transplantation is an option people choose when they have end-stage COPD. 

“Lung transplantation offers renewed hope and extended life expectancy for eligible candidates,” Dr Ravi Shekhar Jha, Director & HOD, Pulmonology, Fortis Escorts Hospital, Faridabad, told ABP Live.

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Personalised therapies and targeted biologics

Targeted biologics, which are isolated from a variety of natural sources such as humans, animals, and microorganisms, and personalised therapies are some science advances that may potentially treat COPD in the future. Cutting-edge inhalers may be developed, and drug delivery systems may be enhanced, which improve patients’ prognosis. Respiratory support can be improved through non-invasive ventilation techniques, especially in severe cases.  

“Advanced pharmaceuticals, such as targeted biologics and personalised therapies, aim to mitigate symptoms and halt disease progression. Cutting-edge inhalers and drug delivery systems enhance efficacy and convenience for patients. Additionally, non-invasive ventilation techniques revolutionise respiratory support, particularly in severe cases. These collective advancements represent a transformative era in COPD care, underscoring a commitment to enhancing both longevity and quality of life for individuals affected by this chronic condition,” said Dr Jha.

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Triple drug combinations

Latest advancements in treatment of COPD include triple drug combinations that involve the use of long-acting beta antagonists (LABAs), long-acting muscarinic antagonists (LAMA), and inhaled steroids.

What are LABAs and LAMAs?

LABAs are used in combination with inhaled corticosteroids for the treatment of bronchoconstriction in patients with COPD, chronic bronchitis, and emphysema. Salmeterol, arformoterol, and formoterol are some LABAs approved by the US Food Drug and Administration (FDA). 

LAMAs improve lung function and reduce exacerbations when they are used with inhaled corticosteroids and LABAs, according to a study published in the Annals of Allergy, Asthma, and Immunology.

Tiotropium, umeclidinium, aclidinium, and glycopyrronium are some examples of LAMAs. 

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What are ultra long-acting bronchodilators?

Ultra long-acting bronchodilators are also some advanced treatments for COPD. These are used to provide control, and should only be used with inhaled steroids. They open the airways, and relieve the symptoms of respiratory conditions. 

According to the NIH, indacaterol, vilanterol, and olodaterol are the three ultra long-acting bronchodilators approved for the treatment of COPD. 

LABAs work for six to 12 hours, and ultra-long-acting bronchodilators work for 24 hours. 

These medications not only control COPD symptoms, but also decrease hospitalisation.

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“Latest advancements in the treatment of COPD include triple-drug combinations of long-acting beta antagonists (LABA), long-acting muscarinic antagonists (LAMA), and inhaled steroids.  Ultra-long-acting bronchodilators, such as indacaterol and vilanterol offer prolonged bronchodilation. They can be consumed once a day. These latest treatment options reduce worsening of COPD, decrease hospitalisation, and improve overall quality of life,” said Dr Mittal.

What are long-term macrolide antibiotics and PDE-4 inhibitors?

Long-term macrolide antibiotics can also be used to treat COPD and reduce the frequency of exacerbations in patients with bronchiectasis, a condition in which the bronchial tubes or airways become damaged, as a result of which they widen, and become loose and scarred. 

Phosphodiesterase-4 (PDE-4) inhibitors are used to block the breakdown of cyclic adenosine monophosphate, which is one of the essential agents involved in suppressing inflammatory responses. Therefore, in this way, PDE-4 inhibitors decrease airway inflammation, but have no direct bronchodilator activity. 

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The only PDE-4 inhibitor approved for the treatment of patients with severe COPD is roflumilast, according to the NIH.

“Other newer pharmacotherapy options are long term macrolides antibiotics and phosphodiesterase-4 (PDE-4) inhibitors, such as roflumilast,” said Dr Mittal.

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Combination inhalers

Combination inhalers are a latest advancement in which bronchodilators are used in combination with steroids to reduce airway inflammation. 

“Some combination inhalers combine the medication of short-acting bronchodilators with anticholinergic inhalers or long-acting bronchodilators with anticholinergic inhalers,” Dr Kuldeep Kumar Grover, Head of Critical care and Pulmonology, CK Birla Hospital, Gurugram, told ABP Live.

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Short-acting bronchodilators are used as short-term relief from sudden, unexpected attacks of breathlessness, and long-acting bronchodilators help control breathlessness in asthma and COPD, according to the National Health Service (NHS). 

Long-acting bronchodilators must always be taken with corticosteroids. 

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Salbutamol, levalbuterol, and pirbuterol are examples of short-acting bronchodilators.

Anticholinergic bronchodilators are drugs that block the action of acetylcholine, which is a chemical released by the nerves that can result in the tightening of the bronchial tubes. Therefore, anticholinergic function by blocking acetylcholine.

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Non-invasive ventilation and long-term oxygen therapy

Other advanced techniques to treat chronic respiratory failure in COPD patients include non-invasive ventilation, in which oxygen is delivered to the lungs with the help of positive pressure without the need for endotracheal intubation. At home, an oronasal mask can be used. As a result, the patient does not need to put much effort into breathing.

Patients who have had respiratory failure must undergo long-term oxygen therapy because it is the treatment proven to improve survival in COPD patients. Long-term oxygen therapy should be used for 15 to 16 hours a day, and if possible, 24 hours a day. It raises arterial oxygen levels to a desirable range. Oxygen cylinders and concentrators can be used to give long-term oxygen therapy. 

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“Non-invasive ventilation (NIV) at home has also improved the management of acute worsening and chronic respiratory failure in COPD patients. Domiciliary NIV means providing ventilatory support through an interface like oronasal mask at home. This reduces the work of breathing, thus improving respiratory failure and reducing mortality. Long-term oxygen therapy (LTOT) is the most important treatment for COPD patients who have developed respiratory failure and it aims to improve low blood oxygen levels, improve exercise tolerance, and quality of life and survival. LTOT can be given through stationary and portable oxygen concentrators, and oxygen cylinders,” said Dr Mittal.

Future potential treatments for COPD

Stem cell therapy and gene therapy are potential treatments for COPD. Stem cells collected from a donor or the body of the COPD patient can be used to repair and regenerate damaged lung tissues. This research is currently in the initial stages of clinical trials, and hence, medical practitioners will have to wait for the results of the ongoing trials to know the effectiveness and long-term safety of stem cell therapy in COPD treatment, according to Dr Mittal.

Researchers hope that once the stem cells are injected into the body of the patient, they will become specialised cells, and can help regenerate damaged lung tissue. 

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“Researchers believe stem cells could be used to create new alveolar cells. These are the cells that are responsible for the exchange of air and gases in the lungs. The FDA has approved stem cell therapy for COPD in human clinical trials, but it is not currently available as a treatment. If approved in the future, this type of treatment could be used to regenerate lung tissue and reverse lung damage,” said Dr Grover.

Gene therapy, which is in the preclinical stage, aims to correct genetic defects in COPD patients.

It is believed that gene therapy can be used to incorporate therapeutic genes into COPD patients to reverse the disease, according to Dr Mittal.

Therefore, triple drug combinations, non-invasive ventilation, lung volume reduction surgery, long-term oxygen therapy, and bullectomy are some advanced treatments for COPD, and stem cell therapy and gene therapy are potential treatments for COPD in the future.

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This World COPD Day (Wed 15 November), Chest Heart & Stroke Scotland is spotlighting the challenges faced by Scots living with COPD.

A new report from the charity reveals a quarter of Scots living with long-term chest conditions weren’t referred for rehabilitation, and more than half needed support that they weren’t able to access.

It is unacceptable that so many people living with COPD and other chest conditions are struggling to access essential rehab and support.

Chest Heart & Stroke Scotland (CHSS) Chief Operating Officer Allan Cowie said: “It is unacceptable that so many people living with COPD and other chest conditions are struggling to access essential rehab and support.

“Access to rehab is the first step in the recovery journey for people living with long term conditions to go on to live full lives. Without it, they are often unable to access wider support in the community, compounding the issues of isolation and loneliness that often go alongside these conditions.

“The Scottish Government and NHS Scotland must work together to improve the availability of, and access to pulmonary rehabilitation programmes, and to better understand the provision and uptake across the country in order to support improvement.”

Earlier this year, CHSS and the Right to Rehab Coalition launched the Right to Rehab campaign to ensure access to rehabilitation is recognised as a human right in Scottish law.

CHSS provides a range of advice and support to people with chest conditions including support groups to help them keep fit and well. However, for safety reasons, people may need to have gone through formal NHS rehab before attending these groups.

Ian Baxter, 75, is chairman of the Forfar Airways Group, a peer support group affiliated to Chest Heart & Stroke Scotland supporting those living with COPD and other chest conditions.

Ian Baxter, 75, is chairman of the Forfar Airways Group, a peer support group affiliated to Chest Heart & Stroke Scotland supporting those living with COPD and other chest conditions.

A long-time smoker who finally quit at the age of 60, Ian was diagnosed with COPD in 2004 but had to wait five years before receiving pulmonary rehab. Ian has also been diagnosed with the long-term lung condition bronchiectasis, pleural plaques and asbestosis. In 2009, he helped set up Forfar Airways to provide exercise, activities and support for others with chest conditions.

“I was diagnosed with COPD in 2004. It was a condition I knew nothing about at the time. I didn’t realise I would be living with COPD for a long time and that there were things I could do to make life easier.

“I asked at the time to get pulmonary rehab, but that didn’t happen until 2009. The problem for people with our condition is there’s nothing after rehab. You get two sessions a week for six weeks. It isn’t long enough to make a difference.

“That’s why a support group is so important because it gives people a social side, too. Forfar Airways first met in the local community hospital and there were nine of us. But we quickly grew in numbers and outgrew the room we had. From 2011, we’ve been meeting in the community fire station in Forfar.

“At one point we had more than 40 members, but those numbers fell away after Covid-19. Now we have around 30 members.

“We do desperately need new members, but the gateway into membership of our group is the official NHS pulmonary rehab. That way we know new people are fit to exercise because they have completed pulmonary rehab. We also take those referred by their GP. Non-members can also come and participate, but they must sign a disclosure for safety.

“Being part of the group is really important. People go out of the door feeling happy after being with each other. Loneliness can be a terrible thing, especially when you’re living with a long-term health condition. And we know there’s a high instance of depression in those with chronic health conditions. I was treated for depression because I felt very low after my diagnosis.

“Pulmonary rehab is absolutely essential for people with COPD. But there’s more the NHS could be doing. I didn’t get a CT scan until 2014, 10 years after the COPD diagnosis. I’d been coughing up blood. But the time spent having the scan and speaking to the consultant was the most valuable half-hour I had spent in years.

“The consultant was terrific and explained that as well as COPD, I also had bronchiectasis, pleural plaques and asbestosis. It’s high time that the NHS gave people a CT scan when they’re diagnosed with COPD so they know exactly what’s wrong with their lungs.”

If you're living with COPD and need advice, information and support, contact our Advice Line on freephone 0808 801 0899 or email [email protected] 

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Non‐cystic fibrosis bronchiectasis (NCFB) is a chronic, progressive respiratory disorder, which is characterized by irreversibly and abnormally dilated airways, persistent cough, excessive sputum production and recurrent pulmonary infections.

Non-Cystic Fibrosis Bronchiectasis (NCFB) Treatment Market Size

Global Non-Cystic Fibrosis Bronchiectasis (NCFB) Treatment Market Set to Reach US$ YY Million by 2030

Market Overview

The global non-cystic fibrosis bronchiectasis (NCFB) treatment market achieved a valuation of US$ YY million in 2022, with a projected growth to US$ YY million by 2030, demonstrating a robust CAGR of YY% during the forecast period 2023-2030.

Non‐cystic fibrosis bronchiectasis (NCFB), a chronic respiratory disorder prevalent among the elderly, is characterized by irreversibly dilated airways, persistent cough, excessive sputum production, and recurrent pulmonary infections. While incurable, NCFB can be effectively managed through various treatment modalities, including airway clearance devices, vaccination, macrolides, antibiotics, physiotherapy, pulmonary rehabilitation, and bronchodilators.

Market Scope Metrics

Market Size: 2021-2030

Forecast Period: 2023-2030

Revenue Units: Value (US$ Mn)

Segments Covered: Treatment Type, Route of Administration, and Sales Channel

Regions Covered: North America, Europe, Asia-Pacific, South America, and Middle East & Africa

Largest Region: North America

Fastest Growing Region: Asia-Pacific

Report Insights Covered: The comprehensive report encompasses Competitive Landscape Analysis, Company Profile Analysis, Market Size, Share, Growth, Demand, Recent Developments, Mergers and Acquisitions, New Product Launches, Growth Strategies, Revenue Analysis, Porter’s Analysis, Pricing Analysis, Regulatory Analysis, Supply-Chain Analysis, and Other Key Insights.

For more details on this report - Request for Sample

Non-Cystic Fibrosis Bronchiectasis (NCFB) Treatment Market Dynamics:


The market is driven by increasing regulatory approvals, novel drug launches, and ongoing clinical trials for innovative treatments. Notably, breakthrough therapy designation granted by the U.S. Food and Drug Administration (FDA) for brensocatib and the initiation of Phase 2 clinical trials for ARINA-1 and AP-PA02 signify significant advancements.


Complications associated with treatment drugs, high treatment costs, side effects of physiotherapy, and limited treatment options pose challenges to market growth.

Non-Cystic Fibrosis Bronchiectasis (NCFB) Treatment Market Segment Analysis

The airway clearance segment dominates, constituting approximately 46.2% of the NCFB treatment market share. With no cure for NCFB, airway clearance treatments play a pivotal role in disease management. Increasing demand for airway clearance is evident, driven by rising NCFB prevalence, especially among the elderly.

Global Non-Cystic Fibrosis Bronchiectasis (NCFB) Treatment Market Geographical Analysis

North America, accounting for 39.6% of the market share, is anticipated to retain the largest share. The region boasts a strong presence of major players, active research activities, and increasing FDA approvals, contributing to the launch of novel therapeutics.

Non-Cystic Fibrosis Bronchiectasis (NCFB) Treatment Market Companies

Key players in the NCFB treatment market include Insmed Incorporated, Johari Digital Healthcare Ltd., HMS Medical Systems, Merck & Co., Inc., Baxter International Inc., Ralington Pharma LLP, AdvaCare Pharma, Pfizer Inc., Life Care Systems, and VIVAN Life Sciences.

Related Reports:

Cystic Fibrosis Market

Myelofibrosis Therapeutics Market

Bronchitis Treatment Market

Chronic Bronchitis Treatment Market

Bronchiectasis Drugs Market

Chronic Bronchitis Treatment Market

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Pulmonary rehabilitation programs (PR) are an important part of the comprehensive treatment of patients with chronic obstructive pulmonary disease (COPD). It is a multidisciplinary program involving interventions from doctors, physical therapists, nurses, dietitians, social workers, psychologists, and occupational therapists. PR also yielded favourable effects in other chronic pulmonary diseases, such as interstitial lung diseases, asthma and bronchiectasis, by ameliorating symptoms, increasing physical performance, reducing exacerbations and medical costs, and thereby improving patient quality of life.1–3 However, the response to PR varies individually, as only some of the expected results and even no improvement at all have been observed in the so-called “nonresponders” or “poor responders”. The exact reasons for such variation are poorly understood.4–6

Although several predictors of success of PR have been identified in studies, their application and comparison are often limited because of differences in rehabilitation programs, enrolled patients, duration of programs, and markers of success. In a study by Troosters and coworkers, ventilatory reserve, inspiratory muscle strength and peripheral muscle strength were found to be significant predictors of training success.7 Using multidimensional response profiling, Spruit and coworkers showed that patients in the “very good responder” cluster had a higher number of dyspnoea symptoms, a higher number of hospitalisations in the past 12 months, poorer physical performance, poorer performance and satisfaction scores for problematic activities of daily life, more symptoms of anxiety and depression, poorer health status, and a higher proportion of patients following an inpatient PR program compared with patients in the other three clusters.5 Garrod and coworkers found that patients baseline characteristics were poor predictors of response to PR, and less improvement was detected only in patients with a high Medical Research Council dyspnoea scale (MRC) grade 5.4 Jones and coworkers also showed that sarcopenia did not affect the response to PR.8 Walsh and coworkers recognised lower baseline quadriceps strength as an independent predictor of response to PR, whereas baseline physical activity or dyspnoea grade could not identify responders.9 Furthermore, Tunsupon and coworkers found that physical capacity improved in patients regardless of body composition.10 Moreover, Barberan-Garcia and coworkers reported a negative association between nonanaemic iron deficiency and aerobic capacity before and after endurance training in COPD patients.11

Since PR is sparsely available to patients, the objective of this study is to identify potential clinical, physiological, or biochemical markers associated with the success of PR. Our study will help identify patients who benefit most from PR and possible reasons why the condition of some patients does not improve with PR. One of the most commonly used markers of success in PR, improvement in the 6-minute walk test (6MWT),12 was chosen as the primary marker of success in this study.

Subjects and Methods


We collected data from 192 consecutive patients with chronic pulmonary diseases who enrolled in our inpatient PR program from May 2017 to August 2021. Only COPD patients who completed PR without an exacerbation of the disease during PR that could affect their progress were included in the final analysis (Figure 1). Inclusion criteria include all consecutive patients with COPD who were identified as PR candidates and enrolled in our PR program. All patients with other chronic pulmonary diseases without concomitant COPD, patients with COPD who ended the PR program prematurely or who completed the PR program but had exacerbation of disease during the PR due to which the PR program had to be stopped or modified were excluded from the study.

Figure 1 Patient inclusion flow chart.


We used the improvement in distance walked on the 6MWT to identify baseline clinical, physiological, or biochemical parameters potentially associated with a gain in physical performance during PR. An increase in distance of ≥30 m on the 6MWT is an appropriate marker of success according to the guidelines and other similar studies.13–16 Patients who improved their distance on the 6MWT by ≥30 m after PR were identified as good responders, others were identified as poor responders. Data were collected and analysed retrospectively. All patients signed an informed consent form and agreed to anonymous analysis of their data for study purposes. The study was approved by The National Medical Ethics Committee of the Republic of Slovenia, Ministry of Health of the Republic of Slovenia (approval no. 0120–284/2020/6). Our study fully complies with the Declaration of Helsinki.

We performed our standard 4-week inpatient PR at the University Clinic of Respiratory and Allergic Diseases Golnik. Before and after the PR, the COPD assessment test (CAT), MRC, St. George’s respiratory questionnaire (SGRQ), 6MWT, incremental shuttle walk test (ISWT), endurance shuttle walk test (ESWT), cycle endurance test (CET), cycloergospirometry, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), dynamometry, and assessment of body composition were performed. Laboratory tests and respiratory function tests were performed only before PR.

Our multidisciplinary team includes a physical therapist, doctor, nurse, clinical dietitian, clinical psychologist and social worker. We assessed the physical status of the patients, and the doctor prescribed an appropriate training level according to the initial test before PR. During PR, all physical exercises were performed under the supervision of physical therapists. The program was balanced and included strength and endurance exercises on bicycle, treadmill, and leg press, each alternating 2–3 times per week, muscle electrostimulation twice daily, and daily breathing exercises, balance exercises, stair walking and relaxation exercises. Before PR, a clinical psychologist performed individual talks with patients. Thereafter, patients had group sessions twice a week and individual sessions as needed. The social worker performed individual interviews to identify possible social problems and provided social help as needed. The nurse educated patients about their disease and checked their inhalation therapy techniques. The clinical dietitian measured weight and height to calculate body mass index (BMI). Body composition was determined by bioelectrical impedance (BIA) using Bodystat QuadSCAN 4000 (Bodystat Ltd. Isle of Man, UK).17 Those patients who had lost weight in the past or whose FFMI was below 17 kg/m2 were prescribed nutritional supplements during and after PR. Laboratory data were obtained in our accredited laboratory using standard methods and validated tests.

Statistical Analysis

Data were collected and analysed using Microsoft Excel 2016 (Microsoft Corporation, Washington, USA), GraphPad Prism for Windows (GraphPad Software, California, USA), and R Statistical Software 2020 (R Foundation for Statistical Computing, Vienna, Austria). Normality was assessed using the Shapiro‒Wilk test. Paired data were compared using the paired-t/Wilcoxon signed-rank test as appropriate. Differences between samples were evaluated using the t/Mann–Whitney U-test. A p value of ≤.05 was considered statistically significant. Data in the tables are presented as the mean ± standard deviation (SD) or frequencies and percentages. To account for interrelations between the observed variables that differed significantly between the good and the poor responders, the variables were used in multiple logistic regression model. We also performed backward and forward selection of predictors using full and null models, respectively (R Foundation for Statistical Computing, Vienna, Austria).


Good and Poor Responders Based on 6MWT

Our results showed a beneficial effect of PR in COPD patients based on the 6MWT. Before PR, the distance walked on the 6MWT (342.9 ± 108.8 m; min 110 m, max 600 m) was significantly less (p ≤.0001) than the distance walked after PR (400.1 ± 106 m; min 160 m, max 635 m). Patients improved their distance by 57.2 ± 54.8 m (min −127 m, max 240 m). Overall, 91 patients improved their distance by 30 m or more (good responders), and 30 patients improved their distance by less than 30 m (poor responders). In the good responder group, patients walked a distance of 334.3 ± 112 m (min 110 m, max 600 m) before PR and a distance of 411.9 ± 104 m (min 160 m, max 635 m) after PR on the 6MWT. The distance walked on the 6MWT in the poor responder group was 368.8 ± 95.5 m (min 182 m, max 555 m) before PR and 364.2 ± 105.6 m (min 200 m, max 570 m) after PR. In contrast to the difference walked after PR (p = 0.045), there was no statistically significant difference in the distance walked on the 6MWT between groups before PR (p = 0.133).

Basic Clinical Characteristics and Therapy

A total of 163 (85%) of the 192 patients with chronic pulmonary diseases completed PR, and 121 (63%) patients with COPD completed PR without exacerbations of COPD that could potentially affect the outcome of rehabilitation. Therefore, only these 121 patients were included in the study (Figure 1): 79 (65%) men with a mean age of 65.9 ± 7.1 years and 42 (35%) women with a mean age of 63.9 ± 7.6 years. Twenty-three (19%) patients received long-term oxygen therapy (LTOT), and 43 (36%) patients were prescribed nutritional supplements during rehabilitation. Each patient smoked at least once in the lifetime; 96 (79%) patients were ex-smokers, and 25 (21%) were current/active smokers who smoked 42.9 ± 26.5 packs/year (min 1.25, max 150).

Besides COPD, 93 (77%) patients had at least one other diagnosis. The most common comorbidities included decreased bone mineral density – osteopenia, diagnosed in 42 (35%) patients, and osteoporosis in 54 (45%) patients. Moreover, 53 (44%) patients had arterial hypertension, and 15 (12%) suffered from diabetes. Psychological examination revealed anxiety in 11 (9%) patients, depression in 15 (12%), and combined anxiety and depression disorder in 33 (27%) patients. In addition, 26 (21%) patients lived alone, while others lived with family members or partners.

There were no statistically significant differences between the good responder group and poor responder group in the abovementioned basic clinical parameters as detailed in Table 1.

Table 1 Clinical Characteristics of Patients

During PR, patients received ongoing medical therapy as prescribed by their pulmonologist. Bronchodilators were prescribed to 118 (97%) patients, either long-acting muscarinic antagonists (LAMA) (110 patients; 91%) or beta-2 agonists (118 patients; 97%). Fourteen (12%) patients received dual bronchodilator therapy, 102 (84%) patients received inhaled corticosteroid, and 95 (78%) patients received triple inhaled therapy including inhaled steroids. Thirty-eight (31%) patients received theophylline and 13 (11%) patients received other pulmonary therapy in addition to inhaled therapy (7 (6%) azitromicin, 2 (2%) roflumilast, 1 (1%) mucolytic, 1 (1%) nintedanib, 1 (1%) omalizumab, 1 (1%) montelukast, 2 (2%) metilprednisolone). Combined inhaled therapy was as follows: 4 (3%) patients used only a bronchodilator or LAMA, 14 (12%) used a beta-2 agonist bronchodilator and LAMA, 7 (6%) used an inhaled steroid and a beta-2 agonist bronchodilator, and 95 (78%) patients received triple inhaled therapy with an inhaled steroid, a beta-2-adrenergic agonist, and LAMA. Prescribed medical therapy did not affect the response to PR between groups, either by individual drug class or by combination of inhaled therapy. Detailed data can be found in Table 2.

Table 2 Medical Therapy of Patients Before/During PR

Physiological Characteristics

Pulmonary Function

In terms of patients baseline pulmonary function, the groups of good responders and poor responders differed significantly only in absolute vital capacity (VC) (3230 ± 970 mL and 2837 ± 855 mL, p = 0.048), while VC expressed as % of predicted did not show statistical significance (86 ± 22% and 81 ± 17%, p = 0.269). Other parameters of lung function also did not reach statistical significance, despite the trend towards reduced lung function in the poor responder group, as shown in Table 3.

Table 3 Physiological Characteristics of Patients Evaluated Before PR

Physical Performance

A significant improvement in physical performance during PR was seen in both groups. Nevertheless, in the group of good responders, patients improved in all measured parameters of physical performance, while in the group of poor responders, patients improved only in some parameters, and the improvement was less obvious.

Before PR, no significant differences were detected between groups of good and poor responders, but after PR, the good responders had significantly better results in ESWT (327.5 ± 157.3 s and 304.8 ± 123.6 s, p = 0.013) and exhibited more power in cycloergometry (67.9 ± 26.8 W and 51.5 ± 16.9 W, p = 0.007) as demonstrated in Table 3 and Table 4. Patients’ overall physical performance improved during PR, as presented in Table 5 further demonstrating the beneficial effect of PR in COPD patients.

Table 4 Physiological Characteristics of Patients Evaluated After PR

Table 5 Absolute Effects (Changes/Gains in Tests Before and After) of PR in COPD Patients

Body Composition

The overall body composition of the patients did not change significantly during PR. However, we found some differences between the good responder and poor responder groups in body composition before PR. Good responders had higher body weight (77.4 ± 19.2 kg and 69.5 ± 15.3 kg, p = 0.036), reduced content of water (51 ± 6% and 54 ± 8%, p = 0.042), higher fat content (26.6 ± 9.0 kg and 23.4 ± 8.3 kg, p = 0.049) and higher dry lean mass (11.7 ± 5.2 kg and 9.3 ± 4.3 kg, p = 0.021). Even more differences between groups were observed after PR. In addition to the changes in the abovementioned parameters, patients in the good responder group also had higher BMI (27.2 ± 5.6 kg/m2 and 24.8 ± 5.1 kg/m2, p = 0.025), FFMI (17.8 ± 3.5 kg/m2 and 16.4 ± 3.2 kg/m2, p =0.040) and lean mass (51.4 ± 13.5 kg and 45.2 ± 10.1 kg, p = 0.027) after PR. All data are presented in detail in Tables 3–5.

Laboratory Blood Tests

Detailed data on laboratory blood tests before PR can be found in Table 6. Electrolytes, renal and liver function tests, CRP, NTproBNP, and HbA1c did not differ statistically between the good and poor responder groups. Statistically significant changes were observed only in erythrocyte-related parameters, including increased iron serum concentration (19.65 ± 7.67 µmol/L and 16.79 ± 6.45 µmol/L, p = 0.028), higher number of erythrocytes (4.68 ± 0.47 × 1012/L and 4.48 ± 0.45 × 1012/L, p = 0.017), higher haemoglobin concentration (145.6 ± 13.7 g/L and 139.7 ± 11.6 g/L, p = 0.040) and higher haematocrit level (0.43 ± 0.03 L/L and 0.41 ± 0.03 L/L, p = 0.030) in the group of good responders.

Table 6 Laboratory Tests Measured Before PR

Despite statistical significance, the differences were not clinically important. There were only 3 patients with haemoglobin levels below normal (male 130 g/l, female 120 g/L) in the poor responder group (min 114 g/L, max 123 g/L) and 5 patients (min 99 g/L, max 127 g/L) in the good responder group. The number of erythrocytes (male < 4.5 × 1012/L, female < 3.8 × 1012/L) was diminished in seven patients in the poor responder group and in 17 patients in the good responder group. The haematocrit level was below normal (male < 0.40 L/L, female < 0.36 L/L) in 5 patients in the poor responder group and 10 patients in the good responder group. Low serum iron was detected only in one patient (male/female < 5.8 μmol/L) in the good responder group, who was also the only patient with a decrease in all four blood parameters that were statistically significantly reduced. In the poor responder group, 3 parameters (erythrocytes, haemoglobin and haematocrit) were below normal values in 3 patients compared with 5 patients in the good responder group.

Interrelations Between the Observed Variables

To account for interrelations between the observed variables that differed significantly between the good and the poor responders, the variables were used in a multiple logistic regression model. In the full model, none of the modelled variables was significant in predicting good responder status. The results can be seen in Table 7. We therefore performed backward and forward selection of predictors using full and null models, respectively. The results of best fit of the backward model demonstrated the importance of body fat with p=0.051, iron p=0.054 and erythrocytes with p=0.040 and forward model demonstrated the importance of iron with p = 0.084 and dry lean mass p = 0.047 (Table 8 and Table 9).

Table 7 Multiple Logistic Regression Full Model

Table 8 Multiple Logistic Regression Backward Selection Model

Table 9 Multiple Logistic Regression Forward Selection Model


The strength of our study is the recruitment of consecutive real-life COPD patients who were clinically and not for study purposes identified as candidates for PR and who completed the program without any exacerbation of their disease during PR that could affect the course and outcomes of rehabilitation.

As previously found in other studies, basic clinical characteristics and comorbidities did not influence the success of PR.4,5,7,18,19 In contrast, Crisafulli and coworkers20 reported that osteoporosis was independently associated with worse rehabilitation outcomes, but our study did not confirm this finding. Nevertheless, caution should be taken when comparing the studies because of differences in pulmonary rehabilitation time, place of PR (inpatient/outpatient) and criteria for successful completion of PR.

Our study confirmed that lung function determined before PR was not a good predictor of success, as has been shown in other studies.4,6,14 However, there was a trend revealing a possible association between better VC and improved 6MWT, but statistical significance was observed only in VC expressed in absolute values. Sahin and coworkers21 demonstrated that COPD patients with severe diffusion defects in diffusing capacity for carbon monoxide (DLCO) experienced a better pulmonary rehabilitation outcome in terms of improvement in dyspnoea level, but there was no significant difference between groups in terms of 6MWT as in our study.

Baseline physical performance did not differ between groups of good and poor responders. Similar results have been shown by others, although some studies revealed a correlation when baseline physical performance was combined with factors including dyspnoea and health status.5,18

Body composition evaluated before PR noticeably affected the outcome of PR. Statistically significant differences between good and poor responders were found in body weight, water and fat content, and dry lean mass. BMI showed only a tendency towards statistical significance (p = 0.067), although heavier patients with more fat had greater chances of improving their physical condition after PR. In accordance, most studies found that BMI or obesity had no effect on PR outcomes.8,10,14,22

Since dry lean mass is the total body mass without water and fat, it represents mainly proteins and minerals. Taking into account the high prevalence of osteopenia and osteoporosis in our COPD patients, who consequently have reduced mineral content, dry lean mass is a good indicator of muscle mass in the body. Therefore, it is possible that patients with lower muscle mass respond poorly to PR. However, Jones and coworkers8 reported that sarcopenia defined by the EWGSOP did not affect the response to PR. Moreover, Tunsupon and coworkers10 showed that muscle depletion or obesity had no effect on the percentage of patients achieving the MCID as a measure of quality of life and physical tolerance after PR. In contrast to our study, a distance of 26 m on the 6MWT was used as the threshold to divide patients into groups, and only BMI, FFM and FFMI were analysed.

We speculate that the higher percentage of body water in the group of poor responders could be the result of water retention as a consequence of congestive heart failure, since there is also a trend towards increased NT-proBNP in poor responders (p = 0.056). However, we did not detect important decompensation of congestive heart failure in any patient during PR. Body fat and dry lean mass were also significant predictors in multiple logistic regression analysis.

Scores on the MRC, CAT, and SQRQ questionnaires acquired before PR were not significantly different between the groups of good and poor responders and were not good predictors of success as also found in other studies.5,14 A similar questionnaire to MRC, mMRC, in combination with baseline physical performance based on the 6MWT, yielded success in predicting clinically meaningful changes after PR.18 Moreover, Garrod and coworkers4 demonstrated that patients with MRC grade 5 correlate with less improvement than patients with less severe MRC score grades.

Regarding laboratory tests, the most striking differences between good and poor responders were erythrocyte-related. Anaemia is common in COPD patients.23–25 There is evidence that iron deficiency affects physical activity in COPD patients.26,27 Furthermore, nonanaemic iron deficiency has been associated with poorer physical performance and response to training.11 Our data confirmed that a reduction in erythrocyte-related factors, including the number of erythrocytes, haematocrit, haemoglobin and iron, might be associated with an unsuccessful physical response. Notably, erythrocytes and iron were also significant predictors in multiple logistic regression analysis.

There are several limitations of our study. First, a relatively small number of patients were included in the study due to overall limited number of patients that we can include in our PR and further limitation to COPD patients who concluded PR without exacerbation of the disease. Also, greatly reduced access to PR because of COVID-19 hospital reorganisations in past years contributed in part to reduced cohort size. Furthermore, we could not ignore the fact that in our country only inpatient PR is available and it lasts only 4 weeks, which is shorter than is common in other countries. Nevertheless, even with this shorter program, we showed that most patients improved their physical condition. Another limitation relevant to interpretation is that we selected only one parameter to identify patients with good response in physical gain. However, we believe that the difference in distance gained in 6MWT after PR is a good overall marker of patients’ physical improvement.


Our study revealed that baseline physical status, dyspnoea level, lung function, comorbidities, social status, and smoking status were not good predictors of improvement in physical performance after PR based on the 6MWT in COPD patients. We found that COPD patients with higher body weight, more body fat—but not obese (did not have higher body fat %), higher dry lean mass, higher haemoglobin levels, more erythrocytes, higher haematocrit and higher iron level may benefit more than others. We can conclude that more muscular body composition and a higher ability to transport oxygen from the blood to the muscles may be associated with better physical improvement during PR in COPD patients as measured with the 6MWT. Our results should be confirmed in larger studies and with other PR settings (place of rehabilitation, duration of rehabilitation, etc.). Nevertheless, we suggest that before sarcopenic or anaemic patients are referred to PR, special care should first be taken to address and remedy their condition to maximise their physical gain in PR.


1-min STS, 1 minute sit-to-stand test; 6MWT, 6-minute walk test; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; BFMI, body fat mass index; BMI, body mass index; CAT, COPD assessment test; CET, cycle endurance test; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; DLCO, diffusing capacity for carbon monoxide; eGF, estimated glomerular filtration; ESWT, endurance shuttle walk test; FEV1, forced expiratory volume in 1 second; FFMI, fat-free mass index; gammaGT, gamma-glutamyl transferase; HbA1c, A1c glycosylated haemoglobin; HDL, high-density lipoprotein cholesterol; ISWT, incremental shuttle walk test; LAMA, long-acting muscarinic antagonist; LDL, low-density lipoprotein cholesterol; LTOT, long-term oxygen treatment; MCH, mean cell haemoglobin; MCHC, mean cell haemoglobin concentration; MCID, minimal clinically important difference; MCV, mean cell volume; MEP, maximal expiratory pressure; MIP, maximal inspiratory pressure; MPV, mean platelet volume; MRC, medical research council dyspnoea scale; NTproBNP, N-terminal pro-Brain natriuretic peptide; PR, pulmonary rehabilitation program; RDW, red cell distribution width; SGRQ, St. George’s Respiratory Questionnaire; TIBC, total iron-binding capacity; UIBC, unsaturated iron-binding capacity; VC, vital capacity.

Data Sharing Statement

Original study data supporting the results can be found at corresponding author on request and are available if needed only to the reviewers for review purposes of this article and no other sharing, comparing or publication of our original data is permitted.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.


All authors declare that they have no conflicts of interest in this work.


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Influenza is a flu-like illness caused by the influenza virus with symptoms such as chills, fever, etc. Most people contract the flu by breathing in tiny airborne droplets from the coughs or sneezes of already infected patients.

Global Influenza Therapeutics Market Sees Rapid Advancements in Clinical Trials and Growing Concerns Over Influenza-Related Deaths

Influenza, a prevalent flu-like illness caused by the influenza virus, continues to pose a significant public health concern, with symptoms that include chills, fever, and more. The primary mode of transmission is through tiny airborne droplets from the coughs or sneezes of infected individuals. To combat this ongoing health threat, the Centers for Disease Control and Prevention (CDC) emphasizes the importance of annual flu vaccinations as a preventative measure against serious health risks and potential fatalities.

Annual outbreaks of influenza remain a pressing issue, with many individuals resorting to over-the-counter medications, including anti-viral and anti-microbial drugs, to manage their flu-like symptoms. According to the World Health Organization (WHO), the global influenza attack rate stands at 20% to 30% among children and approximately 10% in adults, leading to a staggering annual death toll ranging from 290,000 to 650,000.

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Influenza Therapeutics Market Dynamics: Drivers & Restraints

Clinical trials play a pivotal role in advancing the development of vaccines that enhance safety and efficacy while minimizing adverse effects. For instance, Mahidol University and the Government Pharmaceutical Organization have initiated phase 3 clinical trials to evaluate the immunogenicity and safety of Tri Fluvac, a seasonal trivalent inactivated split virion influenza vaccine. Notably, the trials began on August 3, 2020, and are expected to conclude on December 31, 2023.

The National Institute of Allergy and Infectious Diseases (NIAID) is also contributing to influenza vaccine research by conducting a phase 1 clinical trial to assess the safety and tolerability of the Mosaic Hexavalent Influenza Vaccine VRC-FLUMOS0116-00-VP (FluMos-v2) in Healthy Adults. This initiative commenced on August 9, 2023, and is scheduled for completion on December 16, 2024.

Nanjing Zenshine Pharmaceuticals has undertaken phase 2 and 3 trials to compare ZX-7101A in Chinese adult patients with uncomplicated influenza, focusing on both safety and efficacy. The study officially began on September 17, 2022, and is slated for completion by June 30, 2024.

Side effects associated with anti-viral drugs for influenza are generally mild and treatable, including symptoms such as nausea and vomiting. However, some anti-viral drugs can lead to bronchospasm and diarrhea, and it's essential to consider the specific safety profiles of these medications. Pregnant women are advised to opt for oral oseltamivir, as other drugs like Baloxavir pose severe complications in pregnancy and breastfeeding due to a lack of safety data. Zanamivir is an approved early flu treatment for individuals aged seven and older.

Influenza Therapeutics Market Segment Analysis

The global influenza therapeutics market segments are categorized based on disease type, therapeutics, route of administration, end-user, and region. Among these segments, vaccines are the most prominent, accounting for approximately 52.3% of the market share. Vaccines offer effective long-term protection against influenza compared to drugs, with mRNA vaccines gaining significance for their precision and rapid action. Leading vaccine manufacturers, including Pfizer and Moderna, are actively working on the development and launch of mRNA vaccines for influenza.

Pfizer Inc. initiated a phase 3 clinical trial in September 2022 to evaluate the efficacy, tolerability, and immunogenicity of quadrivalent modified RNA (modRNA) influenza vaccine. In February 2023, Moderna commenced a phase 3 clinical trial to assess the safety and efficacy of mRNA-1010, a seasonal influenza vaccine candidate.

Global Influenza Therapeutics Market Geographical Share

In 2022, North America secured the lion's share of the global influenza therapeutics market, accounting for approximately 41.2%. This dominance is attributed to the presence of major vaccine manufacturers such as Pfizer and Moderna, coupled with the escalating prevalence of influenza in the United States and Canada. In North America, influenza affects nearly 8% of the population annually, and WHO reports an estimated 650,000 influenza-related deaths worldwide, with over 90% occurring in adults aged at least 65. Canada's annual report on seasonal influenza reveals that during the 2021-2022 season, 16,126 laboratory-confirmed influenza cases were reported out of 751,900 total laboratory tests, with seniors (65 and older) representing nearly 71% of affected individuals.

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Chronic obstructive pulmonary disease (COPD) is a critical disease, characterized by long-term persistent respiratory symptoms such as cough, expectoration, chest tightness, and asthma. In later stages, COPD is often complicated with frequent acute exacerbations (AEs) and chronic respiratory failure, which seriously affect quality of life and lead to a worse prognosis.

The incidence rate and prevalence of COPD are both high, with an increasing trend and heavy disease burden for COPD all over the world, and chronic respiratory diseases have been the third leading cause of death, mostly due to COPD.1 In China, the prevalence rate of COPD can reach 8.6%, and is higher than 13% among people over 40 years old.2,3 Although the disease-associated burden decreased in the past 30 years, COPD remains a critical public health problem in China.4

In recent years, a series of studies have been performed and gratifying results have been obtained for COPD. Its occurrence and development have been delayed to a certain extent; however, although the constantly updated treatment measures help to improve the clinical symptoms and delay disease progression, most COPD patients are still undergoing rapid progression, especially for severe and very severe patients, and AEs are still critical events, causing decreased pulmonary function, increased hospitalizations, and worse prognoses such as death.5–7 Reducing AEs remains a key target for severe and very severe COPD patients.

Inflammation is an important pathogenesis for COPD, and corticosteroids are an important treatment option. However, oral corticosteroids increase mortality in stable COPD patients.8 Therefore, inhalation corticosteroids have garnered increased attention and are widely used. β2-agonist (LABA) and/or muscarinic antagonist (LAMA) and other combinations are important treatment options for COPD. Triple therapy has also been considered to be an effective treatment for severe and very severe COPD to improve pulmonary function.9 However, triple therapy cannot effectively reduce AEs and mortality, and the prognosis may not improve.10,11 New treatments to improve efficacy are urgently required.

Through long-term clinical practice and experience, traditional Chinese medicine (TCM) has proven to have good clinical efficacy and advantages in the treatment of COPD to improve symptoms, reduce AEs, and improve quality of life. However, there is a lack of uniformity on the prescription thereof, and evidence-based studies are insufficient. Consequently, we performed a series of studies of TCM for COPD.

The core TCM pathogenesis is deficiency of vital energy and accumulated damage.12 Deficiency is the root cause, with manifestation of phlegm and blood stasis. For severe and very severe COPD, treatments should focus on strengthening the vital energy (invigorating the lungs and kidneys, supplemented by strengthening the spleen), and assist in reducing phlegm and promoting blood circulation. We, therefore, previously established TCM treatment schemes and prescriptions for different stages and grades of COPD,13 which were then optimized through clinical practice and basic studies. Here, we aimed to formulate a Bu-fei Yi-shen granule (BYG) for the treatment of COPD and conduct a randomized controlled trial to provide critical references for the treatment of severe and very severe COPD.

Patients and Methods

Study Design

We conducted a multicenter, large sample, randomized, double-blind, placebo-controlled clinical trial. A total of 348 stable COPD patients were randomized in a ratio of 1:1 to receive either the BYGs or a placebo. Each of the treatment arms included 174 participants, recruited from 11 subcenters on the Chinese mainland, including the First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, the Third Affiliated Hospital of Henan University of Traditional Chinese Medicine, the First Affiliated Hospital of Guangzhou Medical University, Shaanxi Provincial Hospital of Traditional Chinese Medicine, Peking University People’s Hospital, the Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, the First Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, the Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, and Hebei Hospital of Traditional Chinese Medicine.

The protocol (version 2019. was approved by the Institution Ethics Committee of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine (No. 2019HL-010) and registered on with an ID of NCT03976713. The study was conducted in strict accordance with the reviewed protocol and adhered to the tenets of the Declaration of Helsinki.


Diagnostic Criteria

We enrolled 348 stable COPD patients, diagnosed according to the following criteria:

(1) Referring to the 2019 edition of the Global Initiative for COPD (GOLD)14 and Chinese Experts’ Consensus on Diagnosis and Treatment of AECOPD (2017 update),15 we diagnosed patients with COPD when there was a history of exposure to risk factors such as smoking and dust harmful gases, characterized by long-term cough and expectoration and excluding other diseases that can cause similar symptoms. The presence of clear airflow restriction shown by pulmonary function examination after inhalation of bronchodilators was a necessary condition for diagnosis (FEV1/FVC < 0.70). AECOPD was diagnosed when patients had worsening symptoms (dyspnea, cough, and expectoration) beyond the daily range of variation characterized by increased shortness of breath, often accompanied by wheezing, chest tightness, increased cough, increased sputum volume, changes in sputum color and/or viscosity, and fever.

(2) Syndrome differentiation met the criteria of Qi deficiency of the lung and spleen ZHENG, Qi deficiency of the lung and kidney ZHENG, or Qi and Yin deficiency of the lung and kidney ZHENG as per the Diagnostic Standards for TCM Syndromes of COPD (2011 Edition).16

Inclusion and Exclusion Criteria

We included participants with (1) a confirmed diagnosis of GOLD 3–4 COPD (according to the GOLD spirometric criteria, GOLD 3 patients: 30%≤ FEV1% predicted <50%; GOLD 4 patients: FEV1% predicted < 30%); (2) syndrome differentiation meeting the criteria of Qi deficiency of the lungs and spleen, Qi deficiency of the lungs and kidneys, or Qi and Yin deficiency of the lungs and kidneys; (3) ages between 40 and 80 years (≥ 40 and ≤ 80), male or female; and (4) those who received the treatment voluntarily and provided informed consent. We excluded (1) pregnant and lactating women; (2) patients with severe cardiovascular and cerebrovascular diseases (malignant arrhythmia, unstable angina, acute myocardial infarction, cardiac function ≥ level 3, stroke, cerebral hemorrhage); (3) patients with bronchiectasis, bronchial asthma, active tuberculosis, obliterative bronchiolitis, diffuse pan bronchiolitis, pulmonary embolism, pneumothorax, and pleural effusion; (4) patients with respiratory failure requiring endotracheal intubation and invasive ventilator assistance; (5) severe hepatorenal diseases (severe liver diseases refer to cirrhosis, portal hypertension, and varicose bleeding; severe kidney diseases include kidney dialysis and kidney transplantation); (6) patients with tumors or neuromuscular diseases that affect respiratory motor function; (7) patients bedridden for a long time; (8) congenital or acquired immunodeficiency; (9) delirium, dementia, and other mental disorders; (10) patients taking oral glucocorticoids within one month before participation; and (11) clinical investigators or patients participating in other interventions within one month before the start of the study.

Elimination Criteria

The principal investigators and data managers made a final decision on the rejection of cases during blind verification. The participants were eliminated under any of the following conditions:

(1) Violation of the inclusion or exclusion criteria.

(2) Failure to take the investigational drug after entering the study group.

(3) Failure to visit for post-treatment follow-up studies.

(4) Those who seriously deviated from the protocol, such that it affected the judgment of curative effects and safety.

Termination Criteria

We would terminate the study under the following conditions:

(1) If a severe safety event occurred during the evaluation.

(2) If the clinical trial scheme was found to have significant errors during the trial. Although the scheme was reasonable, if serious deviations occurred during the implementation, making it difficult to evaluate the efficacy of the investigational drug, the trial would be terminated.

(3) It was found that the investigational drug treatment was ineffective and had no clinical value during the trial, the test would be stopped.

(4) The test was canceled by the administrative department.

Early termination of the clinical trial would be promptly conveyed to all research parties.

Withdraw Criteria

Under the following situations, participants would be withdrawn from the study at any time.

(1) In the case of an allergic reaction or serious adverse event.

(2) If disease/health conditions deteriorated during the study, the participants would quit the test and receive other effective treatments.

(3) The participants have poor compliance, and the use of the investigational drugs does not reach 80% or exceeds 120% of the prescribed amount.

(4) During the study, the participant changed medicines when the study was active or added Chinese and Western medicines prohibited by this program.

(5) Accidental unmasking of the study while the study is active.

Under the following situations, the study participant could withdraw from the study at any time.

(1) For any reason, if the participant wishes to withdraw from participating in the trial, the study investigator can withdraw the participant.

(2) Participants who do not wish to accept any more investigational drugs, although they do not state the withdrawal explicitly.

When the participants withdrew or dropped out of the trial, investigators took active measures to try to complete the last test to analyze the efficacy and safety. Moreover, for these cases, the study conclusions and reasons for dropping out were recorded in the research medical records/case report forms. In case of withdrawal from the trial due to allergic reaction, adverse reaction, and ineffective treatment, investigators took appropriate treatment measures according to the current situation of the participants during that time.

Sample Size

Based on previous relevant research results, the number of AEs decreased by 0.228 ± 1.109 times after treatment with BYG and by 0.138 ± 1.385 times after placebo treatment. In this study, class I error α and class II error β of the study were assumed to be 0.05 and 0.1, respectively, and the ratio of the sample size for the two groups was 1:1. Considering the potential absence from future visits and withdrawal, and according to the calculation formula of sample size to compare average values of two groups of independent samples, the sample size of each group was calculated by PASS software, and was approximately 174 participants. Therefore, the targeted total sample was 348 in this study, with 174 participants in the experimental group and 174 participants in the control group.


According to the international guidelines, GOLD 3–4 COPD patients should also be given long-term maintenance medication. Based on routine treatment of modern medicine, patients in the experimental group were given BYG, with those in the control group receiving a placebo. All the treatments lasted for 52 weeks, and we prescribed other necessary treatments if the patients had AEs. The planned treatment measures continued when the patient’s conditions returned to stable.

Routine Treatment of Modern Medicine

According to the Chinese Guidelines for Diagnosis and Treatment of COPD (2013 Revision), patients could select β 2-Receptor agonists (terbutaline sulfate inhalation powder spray, salbutamol aerosol inhalation solution, or indacaterol inhalation powder spray), anticholinergic drugs (ipratropium bromide aerosol, or tiotropium bromide powder for inhalation), or aminophylline as routine treatment. Participants with hypertension, coronary heart disease, and other diseases were also treated with conventional drugs according to the relevant disease guidelines during the treatment and follow-up period. All the drug names, usage, and dosage were recorded in detail.

TCM Treatment

BYGs could tonify lung and kidney function by strengthening the spleen, promoting blood circulation, and reducing phlegm. The granules and placebo were produced, packaged, and transported by Jiangyin Tianjiang Pharmaceutical Co., Ltd, who meet GMP standards with strict quality control. The Bu-fei Yi-shen placebo granules contain 5% of BYGs; their appearance, weight, color, and smell are the same or similar; and they cannot be distinguished by the participants and/or researchers. BYGs or the placebo were administered orally, twice daily, with 5 days on and 2 days off a week. The raw material components of the daily dose for the BYGs are shown in Table 1.

Table 1 Components of Bu-Fei Yi-Shen Granules


Basic Characteristic Variables

We collected the following baseline data for the study: (1) demographic data, including age, height, and weight; and (2) general clinical data, including comorbidities and medications.

Primary Efficacy outcomes

We recorded the duration and frequency of any AEs, made judgments according to the standards of the stabilization time, and recorded the stable condition time in detail.

Secondary Indices of Curative Efficacy

(1) Mortality, calculated up to 52 weeks.

(2) Pulmonary function: values of FEV1, FVC, and FEV1% were recorded to evaluate the improvement of pulmonary function from baseline to weeks 26 and 52.

(3) Clinical symptoms and signs: including cough, expectoration, gasp, chest tightness, shortness of breath, fatigue, and cyanosis. During the study, data was collected at baseline and weeks 13, 26, 39, and 52.

(4) Exercise capacity: a 6-minute walking distance (6MWD) test was adopted to evaluate exercise capacity, performed and recorded at baseline and weeks 13, 26, 39, and 52.

(5) Evaluation of life quality: the COPD assessment test (CAT), SF-36, modified patient-reported outcome scale for COPD (mCOPD-PRO), and modified efficacy satisfaction questionnaire for COPD (mESQ-COPD) were used to measure quality of life of patients. These scale scores were recorded at baseline and weeks 13, 26, 39, and 52.

(6) Dyspnea: Modified Medical Research Council (mMRC) scores were adopted to evaluate dyspnea, recorded at baseline and weeks 13, 26, 39, and 52.

Safety Assessment

The following safety items were recorded before and after each test:

(1) Vital signs, such as blood pressure, respiration, heart rate, and pulse.

(2) Routine examination of urine and stool.

(3) Routine examination of blood.

(4) Chest CT.

(5) Electrocardiogram.

(6) Liver and renal function, blood glucose, blood lipid, ALT, AST, urea nitrogen, creatinine, and uric acid.

(7) Any adverse events, including dizziness, headache, pruritus, skin rashes, alopecia, gastrointestinal symptoms, hepatorenal toxicity, and leukopenia. The occurrence time, severity, frequency, duration, and outcomes of the adverse events were recorded.

Adverse Events

An adverse event form was set up in the Research Medical Record and Case Report Form (CRF), requiring investigators to record the occurrence time, severity, duration, measures taken, and outcomes of any adverse events. In case of adverse events during the trial, we took all necessary measures to ensure the safety of the participants, and immediately report the events to the local and provincial drug administration within 24 hours. If any aggravation of symptoms occurred, the patient was withdrawn from the study and referred for further treatment.


The method of hierarchical block central random allocation was adopted. According to the clinical trial plan, the random allocation plan was constructed and subsequently implemented and managed through a central random network system. Participants were randomly assigned to the experimental and control groups, with 174 participants in each group. The study investigators acquired the assigned codes of the participants through the network.

The clinical trial doctor obtained the participant assignment code through the internet, and recruitment was performed in the 11 hospitals. Besides direct recruitment, other methods, such as multimedia advertising, were adopted to ensure an adequate sample size.


As this is a double-blind study, blinding was maintained for the study participants, the clinicians, the research assistants, the drug managers, and the statisticians, until the completion of the study. Blinding was completed by the person in charge of the project unit, the drug preparation personnel, and the statistician. Uniformity was maintained while packaging the test and placebo drugs. This was followed by uniform distribution of the packaging boxes. During the trial period, the clinicians, research assistants, and drug managers maintained confidentiality and shared the drug information only with associated physicians.

A detailed written record was maintained for the blinding process, which was signed by responsible and authorized persons. The drug containers were sealed and stamped soon after the drug was dispensed. A person in charge of the project, drug preparation personnel, and the statisticians adjudicated the whole process.

The investigator, and the study site personnel remained blinded to the participant’s treatment group. Blinding was only broken if the participant experienced a medical emergency and knowledge of the blinded treatment assignment was deemed necessary for further management of the participant. The date and reasons for the code break were documented in the source documents and on the appropriate CRF.


After a wash-out of 2 weeks, patients in the experimental and control groups received the BYGs or placebo, respectively, for 52 weeks. We followed up and assessed each participant every 13 weeks. Quality control was performed by checking and recycling all the outer packaging of the experimental drugs at the next follow-up visit.

Data Management and Statistical Analysis

During project implementation, the quality supervision committee was established, composed of clinical and quality inspectors, who performed an inspection on the project every 12 months. An independent data management council (DMC) was also established by the trial steering committee. The DMC included clinical epidemiologists, data monitors, and statisticians.

Per protocol set (PPS) analysis was performed for the efficacy assessment, including data from all cases that met the inclusion and exclusion criteria and completed all treatment requirements. All randomized patients who received at least one dose of treatment and had actual data recorded by safety indices were included in the safety data set.

The enumeration data are described by frequency or composition ratio, while the measurement data are described by mean ± standard deviation ( ± SD). Measurement data, such as pulmonary function, with normal distribution and homogeneous variance, were compared through t-tests with Wilcoxon rank-sum tests used for non-normal distribution or uneven variance. A repeated measurement analysis of variance (ANOVA) was used for data measured more than twice at different time points. Chi-square or Fisher’s exact tests were applied to compare differences in enumeration data, such as the frequencies of AEs and adverse events/reactions. Two-tailed tests were applied with P < 0.05 considered statistically significant. SPSS 25.0 software was used for data analysis, and GraphPad Prism 8 was applied for image generation. Data management and analysis was undertaken by Jiangsu famous Medical Technology Co., Ltd. A flow chart of the study is shown in Figure 1, and the schedule of enrollment, intervention, and assessments is presented in Figure 2.

Figure 1 Study trial procedure.

Figure 2 Procedures for each patient in the study.


From July 2019 to September 2020, a total of 348 stable COPD patients with GOLD 3–4 were recruited and included, with 174 participants in each group. After treatment and follow-up, 44 patients were eliminated for not adhering to the clinical protocol (38 patients) or concealing a history of diabetes (6 patients). A total of 24 patients dropped out of the study (Table 2). Finally, a total of 280 patients (135 cases in the experimental group and 145 in the control group) were included in the data analysis.

Table 2 Summary of Discontinuities/Dropouts/ Withdraw for the Two Groups

Baseline Characteristics

There were no statistical differences in age, gender, nationality, BMI, heart rate, blood pressure, marriage, occupation, educational levels, smoking, drinking, and concomitant medications between the experimental and control groups. No intergroup significant differences were observed in annual numbers and durations of AEs, pulmonary function, or course of disease (Table 3).

Table 3 Baseline Characteristics of Included COPD Patients§

Primary Outcomes

After treatment, significant differences were observed in frequency and duration of AEs and AE-related hospitalization between the experimental and control groups. As shown in Figure 3 and Table S1, frequencies of AEs in the experimental group were 0.35 times lower than those in the control group (95% CI: 0.10, 0.61; P = 0.006). For frequencies of AE-related hospitalizations, the numbers in both groups improved (P < 0.001), and were 0.18 times lower in the experimental group compared to the control group (95% CI: 0.01, 0.36; P < 0.05). Compared to the control group, the duration of AE-related hospitalizations was significantly lower in the experimental group (mean difference: −1.83 days; 95% CI: −2.97, −0.68; P = 0.002).

Figure 3 Comparison of differences between groups regarding AEs.

Secondary Outcomes


After treatment, two patients died in each group. No statistical difference was observed for mortality.

Pulmonary Function

The repeated ANOVA data shows that there are no significant differences in FEV1, FVC, and FEV1% between the experimental and control groups after treatment (Figure 4).

Figure 4 Comparison of differences between groups regarding pulmonary function. Pulmonary function, including FEV1, FVC, and FEV1%, were collected and evaluated. (A-C) represent intergroup differences in FEV1, FVC, and FEV1%, respectively. Lower values reflect worse pulmonary function.

Signs and Symptoms

During the follow-up period, cough, expectoration, wheezing, chest tightness, shortness of breath, fatigue, cyanosis scores, and total scores decreased in both groups. There were no significant intergroup differences at weeks 26, 39, and 52, respectively (P < 0.05). For wheezing, chest tightness scores, and total scores, significant differences were observed at week 13 (P < 0.05). The repeated ANOVA shows that time group effects were observed, indicating that there was a significant difference between the experimental and control groups in cough, with better outcomes in the experimental group (P < 0.001) (Figure 5 and Table S1).

Figure 5 Comparison of differences between groups regarding signs and symptoms. Signs and symptoms, including cough, expectoration, wheezing, chest tightness, shortness of breath, fatigue, cyanosis scores, and total scores were calculated and compared between the groups (represented in A, B, C, D, E, F, G, and H, respectively). Lower scores reflect better signs and symptoms.


6MWD improved in both groups at different follow-up points during the treatment period, with intergroup statistical differences at week 26, 39, and 52, respectively (P = 0.025, P = 0.004, P < 0.001). We also observed time group effects by repeated ANOVA, indicating significant differences between the experimental and control groups in 6MWD, with better outcomes in the experimental group (P < 0.001). After treatment, 6MWD was higher in the experimental group than in the control group, by 40.93 m (95% CI: 32.03 m, 49.83 m, P < 0.001) (Figure 6 and Table S1).

Figure 6 Comparison of differences between groups regarding 6MWD.

Quality of Life

Quality of life assessed by CAT, SF-36, mCOPD-PRO, and mESQ-COPD improved in both groups, with better efficacy in the experimental group compared to the control group (P < 0.001). SF-36 scores, except for BP, improved in each aspect of the score (Figures 7–8 and Table S1).

Figure 7 Comparison of differences between groups regarding CAT, mCOPD-PRO, and mESQ-COPD.

Figure 8 Comparison of differences between groups regarding SF-36.


mMRC decreased in both groups, and significant intergroup differences were found at weeks 26, 39, and 52 (P = 0.006, P < 0.001, P < 0.001). A repeated ANOVA shows that time group effects were also observed, indicating a significant difference between the experimental and control groups in mMRC, with better outcomes in the experimental group (P < 0.001). After treatment, mMRC was lower in the experimental group than in the control group (mean difference: −0.57; 95% CI: −0.76, −0.37; P < 0.001) (Figure 9 and Table S1).

Figure 9 Comparison of differences between groups on mMRC.

Adverse Events

Throughout the treatment and follow-up period, the biochemical tests, urine routine tests, and ECG from all the participants were approximately normal. In the experimental group, four adverse events were observed: two patients died, one patient was diagnosed with diabetes, and one patient was diagnosed with malignancy. In the control group, three adverse events were observed: two patients died, and one patient was diagnosed with malignancy. Additionally, one patient in each group had transient stomach pain. There was no statistical difference in adverse events.

In addition, we have also performed intention-to-treat (ITT) data analysis as a supplement. The results have been shown in the attachment materials (Table S2) not in the body manuscript. The analysis results of ITT and PP are not contradictory. Please find the specific results in Table S2.


We found efficacy advantages of TCM for GOLD 3–4 COPD patients. Compared to the placebo, BYGs were effective in reducing AEs in the 52-week follow-up period. The frequencies and durations of AEs and AE-related hospitalizations decreased in our experimental group. Additionally, clinical symptoms, treatment satisfaction, quality of life, and exercise capacity improved. However, pulmonary function did not improve following treatment using BYGs for GOLD 3–4 COPD patients. To our knowledge, this is the first RCT involving TCM in GOLD 3–4 COPD patients without regard to TCM syndrome. Our results may highlight the core TCM pathogenesis and provide references for clinical applications, especially for severe and very severe COPD patients.

AEs induce worse symptoms and pulmonary function decline with additional treatments. Hospitalization and worse prognoses are also induced by severe AEs, especially for severe and very severe COPD patients.5 The incidence of AEs in COPD patients within one year is as high as 43.7% in China,17 and is 61.7% in Spain.18 Among COPD patients hospitalized due to AE, GOLD 3–4 patients account for 71.1%.19 Severe AE has also been confirmed to be an independent risk factor leading to patient death, with the risk thereof increasing as the frequency of AE increases.20 Therefore, reducing the frequencies of AEs has been the most important treatment target, especially for the GOLD 3–4 COPD patients.

Based on the clinical characteristics of GOLD 3–4 COPD patients with frequent AEs and serious clinical hazards, our research team have summarized the core TCM pathogenesis of deficiency of lung and kidney Qi, combined with spleen deficiency, phlegm turbidity, and blood stasis. We have also developed BYGs with increased efficacy of tonifying the lungs and kidneys, resolving phlegm, and promoting blood circulation. In this study, BYGs showed an advantage in reducing AEs in all the patients regardless of different TCM syndromes. The annual number of AEs in the experimental group decreased by 0.36 times compared to the control group, and the difference was statistically significant, which has confirmed the clinical efficacy of BYGs in reducing AEs. The results are worthy of further promotion.

Dyspnea is a common clinical symptom in COPD patients, gradually worsening with the decline of lung function assessed by the mMRC scale. Levels of dyspnea are also related to quality of life and prognosis.21 Despite standard treatment, 43% of COPD patients still have persistent dyspnea symptoms with mMRC scores ≥ 2.22 In this study, we found that BYGs could reduce the levels of dyspnea for GOLD 3–4 COPD patients compared to a placebo group; the improvement was more outstanding from week 26. The results may also indicate the late effect for TCM, which has been ignored in clinical studies to date.

The CAT scale is internationally recognized as a COPD assessment scale that can help patients understand the impact of COPD on their health and quality of life. The scale negatively correlates with the levels of pulmonary function and positively correlates with the frequency of AEs in the previous year.23 We showed that BYGs can reduce CAT scores, reducing disease severity for GOLD 3–4 COPD patients.

For COPD patients, quality of life will decrease with disease progression. In this study, SF −36, EQ-5D, and mCOPD-PRO scores were adopted to comprehensively assess quality of life. We showed improved quality of life in our experimental group, with some differences in areas related to TCM treatment.

Patients with COPD can also experience clinical symptoms such as cough, expectoration, chest tightness, and asthma. TCM treatment based on syndrome differentiation originates from the symptoms and signs. Therefore, the efficacy of TCM should first show the improvement of symptoms. However, this study was conducted based on disease classification, and summarizes the core pathogenesis and formulates core TCM prescriptions, which may be different and sublimated from TCM treatment based on syndrome differentiation. Our results may still indicate the efficacy of BYGs in improving clinical symptoms and signs, which will further verify the core pathogenesis, and provide critical references for the staging and grading treatment of COPD with TCM.

As pulmonary function declines, exercise capacity in COPD patients will also significantly decrease, especially for GOLD 3–4 patients. Referring to relevant guidelines and studies, we adopted the 6MWD to assess exercise capacity. For COPD patients, skeletal muscle atrophy is very common and may be an important factor leading to decreased exercise capacity.24 Treatment in modern medicine focuses on the lungs, regardless of the peripheral tissues. Although non-drug therapies, such as pulmonary rehabilitation, have shown some improvement in exercise capacity, the quality of evidence is still low.24 BYGs can treat COPD through multiple targets and pathways, and its action is not limited to the lungs. We showed improved 6MWD results, confirming the multi-target mechanism from a clinical perspective.

Pulmonary function did not improve in our follow-up period. This may be related to the effective link of the prescription as well as COPD disease characteristics at this stage. The long-term effects of TCM may also have been discounted. Therefore, the advantages of TCM should be reassessed, as well as the related evaluation of TCM clinical research. A suitable evaluation method and index for TCM to reflect the efficacy advantages should be urgently investigated.

We also considered the role of psychological factors in disease treatment and explored the impact of TCM treatment on patient satisfaction. Since the bio–psycho–social medical model has been recognized, more and more researchers have begun to focus on patient psychological factors and patient satisfaction, which can enrich the cognition of therapeutic effects from different perspectives. As an exploratory study in patient satisfaction, we adopted the ESQ-COPD as an assessment method, as developed by our research team previously.25 ESQ-COPD scores decreased in both groups in the all fields, with a significantly higher reduction rate in the experimental group, indicating that BYGs can significantly improve the satisfaction of patients with therapeutic effects. In addition, the side effects were also recorded and assessed. During the treatment period, there were no significant abnormalities in biochemical and electrocardiogram examinations in both groups. No serious adverse events related to the treatment drug were found.

Inhalers are the mainstay of treatment for stable COPD. Commonly used drugs include inhaled hormones and bronchodilators, which can effectively delay the decline of lung function to a certain extent, and are convenient to use. In the past, dual drugs have been the main treatment with general efficacy. Therefore, in recent years, new triple therapies have been developed, which could be applied in treating COPD and may improve lung function.26 Moreover, triple therapies may have good efficacy in patients without reversible airway lesions and airway eosinophilic inflammation.27 However, studies on clinical symptoms and acute exacerbation are lacking. Unfortunately, when our study protocol was formulated, triple therapy had not been widely promoted and applied.

Studies regarding TCM treatment for COPD are abundant; however, most are exploratory, with small samples and low quality of evidence.28 A study on the efficacy of TCM for a certain syndrome has been conducted.29 The overall efficacy of TCM has been assessed in some studies; however, there are few studies on certain pulmonary function levels.30 These studies failed to comprehensively and carefully evaluate the clinical efficacy of TCM in treating COPD.

We have studied the prevention and treatment of COPD with TCM for a long time. Different studies have been performed to explore ways to determine traditional syndrome differentiation and one-person treatment models for different disease stages and periods,13,31,32 providing critical references for further studies and more convenient clinical applications. This study is also an in-depth investigation based on the former foundations, with regard for the summary of the disease and pathogenesis characteristics of severe and extremely severe COPD patients with TCM. New studies need to clarify and improve the efficacy of TCM in patients with severe pulmonary function and extremely severe COPD, to further enrich the advantages and strategies thereof.


This study had some limitations. First, the total target sample size was calculated based on the whole study, regardless of sub-group, which induces uneven results among different syndrome subgroups. Our sub-group analysis was abandoned. Second, because of COVID-19, some patients could only be followed up by telephone, which may not fully reflect the required information, and may cause some bias. Finally, due to a lack of time, we only conducted the study for 52 weeks, and failed to follow up on patient disease status after our treatment. We, therefore, failed to evaluate the late effect of the BYGs.


BYGs could reduce the frequencies of AEs and AE-related hospitalization for GOLD 3–4 COPD patients significantly with acceptable side effects. Patient clinical symptoms, treatment satisfaction, quality of life, and exercise capacity were improved by BYGs, with no significant improvement in pulmonary function and mortality.


6MWD, 6-min walk distance; ANOVA, Analysis of Variance; CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease; GOLD, global initiative for chronic obstructive lung disease; mCOPD-PRO, modified patient-reported outcome scale for COPD; mESQ-COPD, modified efficacy satisfaction questionnaire for COPD; mMRC, Modified Medical Research Council; PPS, Per Protocol Set; TCM, traditional Chinese Medicine.

Data Sharing Statement

The raw data for this study could be available from corresponding author under request only for researches, and cannot be disseminated.

Ethics Approval and Informed Consent

The trial protocol (version 2019. was approved by the Institution Ethics Committee of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine (No. 2019HL-010). The study obtained informed consent and handwritten informed consent forms from each participant before trial. The study was conducted in strict accordance with the reviewed protocol and adhered to the tenets of the Declaration of Helsinki.

Consent for Publication

All authors have read the manuscript and agree to publish.


This study has been supported by the National Key Research & Development Program of China (grant number: 2018YFC1704800, 2018YFC1704802). All the participant experts are appreciated for their diligence in this study.


The authors report no conflicts of interest in this work.


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A hospital in Connaught Place even witnesses cases of child deaths as it lacks availability of oxygen ports, flow meters and even beds

Even as the capital of India has recorded severely bad air quality since November 2, 2023, a tour of Delhi hospitals by Down To Earth (DTE) showed how the maximum impact of the smog was often felt by the youngest: children under five years of age.

“There is an exponential increase in paediatric cases (in Delhi and the National Capital Region), as seen among newborns and also children from other age groups up to 12 years since pre-October. The worst-affected are those in the age range of two to five years,” Sanjeev Bagai, paediatrician and paediatric nephrologist told DTE.

On the morning of November 3, Delhi’s air quality plummeted to “severe plus”, surpassing the 450-mark. The data was outlined in a policy document from the Commission for Air Quality Management.

On the same day, as recorded by the Central Pollution Control Board (CPCB), the Air Quality Index (AQI) reading at Mundka station was the worst at 498. November 4 saw slight improvement in Delhi’s AQI conditions — 413 at 6 a.m. on November 4, from 468 at 4 pm on November 3.

The impact was to be seen in the hospitals that DTE visited.

Staff at Kalawati Saran Children’s Hospital—a government-run hospital in Connaught Place (Rajiv Chowk) dedicated to children—made some alarming revelations.

“Since the last 2-3 months, at least 70-80 per cent of an entire hospital ward known as ‘Unit 3’ have been child patients diagnosed with diseases like bronchitis, bronchiolitis, tuberculosis, asthma, pneumonia or lung diseases,” the staff told DTE on the condition of anonymity.

The number of child patients have doubled with the onset of winters, according to the hospital staff.

“The hospital does see cases of child deaths as it lacks availability of oxygen ports, flow meters and even beds. Due to the lack of facilities, the concerned doctors are often compelled to admit children with severe respiratory diseases or are compelled to make 3-4 children share one hospital bed. Such children do suffer fatal consequences,” said another hospital staff concerned with the ward, who does not want to be named.

The parents of a 10-month-old admitted in Ward 3 Cubicle 1 at Kalavati shared their distress. Her father, Naresh Kumar works as a painter near his house in Sangam Vihar, said:

Payal, our daughter, fell sick for the first time ever since her birth. She developed breathing problems 10 days ago and was admitted here four days ago. She is able to breathe with the help of oxygen support. The hospital staff are yet to tell us what disease it is. There is hardly any update on her health improvement, only hollow assurances.

Bharti, Payal’s mother, was inconsolable.

“There is almost a 100 per cent increase in respiratory illnesses among children since the said timescale this year. These include throat infection, ear infection, wheezing, bronchitis, laryngitis and pneumonia,” Bagai told DTE.

This is because during the morning hours, when the temperature and the smog situation is the worst, children are more predisposed to respiratory involvement due to their paediatric airways smaller and shorter in diameter and length against adults. Also, children’s reserved capacity of lung function is much lesser than adults,” Bagai added.

Prior data from CPCB had called Delhi “India’s most polluted city” in 2022, with its Particulate Matter (PM) 2.5 levels surpassing safe limits. The city also had the third-highest average PM10 concentration then.

“This air pollution not only involves PM2.5, it is also PM 5, PM 10, dust, allergens, toxic gases including NOx and other particulate matter. It is difficult for children to wear a mask, especially during school hours. Hence, their exposure to air pollution is very high,” explained Bagai.    

A young doctor at Kalavati named Saumya seconded that most of the child patients admitted with respiratory issues were aged between 2 and 5 years.

During a visit to AIIMS, New Delhi, this reporter witnessed a greater patient influx in the OPD dedicated to paediatric cases than in the one under the pulmonology department.

“The proportion of children with respiratory problems has increased, especially over the past 3-4 weeks. Those who already have respiratory problems (asthma, bronchiectasis, cystic fibrosis, etc) have developed worsening of symptoms despite taking their regular treatment,” SK Kabra, head of department of the AIIMS Paediatric Department told DTE a day later on November 4.

DTE also met Raj Kumar, director of Vallabhai Patel Chest Hospital, who said: “The condition of individuals suffering from respiratory problems aggravates during the period every year.” The hospital is located in Delhi University’s North Campus.

CPCB’s AQI has several categories. An AQI of 1-50 is ‘good’, 51-100 is ‘satisfactory’, 101-200 is ‘moderate’, 201-300 is ‘poor’, 301-400 is ‘very poor’ and 401-500 is ‘severe’ category. An air quality of more than 501 is in an ‘emergency’ zone.

Each of these categories are decided based on ambient concentration values of air pollutants and their likely health impacts (known as health breakpoints), according to System of Air Quality and Weather Forecasting and Research (SAFAR). The latter is a national initiative introduced by the Union Ministry of Earth Sciences to measure the air quality of a metropolitan city.

“There is need to have long-term and short-term plans covering the whole year, since air pollution is not a seasonal issue in Delhi. One-time measures cannot tackle the situation. At individual level, measures like use of gas for cooking food, avoiding the use of kerosene, biofuel, avoidance of the use of disease generators, etc is necessary,” Kabra said.

“Also, try to reduce the use of vehicles and encourage car-pooling. At the level of the government, a comprehensive plan to reduce air pollution due to vehicles, industry, construction work, etc in accordance with existing laws should be considered,” he added.  

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From a Lace Up for Lungs challenge to learning about the impact of chronic obstructive pulmonary disease (COPD) in individual U.S. states, supporters are poised to participate in COPD Awareness Month, observed each November. World COPD Awareness Day is Nov. 15.

Each fall, the COPD Foundation and the lung health community mark the month by raising awareness and critical funds for COPD and two other chronic lung conditions called bronchiectasis and nontuberculous mycobacterial lung disease, while encouraging early diagnoses.

“With your help, we can spread the word about COPD and chronic lung disease awareness, prevention, and treatment, and advocate for better research, funding, and support for all who are affected,” the foundations states on its awareness month webpage.

The COPD foundation is sharing a number of events and ways to help through its Lace Up for Lungs initiative.

“There are many creative ways you can get involved with this year’s efforts,” the foundation states on the initiative’s webpage.

Recommended Reading

An illustration of doctors checking a patient's status using a tablet.

Lace Up for Lungs challenges people to ‘get moving’

The foundation’s Lace Up for Lungs initiative challenges community members to “get moving” for 30 minutes daily in November. Joining the challenge involves setting up a Facebook fundraiser and posting progress in a support group on the platform.

Awareness month supporters are encouraged to create their own fundraisers such as a bake sale, backyard barbecue, pickleball tournament, or exercise challenge, and offers tips on getting started. In addition, the foundation offers a social media toolkit with images, downloadable signs, sample posts, and other resources.

In its Light the Night Orange initiative, supporters — called Lung Health Champions — are asked to get their local governments to have landmarks and official buildings illuminated in orange, the official color for awareness month.

They also are asked to wear orange Nov. 15, take a photo of themselves, and post the photo on social media using the hashtags #COPDAwarenessMonth, #LaceUpForLungs, and #LungHealthChampions, and/or #COPDChampions.

“When you become a Lung Health Champion this fall, you’re contributing to research, early diagnosis, and supporting educational efforts – all while advocating for and supporting individuals living with chronic lung disease and their families,” the foundation states in the initiative’s webpage.

The organization also is offering shareable information about COPD and a COPD screener, which individuals can use to see whether they should consult a healthcare professional about possible COPD symptoms.

The American Lung Association also invites supporters to get involved by understanding the impact of the chronic inflammatory lung disease on their state and act to help mitigate the disease’s burden.

In the U.S. alone, COPD is estimated to affect more than 12.5 million people. According to the association’s COPD State Briefs, announced earlier this month,  the 11 states with the nation’s highest COPD rates and burden are Alabama, Arkansas, Indiana, Kentucky, Louisiana, Missouri, Maine, Mississippi, Ohio, Tennessee, and West Virginia. Prevalence rates range by state from 3.7% in Hawaii to 13.6% in West Virginia.

The overarching aim of the state briefs is to heighten COPD awareness and empower healthcare and public health professionals to take steps to prevent disease onset, decrease health inequities, and ensure the use of clinical guidelines.

The association offers other ways to participate in this year’s awareness month, including learning the early warning signs of COPD and sharing a “Could It Be COPD?” questionnaire. Other suggestions include becoming a facilitator for the association’s Better Breathers Club, support groups for those with lung disease.

The organization also highlights free learning opportunities for healthcare professionals, patients, and caregivers, with topics including COPD basics, planning for the future, and changes people can make to improve the air they breathe.

 World COPD Day

Meanwhile, World COPD Day is organized each year by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in collaboration with healthcare professionals and COPD patient groups globally.

“Its aim is to raise awareness, share knowledge, and discuss ways to reduce the burden of COPD worldwide,” GOLD states on this year’s event webpage.

The theme this year, “Breathing is Life – Act Earlier,” seeks to underscore the importance of early lung health, diagnosis, and interventions.

“This campaign will focus on highlighting the importance of early lung health and how we can expand the horizon of COPD prevention and treatment by acting earlier,” GOLD adds. “This can include preventing early risk factors, monitoring lung health from birth, diagnosing COPD in a precursor state and providing treatment promptly.”

There is a World COPD Day graphic available as well as information about Big Baton Pass, a Nov. 15 challenge designed to raise awareness of the impact of living with COPD and the benefits of staying active.

Participants may choose their own activity, such as walking, biking, or swimming, and record miles, minutes, or steps.  During the event, a virtual baton will be passed among countries hosting teams.

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Australia’s bushfire season is officially under way during an El Niño. And after three wet years, and the plant growth that comes with it, there’s fuel to burn.

With the prospect of catastrophic bushfire comes smoke. This not only affects people in bushfire regions, but those in cities and towns far away, as smoke travels.

People with a lung condition are among those especially affected.

Read more:
Our mood usually lifts in spring. But after early heatwaves and bushfires, this year may be different

What’s so dangerous about bushfire smoke?

Bushfire smoke pollutes the air we breathe by increasing the concentration of particulate matter (or PM).

Once inhaled, small particles (especially with a diameter of 2.5 micrometres or less, known as PM2.5) can get deep into the lungs and into the bloodstream.

Concentration of gases in the air – such as ozone, nitrogen dioxide and sulfur dioxide – also increase, to pollute the air.

All these cause the airway to narrow and spasm, making it hard to breathe.

This can be even worse for people with existing asthma or other respiratory conditions whose airways are already inflamed.

Read more:
Bushfire smoke is everywhere in our cities. Here's exactly what you are inhaling

Emergency department visits and hospital admissions for asthma-related symptoms rise after exposure to bushfire smoke.

Smoke from the bushfires in summer 2019/20 resulted in an estimated 400 deaths or more from any cause, more than 1,300 emergency department visits for asthma symptoms, and more than 2,000 hospital admissions for respiratory issues.

Even if symptoms are not serious enough to warrant emergency medical attention, exposure to bushfire smoke can lead to cough, nasal congestion, wheezing and asthma flares.

If you have asthma, chronic obstructive pulmonary disease, bronchiectasis or another lung condition, or you care for someone who has, here’s what you can do to prepare for the season ahead.

1. Avoid smoke

Monitor your local air quality by downloading one or both of these apps:

  • AirSmart from Asthma Australia has live air-quality information to help you plan and act

  • AirRater, developed by Australian scientists, can be another useful app to monitor your environment, track your symptoms and help manage your health.

During times of poor air quality and smoke stay indoors and avoid smoke exposure. Close windows and doors, and if you have one, use an air conditioner to recirculate the air.

Avoid unnecessary physical activity which makes us breathe more to deliver more oxygen to the body, but also means we inhale more polluted air. Consider temporarily moving to a safer residence.

Well-fitting N95/P2 masks can reduce your exposure to fine smoke particles if you must travel. However they can make it more difficult to breathe if you are unwell. In that case, you may find a mask with a valve more comfortable.

Person holding a N95/P2 respirator

Well-fitting N95/P2 masks can help.
Daria Nipot/Shutterstock

Read more:
How to protect yourself against bushfire smoke this summer

2. Have an action plan

Taking your regular preventer medication ensures your lung health is optimised before the danger period.

Ensure you have a written action plan. This provides you with clear instructions on how to take early actions to prevent symptoms deteriorating or to reduce the severity of flare-ups. Review this plan with your GP, share it with a family member, pin it to the fridge.

Make sure you have emergency medication available, know when to call for help, and what medication to take while you wait. You may consider storing an emergency “reliever puffer” in your home or with a neighbour.

Read more:
How to manage your essential medicines in a bushfire or other emergency

3. Have the right equipment

High-efficiency particulate air (HEPA) filters can reduce smoke exposure inside the home during a fire event by 30-74%. These filters remove particulate matter from the air.

A spacer, which is a small chamber to contain inhaled medication, can help you take emergency medication if you are breathing quickly. You may want to have one to hand.

Read more:
From face masks to air purifiers: what actually works to protect us from bushfire smoke?

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The three years of the Sars-CoV-2 pandemic have not only said that we are vulnerable and that some – the elderly, the frail – are more vulnerable than others. They also made us discover the importance of our breathing and that we need to pay attention to the health of our lungs. This is the first data that catches the eye when analyzing the survey conducted by Doxa Pharma on 100 pulmonologists to see if (and how) Covid has changed the perception – and consequently the behavior – of respiratory diseases in the Italian population, and particularly COPD.

41% of those interviewed – according to a note – declare that visits to the clinic in the post-emergency period have increased and 46% that the reason is due precisely to a greater awareness of the disease, while another 20% say that pushing the patient to the specialist is the fear of complications. Exacerbations are in fact a decisive watershed in the decline of respiratory capacity. So much so that the international Gold 2023 recommendations even suggest the need to prescribe the maximum therapy, the triple therapy, already after the first episode.

The other fact that is worth immediately focusing on is the gender difference. Women (35% of patients vs 65% of males) are better than men, but this is nothing new. They have a shorter history of illness: 9 years compared to 12. They have a less serious condition and comorbidities: mood disorders and osteoporosis, while men suffer mainly from cardiovascular diseases and diabetes. What makes the difference is that women become worried at the first symptoms (41% compared to 11% of men); they are more attentive to their health (here the gap is more marked: 62% vs 22%); to the doctor’s prescriptions and advice (39% compared to 21%), they are treated better (39% – 24%). The third element that emerges from the study – continues the note – is that COPD is not a disease for old people. The habit of smoking and the precociousness in lighting up a cigarette (and we will see the consequences of surrogates shortly) has lowered the age of diagnosis to 50 years.

Around the world, more than half a billion people live with chronic respiratory diseases such as asthma, COPD, bronchiectasis and other serious diseases. In Italy – the note details – there are 2.6 million who suffer from asthma, 3.3 million from COPD, more than 50 thousand have lower respiratory tract infections and over 60 thousand suffer from lung cancer. Therefore, we are faced with the third cause of death on the planet, with an estimate of more than 50 thousand deaths per year. Which equates to direct and indirect costs of 45.7 billion euros (medical care, loss of working days, decreased productivity and consumption of drugs and oxygen). Numbers are increasing, due to the progressive aging of the population and the growing number of smokers. According to data from the Report on Smoking in Italy by the Higher Institute of Health, presented on the occasion of World No Tobacco Day, almost one in 4 Italians, 24.2%, is a smoker: a percentage that has not been recorded since 2006. .

The pandemic has therefore awakened some attention. And this is certainly a good thing. But the picture that Doxa Pharma shows presents large shades of grey. Let’s continue the story. Eight out of 10 pulmonologists confirm that Covid has brought about a change in the management and treatment of COPD patients. The biggest problems are follow-up (57%); referring patients to their attention (42%); the diagnosis (28%). Greater awareness or apprehension has, on the other hand, changed the doctor-patient relationship for 40% of those interviewed. Patient who first asks to be reassured: 23% of clinicians say this; undergoes checks more frequently (10%); also through telemedicine (13%).

For 6 out of 10 pulmonologists the most negative notes come from the ‘patient journey’. Despite a greater demand for diagnostic tests (18%), there are still long waiting times (38%) and difficulties in accessing spirometry (18%). And this is what patients’ requests are based on: reduction of waiting lists (42%), resumption of adequate follow-up (21%), the eternal theme of early diagnosis (15%). For specialists, the priority is to increase monitoring (35%), spirometry first of all, but also other tests; reduce waiting times for visits (30%). It is worth highlighting the hope of 16% for a more central role of the general practitioner. Not only. 79% believe that it is necessary to structure a care network that sees the close collaboration of local healthcare with hospital healthcare. The same percentage, consistently – concludes the note – thinks that it is a good idea to rethink local healthcare and the related methods of taking care of patients with COPD. One in two also looks at digital tools and adequate infrastructures to be able to provide adequate support and responses to patients. Women are mainly treated with double bronchodilation (Laba+Lama), men with triple (Ics+Laba+Lama).

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COPD exacerbations are devastating episodes in the natural course of the disease, leading acutely to increased morbidity and mortality.1 Moreover, in COPD, the rate of exacerbations has been correlated with an accelerated decline in lung function.2 Although the mechanism for this association is not determined, increased lung and systemic inflammation during an exacerbation could promote long term lung functional decline in COPD patients, especially in frequent exacerbators.3 A frequent cause of COPD exacerbation is pulmonary infection with Pseudomonas aeruginosa, especially in patients with severely impaired lung function, bronchiectasis and in COPD exacerbations leading to mechanical ventilation.4 In general, COPD exacerbations are characterized by increased airway inflammation and the bacterial load during COPD exacerbations has been also associated with augmented pulmonary inflammation.5

Resistive breathing, ie breathing through increased airway resistance, leading to severe airflow limitation and hyperinflation, is the main characteristic of the pathophysiology of COPD exacerbations. Forceful contractions of the diaphragm during resistive breathing are associated with large negative intrathoracic pressures that together with hyperinflation lead to increased mechanical stress, imposed on the lung.6,7 We have shown that resistive breathing through tracheal banding (as a model of severe airway obstruction) induces acute lung injury and inflammation, possible due to exposure of the lung to increased mechanical stress.8 The aforementioned study was performed in previously healthy animals and whether resistive breathing could augment pulmonary inflammation in mice suffering an underlying inflammation due to prior pulmonary lipopolysaccharide (LPS) exposure, as would be more clinically relevant, is unknown.

COPD exacerbations are a frequent cause of hospitalizations in intensive care units, where the incidence of nosocomial infections with gram-negative bacteria, such as Pseudomonas aeruginosa, is high, leading to sepsis and indirect lung injury.9 Again, whether the mechanical consequences of a COPD exacerbation, could have an additive effect on pulmonary inflammation, following a systemic exposure to LPS has not been tested before.

Therefore, we hypothesized that resistive breathing could have a synergistic effect on pulmonary inflammation and injury, when combined to either inhale of systemic exposure to endotoxin (LPS) from Pseudomonas aeruginosa bacteria. To achieve our aim, we have combined our model of severe airway obstruction (via tracheal banding) with the model of endotoxin exposure, administered either as an aerosol (direct pulmonary insult) or intraperitoneally (systemic – secondary pulmonary insult).



Male C57BL/6 mice [8–12 weeks old (Biomedical Sciences Research Center “A. Fleming”)] were housed in a 12-hour day/night cycle and had an ad libitum access to water and food. The number of animals per group is stated in figure legends.

Endotoxin Exposure

Two independent sets of experiments were performed with lipopolysaccharide (LPS) from Pseudomonas aeruginosa serotype 10 (Sigma-Aldrich) being administered either through inhalation (aerosol challenge) or intraperitoneally.

Aerosol Administration (Inhalational)

An LPS solution was prepared (10 mg/3 mL in sterile normal saline) and was administered over a 20-min period in a nebulization chamber under continuous oxygen flow, as previously described.10 Animals exposed to nebulized sterile normal saline alone were used as control.

Intraperitoneal Administration

LPS was administered via an intraperitoneal injection (10 mg/kg) in sterile normal saline. This dose was based on a pilot study (5, 10 and 20 mg/kg ip doses) showing that animals develop significant pulmonary injury with minimal mortality (data not shown). Animals receiving an equal volume of sterile normal saline alone served as controls.

Animal Model of Resistive Breathing Through Tracheal Banding

Animals were anaesthetized [ketamine (90 mg/kg) and xylazine (5mg/kg) ip], an incision was performed in the anterior cervix and the trachea was exposed. Then, the diameter of the trachea was measured using a caliber gauge through a surgical microscope (Zeiss Inc.). Following, a new perimeter of the trachea was calculated that corresponds to a total surface area, reduced to half of the initial, and a nylon band of the pre-specified length was sutured around the trachea, to provoke resistive breathing.8 The animals recovered from the anesthesia and returned to their cage.

The animals underwent tracheal banding 30 minutes following inhalation or intraperitoneal LPS (or sterile normal saline-control) administration and resistive breathing lasted for 24h in total. Sham operation included anesthesia and skin incision, but no band placement.

Respiratory System Mechanics

A small animal ventilator (FlexiVent, Scireq) was employed to estimate the mechanics of the respiratory system at the end of the resistive breathing session. The animals received a dose of anaesthesia [ketamine (90 mg/kg) and xylazine (10 mg/kg)] and a tracheal tube was inserted to the trachea, after removal of the nylon band. The dynamic compliance and the total respiratory system resistance were measured (single compartment linear model,11 values reported are the average of 3 snapshot perturbations). Prior to measurements, a deep inspiration in the ventilator, pressure-limited to 30 cmH20, was used to establish the lung volume history and succinylcholine (8−1) was administered to inhibit spontaneous breathing.

Bronchoalveolar Lavage (BAL)

Following the measurement of the respiratory system mechanics, the animals received a further dose of anesthesia and were sacrificed by vena cava dissection (exsanguination). Then, the thoracic cavity was opened, the left main bronchus was temporally ligated, and BAL was performed at the right lung with 3 aliquots of 0.5 mL normal saline. BAL fluid was centrifuged (300xg, 5 min, 4°C), the cell pellet was resuspended, and the BAL fluid supernatant was stored at −80°C for further analysis.

Total Protein in BAL Fluid

The total protein levels in the BAL fluid supernatant were estimated with a colorimetric protein assay (BioRad). Standard curves were created using bovine serum albumin.

Cell Count (Total – Differential)

After BAL fluid centrifugation, the cell pellet was diluted in 1 mL normal saline and the total cells were counted. Following, May-Grűnwald-stained cytospins were prepared to measure the percentages of macrophages, neutrophils, lymphocytes and eosinophils/basophils. Eosinophils/basophils were omitted from analysis, due to minimal counts.

Cytokine Levels in BAL Fluid

IL-6 and TNF-α protein levels, central cytokines in the pathogenesis of acute lung injury, were estimated in samples of BAL fluid supernatant by ELISA (DuoSet, R&D Systems).

Lung Histology

Following BAL, the right main bronchus was ligated, and the right lung was removed, and the left lung was fixed with 4% formaldehyde under 20 cm H2O pressure. Haematoxylin and eosin-stained lung tissue sections were prepared, and a lung injury score was determined, as previously described.12 Briefly, (i) focal alveolar membrane thickening, (ii) capillary congestion, (iii) intra-alveolar haemorrhage, (iv) interstitial and (v) intra-alveolar leukocyte infiltration were evaluated and scored from 0 to 3 based on their absence (0) or presence to a mild (1), moderate (2), or severe (3) degree. Moreover, the mean linear intercept (Lm) was estimated, as previously described by our group.13 Briefly, 4 random optical fields were selected per lung tissue section, avoiding large vessels or airways. Then, seven equally distributed horizontal lines were superimposed on each field, using the ImageJ software. The total length of each line of the grid was divided by the number of alveolar intercepts, to provide the mean linear intercept (Lm).

cGMP Measurement

cGMP levels were measured in the BAL fluid, as previously described by our group.10 Briefly, following BAL collection, cells were pelleted and incubated in Hanks’ balanced salt solution for 15 min and then lysed with 0.1 N HCl. cGMP levels were analyzed in the extracts using a commercially available enzyme immunoassay kit (Direct cGMP Elisa Kit; Enzo Life Sciences), according to the manufacturer’s instructions. cGMP values were normalized per milligram of total protein.

Statistical Analysis

Data are presented as mean ± standard error of the mean. The one-way analysis of variance (ANOVA) was used for statistical analysis and when significant, with Fisher’s least significant difference (LSD) test for post hoc comparisons (Statistica Software, StatSoft). Analysis of the histological data was performed with the non-parametric Kruskal–Wallis ANOVA. When significant, between two group comparisons were performed with the Mann–Whitney U-test and a Holm–Bonferroni method was followed to correct for multiple comparisons. A p <0.05 is considered as statistically significant. For all measurements (except BAL fluid cytokine levels), sham operated or tracheal banding groups that received normal saline, either inhaled or intraperitoneally, were pooled into one group.


The Effect of Resistive Breathing on BAL Cellularity Following Endotoxin Exposure

LPS aerosol exposure resulted in a significant increase of the total cell count in BAL fluid (p < 0.001 to ctr, Figure 1), due to raised neutrophil numbers (p < 0.001 to ctr) (differential cell percentages are presented in Table 1). Superimposed RB for 24h on LPS aerosol exposure significantly augmented both macrophage (p < 0.001 to LPS inh) and neutrophil count (p = 0.004 to LPS inh). Total cell count in BAL fluid was increased following intraperitoneal LPS exposure (p < 0.001 to ctr), caused by increased macrophage numbers (p < 0.001 to ctr). RB for 24h did not affect BAL cellularity following LPS ip exposure. Lymphocyte count was not affected by either LPS aerosol exposure (ANOVA, p = 0.185), or LPS ip administration (ANOVA, p = 0.354).

Table 1 Differential Cell Percentage in BAL Fluid Following Either Aerosol (Inhalation) or Intraperitoneal Endotoxin (LPS) Administration and the Synergistic Effect of Resistive Breathing (RB)

Figure 1 BAL cellularity following resistive breathing and endotoxin exposure. Increased total cell count in BAL fluid was noticed following LPS inhalation (A), due to infiltration of neutrophils. Combined resistive breathing and inhaled LPS further increased total cell number, due to rise of both macrophages (B) and neutrophils (C). In contrast, combination of RB and intraperitoneal LPS did not cause a further increase in total cell numbers, compared to each treatment alone. Data presented as mean ± sem, with overlapped data points, n=7–13 per group, *p<0.05 to ctr, #p<0.05 to LPS inh.

The Effect of Resistive Breathing on Total Protein Levels in BAL Fluid Following Endotoxin Exposure

Total protein levels in BAL fluid, an indirect marker of lung permeability,14 were increased by LPS aerosol inhalation (p < 0.001 to ctr) (see Figure 2). Combining 24h of RB plus LPS aerosol resulted in an additive effect on total protein levels in BAL fluid (~35% increase, p = 0.016 to LPS inh). Combining RB and LPS ip exposure did not result in a significant change in total protein levels in BAL fluid, in comparison to each treatment alone.

Figure 2 BAL total protein levels following resistive breathing and endotoxin exposure. Increased total protein in BAL fluid was noticed following LPS inhalation. Combining resistive breathing with inhaled LPS caused a further increase of total protein. LPS ip also increased protein levels in BAL fluid, however, a combination of RB and intraperitoneal LPS did not cause a further rise. Data presented as mean ± sem with overlapped data points, n=5–9 per group, *p<0.05 to ctr, #p<0.05 to LPS inh.

The Effect of Resistive Breathing on Respiratory System Mechanics Following Endotoxin Exposure

As we have previously reported, resistive breathing alone resulted in decreased respiratory system compliance and increased total resistance, a finding supporting the presence of acute lung injury (p = 0.009 and p = 0.01 to ctr, respectively). LPS inhalation did not affect respiratory system mechanics, neither dynamic compliance nor total resistance, either alone or after combining with resistive breathing (Figure 3). In contrast, intraperitoneal LPS resulted in decreased compliance and increased resistance of the respiratory system (p = 0.004 and p = 0.01 to ctr, respectively), although no synergy was observed when combined with resistive breathing.

Figure 3 Respiratory system mechanics following resistive breathing and endotoxin exposure. Resistive breathing alone was associated with increased resistance (A) and decreased dynamic compliance (B), compared to control. Inhalation of LPS did not result in a derangement of respiratory system mechanics. In contrast, ip LPS increased resistance and decreased dynamic compliance, although no synergy was observed, when combined with resistive breathing. Data presented as mean ± sem with overlapped data points, n=5–11 per group, *p<0.05 to ctr.

The Effect of Resistive Breathing on BAL Fluid Cytokine Levels Following Endotoxin Exposure

As expected, inhaled LPS resulted in a significantly raised IL-6 protein level in BAL fluid compared to control (p < 0.001), however combining RB and LPS did not result in augmented IL-6 levels (p = 0.14 to LPS inhalation). In contrast, the addition of resistive breathing to LPS inhalation increased TNFa levels in BAL fluid, compared to endotoxin alone (~3-fold, p = 0.011) (see Figure 4). Intraperitoneal administration of LPS did not affect TNF or IL-6 in BAL fluid, under our experimental settings [TNFa (pg/mL) control 2.74 ± 1.34, LPS ip 1.84 ± 0.45, p = 0.55, IL-6 (pg/mL) control 4.89 ± 1.12, LPS ip 9.68 ± 2.10, p = 0.15].

Figure 4 Protein levels of inflammatory cytokines in BAL fluid following resistive breathing and inhalational LPS administration. Inhalation of LPS caused a significant increase in ΙL-6 level in the BAL fluid that was not further increased by resistive breathing (A). On the other hand, combining RB with inhaled LPS resulted in a significant synergy in TNFα protein levels in BAL fluid, compared to LPS alone (B). Data presented as mean ± sem with overlapped data points, n=5–12 per group, *p<0.05 to ctr, #p<0.05 to LPS inh.

The Effect of Resistive Breathing on Histological Features of Lung Injury Following Endotoxin Exposure

Adding resistive breathing to LPS administration significantly increased the total lung injury for both inhalation (p = 0.001) and intraperitoneal (p = 0.022) LPS administration (see Figure 5). Regarding the individual histological features, resistive breathing added to inhalation LPS administration mainly increased interstitial and intra-alveolar leukocyte infiltration, while when added to intraperitoneal LPS administration, RB augmented capillary congestion and interstitial leukocyte infiltration (for a complete description of histological indices of lung injury please see Table 2). No statistically significant difference was detected for the mean linear intercept (Lm), neither after inhaled nor after intraperitoneal LPS exposure (ANOVA, p = 0.74 and p = 0.30, respectively, Table 3).

Table 2 Histological Features of Lung Injury Following Either Aerosol (Inhalation) or Intraperitoneal Endotoxin (LPS) Administration and the Synergistic Effect of Resistive Breathing (RB)

Table 3 Mean Linear Intercept (Lm) of Lung Tissue Sections Following Either Aerosol (Inhalation) or Intraperitoneal Endotoxin (LPS) Administration and the Effect of Resistive Breathing (RB)

Figure 5 Histological evidence of lung injury following resistive breathing and endotoxin exposure. Upper: Combining resistive breathing with LPS exposure, either inhaled or intraperitoneal, resulted in a significant augmentation of histological lung injury, compared to each exposure alone. Lower: Representative figures of H&E-stained lung tissue sections (x400 magnification) from all experimental groups. Please note the significant augmentation of lung injury when RB was combined to LPS inhalation (mainly due to increased interstitial and intra-alveolar leukocyte infiltration) and to LPS ip exposure (mainly due to increased interstitial leukocyte infiltration and capillary congestion). Data presented as mean ± sem with overlapped data points, n=7–15 per group, *p<0.05 to ctr, #p<0.05 to LPS inh, ^p<0.05 to LPS ip.

The Effect of Resistive Breathing on cGMP Levels Following Endotoxin Exposure

Combining resistive breathing with inhalational LPS exposure caused a synergistic reduction in cGMP levels, compared to LPS alone (p = 0.04) (Figure 6). On the contrary, the reduction in cGMP levels following addition of RB to intraperitoneal LPS was not statistically significant, compared to LPS alone (p = 0.11).

Figure 6 cGMP levels following resistive breathing and endotoxin exposure. As previously described by our group, both RB and LPS exposure reduced cGMP levels in BAL, relative to control values. Combining RB with inhaled LPS caused a significant further reduction in cGMP levels, compared to LPS alone, an effect that was not seen when RB was added to intraperitoneal LPS. Data presented as mean ± sem with overlapped data points, n=5–6 per group, *p<0.05 to LPS inh.


The key outcome of our study is that resistive breathing exaggerates pulmonary inflammation and injury caused by either inhaled or intraperitoneally administered LPS, with the more significant synergistic effect being noticed in inhalational LPS injury.

Resistive breathing is amongst the main pathophysiological features of obstructive airway diseases, such as COPD, especially in severe stable state and while on exacerbation. In stable COPD, mainly due to cigarette smoke exposure, small airway inflammation and remodelling and loss of alveolar attachments results in airway obstruction and airflow limitation15,16 During exacerbations, excessive inflammation triggered by various stimuli, including bacterial infections, exaggerates airflow limitation leading to resistive breathing.6 RB results in severe mechanical stress on the lung, due to forceful contractions of the diaphragm to overcome increased resistance, that causes more negative intrathoracic pressures and/or the presence of hyperinflation, due to raised expiratory resistance.7 Although increased mechanical stress has been clearly shown to promote lung injury, especially during the application of mechanical ventilation,17 the significance of mechanical forces in the natural course of airway diseases is largely unknown. Indeed, recent data have suggested that mechanical stress may promote the progress of COPD.18

We have shown in a series of studies that the induction of resistive breathing (to mimic severe airway obstruction) provokes pulmonary inflammation and injury.8,19 However, since these studies were performed in previously healthy animals, the effect of resistive breathing in the presence of acute inflammation, such as during an infectious exacerbation, is largely unknown. Pseudomonas aeruginosa infection is a common cause of a COPD exacerbation,20 especially amongst severe patients21 and bacterial colonization is associated with increased frequency of COPD exacerbation.22 The net outcome is an augmentation of systemic and pulmonary inflammation during a COPD exacerbation, compared to baseline.23

Our results showed that combining resistive breathing with inhalational LPS exposure resulted in a significant increase in pulmonary inflammation. As expected, LPS exposure induced neutrophilic inflammation that was further augmented when combined with resistive breathing. Interestingly, when resistive breathing was added to LPS exposure, the macrophage number also increased, compared to inhaled LPS alone. In accordance, Rizzo et al reported increased BAL neutrophilia, when intratracheal LPS was combined with raised mechanical stress applied to the lung, through high tidal volume mechanical ventilation.24 As previously reported, inhaled LPS induced the expression of proinflammatory cytokines in BAL fluid, including IL-6 and TNF-a in vivo,25,26 and in vitro, treatment with LPS resulted in increased expression of IL-6 and TNF-a in both macrophages and neutrophils.27 Our data suggest that resistive breathing exerts a synergistic effect by augmenting pro-inflammatory cytokine expression in the lung in combination with LPS exposure.

The increased levels of total protein in BAL fluid suggest that combining resistive breathing with inhaled LPS also aggravated the derangement of lung permeability, although it must be acknowledged that the total protein level in BAL fluid is an indirect and not specific marker of lung epithelial permeability.28 This is in accordance with a previously presented study in mice, where a “two-hit” model of lung injury was established by combining LPS or acid (HCL) intratracheal exposure and increased mechanical stress applied to the lung, through high tidal volume ventilation.29 Exposure to LPS aerosol alone was not associated with a derangement in the mechanical properties of the respiratory system in our experimental settings. In contrast, resistive breathing, as has been previously shown by our group,8 resulted in decreased compliance. When combined with RB, inhaled LPS numerically decreased the dynamic compliance of the respiratory system, probable to the greater increase in alveolar-capillary permeability, compared to LPS alone, although this finding did not reach statistical significance (p = 0.09).

Regarding the histological analysis, adding resistive breathing to LPS-induced lung injury significantly increased neutrophil infiltration in the lung. Although our study has the limitation that it did not investigate the underlying molecular mechanism for the increase in pulmonary inflammation, some assumptions can be made. Interestingly, both inhaled LPS and resistive breathing have been shown to reduce soluble guanylyl cyclase (sGC) levels in the lung and in both models further pharmaceutical inhibition of sGC, led to augmentation of lung injury.8,10 Thus, it is plausible that combining resistive breathing with LPS exposure could lead to further inhibition of the sGC pathway and worse outcomes. Indeed, combining RB with LPS resulted in a further reduction in cGMP levels in the BAL, compared to LPS alone, although this effect was statistically significant only for inhalational LPS exposure. Moreover, in vivo, expression microarray analysis revealed that when intratracheal LPS exposure was combined with mechanical stress, the great percentage of highly expressed genes belonged to the inflammatory/immunity cascade.30

The combination of intraperitoneal endotoxin with resistive breathing resulted in a modest synergy, as shown by the histological analysis ie, increased capillary congestion and interstitial leukocyte infiltration in the combined group. In contrast, no synergy was detected in lung permeability, BAL cellularity and derangement of mechanics. Although a direct comparison between inhaled and systemic (intraperitoneal) administration of LPS is out of scope of our study, differences in the features of acute lung injury between the two models (eg, the lack of intra-alveolar neutrophils in systemic LPS exposure) may account for the differential additive effect of resistive breathing. Previously, in contrast to our results, Altemeier et al reported that combining systemic endotoxin administration (intravenous LPS) with mechanical ventilation results in augmented cytokine production in the lung and altered lung permeability, compared to LPS i.v. alone.31

The development of a “two-hit” animal model allows a better simulation of complex clinical states, such as the COPD exacerbation. Hitherto, LPS exposure has been combined with models of stable COPD, such as cigarette smoke exposure, to investigate the effects of acute LPS exposure on lung inflammation and emphysema, given the central role of smoking in lung functional decline in COPD.32 In mice, the combination of sub-acute exposure to cigarette smoke and intratracheal instillation of LPS resulted in augmented pulmonary inflammation.33 Moreover, combination of a single dose of intratracheal LPS with elastase exposure resulted in worsening of pulmonary inflammation in mice and subsequently augmented emphysema progression.34 Interestingly, da Fonseca et al found a synergy between elastase and LPS in pulmonary inflammation, even when LPS was administered intraperitoneally in the same dose, as in our model.35 To our knowledge, our study is the first to combine LPS exposure with resistive breathing. Although, tracheal banding is clinically more relevant to upper airway obstruction, the mechanical consequences of resistive breathing ie, increased airway resistance and forceful contractions of the respiratory muscles, leading to large negative intrathoracic pressures,13 may provide useful insights for the pathophysiology of COPD exacerbations.

In conclusion, our findings suggest that combining LPS with a model of severe airway obstruction aggravates pulmonary inflammation and injury, mainly in intrapulmonary LPS administration, while in systemic LPS exposure, the effect is modest.

Data Sharing Statement

The data of the study are available from the corresponding author on reasonable request.

Ethics Approval

Experimental procedures and protocols were approved by the ethics committee of the Experimental Surgery Department of “Evangelismos” hospital and follow the European Union Directive (2010/63/EU) on the protection of laboratory animals used for scientific causes.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.


Funding for this study was provided by the Thorax Foundation (Athens, Greece).


The authors have no conflicts of interest to disclose in this work.


1. Mathioudakis AG, Abroug F, Agusti A, et al. ERS statement: a core outcome set for clinical trials evaluating the management of COPD exacerbations. Eur Respir J. 2022;59(5):2102006. doi:10.1183/13993003.02006-2021

2. Celli BR, Thomas NE, Anderson JA, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med. 2008;178(4):332–338. doi:10.1164/rccm.200712-1869OC

3. Donaldson GC, Seemungal TA, Patel IS, et al. Airway and systemic inflammation and decline in lung function in patients with COPD. Chest. 2005;128(4):1995–2004. doi:10.1378/chest.128.4.1995

4. Miravitlles M. Exacerbations of chronic obstructive pulmonary disease: when are bacteria important? Eur Respir J Suppl. 2002;36(Supplement 36):9s–19s. doi:10.1183/09031936.02.00400302

5. Hurst JR, Perera WR, Wilkinson TM, Donaldson GC, Wedzicha JA. Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173(1):71–78. doi:10.1164/rccm.200505-704OC

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7. Vassilakopoulos T, Toumpanakis D. Can resistive breathing injure the lung? Implications for COPD exacerbations. Int J Chron Obstruct Pulmon Dis. 2016;11:2377–2384. doi:10.2147/COPD.S113877

8. Glynos C, Toumpanakis D, Loverdos K, et al. Guanylyl cyclase activation reverses resistive breathing-induced lung injury and inflammation. Am J Respir Cell Mol Biol. 2015;52(6):762–771. doi:10.1165/rcmb.2014-0092OC

9. Luo L, Shaver CM, Zhao Z, et al. Clinical predictors of hospital mortality differ between direct and indirect ARDS. Chest. 2017;151(4):755–763. doi:10.1016/j.chest.2016.09.004

10. Glynos C, Kotanidou A, Orfanos SE, et al. Soluble guanylyl cyclase expression is reduced in LPS-induced lung injury. Am J Physiol Regul Integr Comp Physiol. 2007;292(4):R1448–R1455. doi:10.1152/ajpregu.00341.2006

11. Bates JH, Irvin CG. Measuring lung function in mice: the phenotyping uncertainty principle. J Appl Physiol. 2003;94(4):1297–1306. doi:10.1152/japplphysiol.00706.2002

12. Toumpanakis D, Vassilakopoulou V, Mizi E, et al. p38 inhibition ameliorates inspiratory resistive breathing-induced pulmonary inflammation. Inflammation. 2018;41(5):1873–1887. doi:10.1007/s10753-018-0831-6

13. Toumpanakis D, Mizi E, Vassilakopoulou V, et al. Spontaneous breathing through increased airway resistance augments elastase-induced pulmonary emphysema. Int J Chron Obstruct Pulmon Dis. 2020;15:1679–1688. doi:10.2147/COPD.S256750

14. Parker JC, Townsley MI. Evaluation of lung injury in rats and mice. Am J Physiol Lung Cell Mol Physiol. 2004;286(2):L231–L246. doi:10.1152/ajplung.00049.2003

15. Booth S, Hsieh A, Mostaco-Guidolin L, et al. A single-cell atlas of small airway disease in chronic obstructive pulmonary disease: a cross-sectional study. Am J Respir Crit Care Med. 2023;208(4):472–486. doi:10.1164/rccm.202303-0534OC

16. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645–2653. doi:10.1056/NEJMoa032158

17. Curley GF, Laffey JG, Zhang H, Slutsky AS. Biotrauma and Ventilator-Induced Lung Injury: clinical Implications. Chest. 2016;150(5):1109–1117. doi:10.1016/j.chest.2016.07.019

18. Suki B, Sato S, Parameswaran H, Szabari MV, Takahashi A, Bartolak-Suki E. Emphysema and mechanical stress-induced lung remodeling. Physiolog. 2013;28(6):404–413. doi:10.1152/physiol.00041.2013

19. Toumpanakis D, Kastis GA, Zacharatos P, et al. Inspiratory resistive breathing induces acute lung injury. Am J Respir Crit Care Med. 2010;182(9):1129–1136. doi:10.1164/rccm.201001-0116OC

20. Sethi S, Evans N, Grant BJ, Murphy TF. New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 2002;347(7):465–471. doi:10.1056/NEJMoa012561

21. Miravitlles M, Espinosa C, Fernandez-Laso E, Martos JA, Maldonado JA, Gallego M. Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD. Chest. 1999;116(1):40–46. doi:10.1378/chest.116.1.40

22. Patel IS, Seemungal TA, Wilks M, Lloyd-Owen SJ, Donaldson GC, Wedzicha JA. Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations. Thorax. 2002;57(9):759–764. doi:10.1136/thorax.57.9.759

23. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370(9589):786–796. doi:10.1016/S0140-6736(07)61382-8

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Are you struggling to breathe? Are you looking for a solution to naturally improve your breathing and lung health without compromising on safety and efficacy? AirPhysio is an innovative device designed specifically to provide relief from respiratory problems.

This OPEP Device combines natural air pressure with an oscillation that helps clear the lungs of mucus, expand the airways, and reduce breathing difficulty. Through this blog post, we’ll explore AirPhysio’s benefits, what it does, where it came from, and how best to use it.

So, come along as we discuss AirPhysio: All You Need To Know With Latest Updates In 2023!

Content Highlights

  • Airphysio is a handheld device that helps to naturally improve breathing, open and expand airways, and clear mucus.
  • Airphysio utilizes oscillating positive expiratory pressure (OPEP) therapy which creates tiny pressure waves in the lungs during exhalation.
  • Clearing mucus is important for maintaining optimal lung health; AirPhysio makes it easier to do so with its effective OPEP therapy.
  • The device has been featured on Modern Living with Kathy Ireland®, 7 News Gold Coast, and discussed by the Federal Minister of Dawson – demonstrating its effectiveness in relieving symptoms associated with respiratory conditions such as asthma, COPD, bronchiectasis & cystic fibrosis.

Benefits of Airphysio

Benefits of Airphysio
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In this segment, we’ll be discussing a few benefits of Airphysio.

Naturally, Improve Breathing

AirPhysio is a unique mucus clearance and lung expansion device that uses Oscillating Positive Expiratory Pressure (OPEP) as an alternative to traditional treatments. This effective remedy utilizes positive pressure and vibrations to clear the airways from congestion while also strengthening and expanding the lungs for easier breathing.

It’s an innovative, drug-free option that can be used by people with different respiratory issues such as asthma, COPD, bronchiectasis, or cystic fibrosis. AirPhysio helps improve quality of life without the use of any medication; it allows natural breathability by creating smooth airflow in a simple yet sophisticated manner.

By using regular positive pressure during expirations, just like during normal inhalations but reversed this device helps restore balance in breathing states improving oxygen flow overall and promoting better health naturally.

Improve Lung Health

AirPhysio is a revolutionary device that uses Oscillating Positive Expiratory Pressure (OPEP) technology to naturally improve breathing, open and expand airways, and clear mucus. This helps to boost lung health for people living with conditions like asthma, COPD, or cystic fibrosis.

OPEP creates tiny pressure waves in the lungs, stimulating expired air drainage when exhaling out of the nose or mouth. It works by strengthening respiratory muscles on the way up and down — resulting in better airflow through your lungs over time.

Additionally, users have reported feeling less breathless after using AirPhysio during their workouts, proving it’s an invaluable tool for maintaining optimum lung exercise performance as well as speeding up recovery times after exercise.

Open & Expand Airways

The AirPhysio OPEP device helps promote better lung health by opening up semi-closed airways and expanding them to an optimal size. The oscillations that come from using the device can help regulate airflow throughout the lungs, facilitating easier breathing.

Regular use allows users to experience improved lung function and relief from respiratory issues. The device’s motion also encourages mucus clearance which helps reduce infection risk and improve overall respiratory hygiene.

The range of motion created by AirPhysio is great enough for deep breathing exercises which oxygenates the body whilst helping to keep those with lung conditions healthy.

Clear Mucus

Mucus accumulation in the lungs can lead to respiratory problems, especially for those already suffering from asthma and other related breathing issues. Clearing mucus is an important factor in maintaining optimal lung health.

The AirPhysio device makes it easier to do so using Oscillating Positive Expiratory Pressure (OPEP) therapy, which produces gentle pulses of air that expand the lungs and reduce mucus viscoelasticity.

This combination helps open up airways while loosening and clearing congestion from within the chest cavity – resulting in better overall breathing quality. Using this cutting-edge technology helps improve your breathing capacity over time as well as your long-term pulmonary health, aiding people with current respiratory concerns or preventing any further ones down the line. Additionally, you can also read about how Breathing Polluted Air in Childhood Affects Mental Health.

What is the AirPhysio OPEP Device?

AirPhysio OPEP Device
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The AirPhysio OPEP Device is a unique, handheld device that aids in naturally improving breathing and lung health by helping to open and expand airways, clear mucus, and provide other beneficial effects.

Overview and Function

The AirPhysio OPEP device is a handheld respiratory device designed to naturally improve breathing, improve lung health, open and expand airways, and clear mucus. It uses Oscillating Positive Expiratory Pressure (OPEP) therapy combined with simple physics principles to create positive pressure in the lungs and airway when used correctly.

Once inhaled into the mouthpiece of the device, users then blow out through two valves that work together to generate vibrations, compressions, and expirations which help loosen mucus buildup from deep within the airways before it can be exhaled – resulting in improved breathability and clearer lung passages and better oxygen intake.

The simplicity of its design makes it easy to use while also being highly effective at helping to prevent respiratory issues related to asthma or chronic obstructive pulmonary disease (COPD).

Importance of Mucus Clearance

The mucus is a key part of the lung system; its role in preventing and fighting infection, helping to humidify air, and keeping your airways clear can never be understated. It’s therefore critical that mucus clearance is properly managed for optimal pulmonary health.

Chronic obstructive pulmonary disease (COPD) sufferers particularly need to pay special attention as the build-up of mucus within their lungs may increase the risk for further problems. AirPhysio provides an all-natural oscillating Positive Expiratory Pressure therapy providing effective clearance of thickened secretions observed in asthma, COPD, or cystic fibrosis patients leading to improved lung function and increased efficiency in treatment outcomes.

The device applies gentle vibrations while inhaling which helps move stuck Phlegm (Assumedly when coughing does not help sufficiently) thus allowing deeper breathing with less effort than conventional methods such as huffing or pursed lip breathing exercises normally used by people with chronic respiratory conditions like asthma, bronchitis etc due to constricted airway passages.

The vibrational forces generated target loosening stubborn mucous plugs from the walls of differing shapes found throughout the respiratory tree at larger bronchi divisions through smaller tributaries ultimately improving both airflow velocities and patient comfort levels associated with acute flare-ups commonplace among COPD sufferers.

Impact on Lung Function

AirPhysio has been clinically proven to improve lung function, as it helps open and expand airways while clearing mucus. By increasing airflow into the lungs, AirPhysio can reduce breathlessness and provide relief from symptoms of asthma, COPD, and cystic fibrosis.

The device uses Positive Expiratory Pressure (PEP) technology, designed to create airway resistance upon exhale that helps break down mucus plugs so they can be removed more easily from your body.

This process also reduces fluid buildup in the lungs, leading to improved lung capacity, and allowing those suffering from respiratory diseases to access a new level of breathing comfort without needing inhaled medication or traditional inhalers.

AirPhysio in the Media

Learn more on how AirPhysio has made waves in the media and be sure to check out their entertaining video testimonials!

Appearance on Modern Living With Kathy Ireland®

AirPhysio recently became a household name after it appeared on Modern Living with Kathy Ireland, a popular TV show that is broadcast to an international audience. The Managing Director of AirPhysio, Paul O’Brien was featured in the discussion, and he talked about the device’s ability to improve breathing, open airways, and clear mucus naturally – all of which are important aspects for maintaining lung health.

The success of this appearance has galvanized the device as being an effective tool for respiratory therapy & mucus clearance among many viewers as to date there have been repeated interviews on 7 News Gold Coast and discussions with Federal Minister Cameron Dicker confirming in aid.

Kathy Ireland serves as a reliable host, and her mention goes a long way towards giving customers comfort when seeking out products related to our wellness.

Interview on 7 News Gold Coast

The AirPhysio device recently gained immense attention when it was featured on 7 News Gold Coast in 2023, dedicating a full segment to discuss the latest updates and benefits of using this revolutionary new respiratory device.

During the interview, the Federal Minister of Dawson praised the effectiveness of AirPhysio in helping individuals with pulmonary conditions achieve better lung health through mucus clearance.

An impressive podiatrist also highlighted how he has already seen vast improvements in his patient’s breathing since beginning therapy with AirPhysio. Further discussing its features and applications on airway opening and expanding capabilities that come from compression waves breaking up mucus inside lungs, Therefore highlighting the importance of regular cleaning for optimal lung function – by for example removing sticky phlegm or clearing blocked bronchi considerably quicker without needing medication.

Discussion With the Federal Minister of Dawson

The discussion between George Christensen, the Federal Minister for Dawson, and Airphysio was widely covered in the media. The purpose of this important exchange was to provide readers (erstwhile potential customers) with comprehensive updates on the advancements and availability of the AirPhysio lung care device in 2023.

During the interview, Minister Christensen discussed updates about increased product availability across Australia as well as internationally. He also highlighted various solutions such as access to clinical-grade mucus clearance technology through OPEP Devices which are easily available through a prescription from your doctor or other healthcare provider, allowing people suffering from COPD and other respiratory conditions to have access to an effective tool to aid their breathing issues.

Mentions official Australian government statement confirming that 90% of COPD cases reported amongst Australians could be eliminated if people took preventive measures such as regular mucus clearance brought forward by Airphysio’s powerful devices – a message reiterated during his communication with facts providing evidence toward effective procedural protocols recommended by doctors around the globe – minister Christiansen closed off emphasizing idea of maintaining personal responsibility towards own health and wellbeing provided innovative tools made life easier by making procedures more pleasant rather than painful experience majority is used too from traditional treatments.

Testimonials From Satisfied Customers

Hear from those who’ve experienced the benefits of AirPhysio first-hand with video testimonials, and register for a warranty to ensure top-quality care.

Warranty Registration

AirPhysio understands how important customer satisfaction is, and offers a comprehensive warranty registration process to ensure customers get the most out of their device. With an included 30-day satisfaction guarantee and a 1-year limited warranty, customers can become confident in their purchase knowing that they’ll receive quality support should they need it.

By registering with AirPhysio, links are made between the AirPhysio product/version and a customer’s contact details which allows for personalized support from Support Consultants when needed.

This ensures maximum career of the device as well as providing real answers to any questions or queries allowing customers to continue benefiting from using their airphysio devices.

The Science Behind AirPhysio

Research suggests that regular use of the AirPhysio OPEP device can positively impact lung health by improving airways and clearing mucus.

Importance of Lung Hygiene and Fitness

Maintaining optimal lung health is essential for overall well-being. In order to keep our lungs healthy, we need to practice good respiratory hygiene and fitness. Good lung hygiene means regularly clearing out mucus in the lungs which can build up and lead to severe conditions such as asthma, COPD, and cystic fibrosis.

Additionally, regular exercise helps maintain a strong cardiovascular capacity for better breathing during physical activity or when exposed to allergens or smoke. AirPhysio devices help with this process by opening airways and assisting our body’s natural cleaning system; they provide effective support in maintaining a healthy level of mucus clearance which can have a huge impact on our breathing ability.

Through expanding bronchial passages and efficient removal of excess mucus from the lungs, AirPhysio makes it easier to take deep breaths while also improving the exchange of oxygen into the bloodstream for better functioning throughout daily activities.

How Mucus Clearance Affects Lung Function

Mucus, produced by the mucosa of the airways – including bronchi and alveoli – performs an important role in protecting lung tissue from inhaled environmental irritants. However, when left to accumulate, it can have serious consequences for both preventative and acute breathing health.

Clearing out the pocketed air that accumulates in the lungs due to mucositis is vital for proper respiration. The AirPhysio OPEP (Oscillating Positive Expiratory Pressure) device uses oscillations to create a “pulse” that breaks down and removes excess accumulated muces through deep coughing motions.

This helps ensure proper ventilation within various parts of the respiratory system, improving overall lung function including increased airflow, improved breath capacity, and reduced inflammation caused by over-accumulation of mucus.

The Dangers of Smoking

Smoking can have a serious and lasting impact on your lung health, underscoring the importance of regular mucus clearance for optimal fitness.

Impact on Lung Health

Cigarette smoking is one of the leading causes of lung cancer and chronic obstructive pulmonary disease (COPD). Smoking cigarettes can lead to acute changes in the lungs, causing airflow resistance, cough, wheezing, and breathlessness.

Vaping has been proven to decrease mucus clearance from the lungs which results in an increased susceptibility for infections. Fathers who smoke or have smoked previously can pass on genetic issues that increase their children’s likelihood of developing pulmonary edema—a condition where fluid accumulates within the lungs due to prolonged exposure to cigarette smoke or other triggers like genetics.

Inhaling tobacco smoke damages airways and accelerates cellular aging. Consequently, studies showed that 92% of all lung cancer deaths are attributed entirely or partly to smoking habits indicating how hazardous it is for longevity and health long term.

Importance of Regular Mucus Clearance

Regular mucus clearance is important to maintain lung health as the process helps to prevent infections and promote efficient breathing. Inhaled particles, such as dirt, allergens, or pollutants can get trapped in the lungs by a sticky layer of mucus.

This collection of materials is known as sputum or mucus and needs to be removed from time to time so that the lungs are not impaired by it. The physiological mechanism by which this happens is termed ‘mucociliary clearance’, wherein cilia – tiny hairlike projections inside our airways assist with flushing out unwanted substances like bacteria & viruses from the respiratory system while a sticky layer of mucus helps trap them before they reach deep into your airway tissue.

It has been found that smoking and vaping can negatively impact this process due to irritation caused, making people with chronic respiratory conditions more vulnerable to contracting an infection. If you want, you can also read How to Deal With Bad Breath Effectively.

How to Use AirPhysio

Carefully follow the instructions provided in the user manual for safe and effective use.

Directions for Use

Using the AirPhysio device is simple and easy. First, thoroughly wash your hands with water and soap before handling the device. Then, disassemble the device so you can clean each part separately in warm soapy water or using a misty sanitizer made for medical equipment.

Once that’s done, use the included adaptor to connect your phone/tablet directly to the OPEP unit of the Airphysio. Unlock the mouthpiece and set it up against your lips as if playing a flute, just like shown in its instructions book.

Place both thumbs gently on top of either side of its cellophane wings while blowing into it regularly following its recommended breathing techniques which are explained in detail in its user manual.

Warnings and Safety Precautions

It is important to read and follow the User’s Guide for AirPhysio carefully before use. Use of AirPhysio should be avoided if a patient has asthma, severe airway obstruction diseases, or any bleeding or ulcerated lesions in the nose or throat until consulted with a medical professional.

Re-hydrationSteam inhalation with saline solution should occur prior to OPEPuse as well as take breaks from using the device every 15 minutes during treatments for best results. Make sure to position yourself at an angle slightly tilted towards your dominant side when inhaling/exhaling through Airphysio so that lung capacity is maximized and mucus can effectively exit via the cough mechanism afterward.

Lastly, it’s important that any accessories come with FDA-approved packaging only; refer to manual and safety instructions properly before beginning experimentations with product modifications.

Where to Purchase AirPhysio

Customers can conveniently purchase AirPhysio online through the company’s website or in select retailers across Australia.

Online and Offline Options

The AirPhysio device is available for purchase online from major retailers including and, where you can find the best price and different packages to choose from. Depending on your local area, there may be some offline stores that also carry the product such as pharmacies or convenience stores. You can also purchase helpful add-ons with your original purchase such as replacement filters or additional attachments for various breathing therapies.

Add-ons and Purchase Options

AirPhysio devices are available with add-ons and purchase options to cater to different requirements. Options include the single device, two airway cleaning system packages, three package special editions, and accessories bundles. Each option includes a warranty registration card which offers a 25% discount on any additional purchases as well as access to ongoing product updates and customer support.

Alternative Products and Resources

Consumers looking for similar products can explore brands available on Amazon, read customer reviews and ratings to make an informed purchase decision or find additional resources with airway health information.

Similar Brands on Amazon

There are a few alternative devices available on Amazon that compete with AirPhysio, such as PumStyl and Boiron Respiratory Care. The PumStyl is a pocket-sized device that utilizes pressure wave technology to help open airways and increase airflow into the lungs with each breath.

Boiron Respiratory Care is a plant-based dietary supplement designed to reduce respiratory discomfort associated with colds, allergies, sinus irritations, coughs, and sore throats. Both of these alternatives claim to offer an easier and more natural way for people to experience relief from breathing difficulties without the need for medications or over-the-counter medicines.

Though similar in idea to Airphysio’s OPEP device, both products have different designs which can affect their effectiveness in improving outcomes related to breathing & lung health and mucus clearance.

Customer Reviews and Ratings

Despite having limited reviews or feedback from medical organizations like the NHS, AirPhysio has still earned a remarkable reputation through customer feedback. With 180+ reviews on Amazon alone, the device boasts an average rating of 4.2 out of 5 stars; customers have found it to be reliable and efficient for clearing mucus from their lungs with added benefits to respiratory health.

The vast majority of positive experiences highlight AirPhysio’s effectiveness in improving lung fitness and overall breathing comfort. However, there have been some cases where consumers claim they did not notice any major difference using the device – leading them to question its effectiveness.

Nonetheless, these negative experiences are quite rare when compared to the impressive amount of satisfied consumers who regularly report small victories after several weeks of using this device consistently even though results vary across individuals.

Additional Resources

For readers looking for more information on airway health and mucus clearance, it’s important to explore what other resources are available. Many similar products such as the VersaPAP device can be found on Amazon, offering many of the same benefits as AirPhysio.

It is always important to do research and read customer reviews before using any product; this applies especially when considering lung-health-related treatments or gadgets. Additionally, websites like Masterson Method provide educational materials about breathing mechanics for those hoping to maintain proper lung hygiene with a holistic approach.

Lastly, organizations like the National Heart and Lung Blood Institute offer valuable educational tools and programs around respiratory healthcare solutions that could be beneficial in preventative healthcare routines related to airway management.

Frequently Asked Questions (FAQs)

Now, let’s delve into some frequently asked questions regarding Airphysio.

1. What is Airphysio?

Airphysio is a new device that uses pulsed air pressure to help open the lungs, loosen mucus, and reduce breathing difficulty for people with respiratory issues such as asthma or COPD.

2. How does Airphysio work?

Airphysio works by delivering short pulses of air pressure into the lungs through a mouthpiece connected to the device. The pulses deeply penetrate into your chest and vibrate against your throat walls which helps break up thick mucus and fluid in order to keep your airways clear.

3. Who can benefit from using Airphysio?

People with asthma, chronic bronchitis, COPD, cystic fibrosis, lung scarring (pulmonary fibrosis), smoker’s coughs, or other lung-related conditions may find relief from symptoms when using Airphysio regularly as part of their daily routine.

4. Are there any side effects associated with using Airphysio?

No adverse side effects have been reported so far from using Airphyso regularly; however, if you experience increased discomfort during use it would be recommended to consult your physician before continuing treatment whilst being monitored for any unexpected reactions over time.


AirPhysio is a great device to help with respiratory health and lung expansion. It’s easy to use, powered by air, and clinically proven to be effective. It uses the natural process of oscillating positive expiratory pressure (OPEP) for clearing mucus and expanding lungs, helping those suffering from conditions such as asthma, COPD, bronchiectasis, and cystic fibrosis breathe easier.

The device has seen widespread success in being covered on shows like Modern Living with Kathy Ireland® as featured testimonials have praised its effectiveness in relieving symptoms associated with these illnesses.


Disclaimer: This content is for informational purposes only and does not replace professional medical advice, diagnosis, or treatment. This information is not comprehensive and should not be used to make health or well-being decisions. Consult a qualified healthcare professional with questions about a medical condition, treatment options, or health regimen. This website or the content should never replace professional medical advice.

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New York, NY, Sept. 29, 2023 (GLOBE NEWSWIRE) -- Zion Market Research has published a new research report titled “High-Flow Nasal Cannula Market By End-User (Long-Term Care Centers, Hospitals, Ambulatory Care Services, And Others), By Application (Carbon Monoxide Toxicity, Acute Respiratory Failure, Bronchiectasis, Chronic Obstructive Pulmonary Disease (COPD), Sleep Apnea, And Others), By Component (Nasal Cannulas, Air Humidifiers, Single Heated Tubes, Air/Oxygen Blenders, And Others), And By Region - Global And Regional Industry Overview, Market Intelligence, Comprehensive Analysis, Historical Data, And Forecasts 2023 – 2030” in its research database.

“According to the latest research study, the demand of global High-flow Nasal Cannula Market size & share in terms of revenue was valued at USD 7.45 billion in 2022 and it is expected to surpass around USD 18.65 billion mark by 2030, growing at a compound annual growth rate (CAGR) of approximately 12.18% during the forecast period 2023 to 2030.”

What is High-flow Nasal Cannula? How big is the High-flow Nasal Cannula Industry?

Report Overview:

The global high-flow nasal cannula market size was worth around USD 7.45 billion in 2022 and is predicted to grow to around USD 18.65 billion by 2030 with a compound annual growth rate (CAGR) of roughly 12.18% between 2023 and 2030.

A medical equipment known as a high-flow nasal cannula is utilized in order to facilitate heated humidified high-flow therapy, which is more commonly referred to simply as high-flow therapy. The cannula is a component of a respiratory support system that is utilized in the process of providing patients who are afflicted with respiratory ailments with a steady flow of therapeutic gas through the system. The high-flow nasal cannula's most notable quality is that it facilitates the delivery of sixty liters of therapeutic gas per minute in addition to one hundred percent oxygen. The nasal cannula that is used traditionally for medical gas delivery systems and is able to supply 1-6 liters per minute of medical gas has been partially replaced by the high-flow nasal cannula, which has helped to facilitate this replacement.

Patients who are suffering from respiratory disorders that are either life-threatening or serious can have their medical demands covered by the device because it enables high flow. Patients who are breathing on their own but are experiencing respiratory obstruction or failure as a result of illnesses such as bronchiolitis, acute exacerbations of chronic obstructive pulmonary disease (COPD), congestive heart failure, asthma, pneumonia, and several other conditions are often the ones who benefit from this treatment. As the number of people who require medical treatment around the world continues to rise, the market for high-flow nasal cannulas is expanding at a breakneck speed. It is anticipated that there will be a continued increase in the demand for high-performance high-flow nasal cannulas over the course of the period covered by the forecast.

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Global High-flow Nasal Cannula Market: Growth Factors

Market expansion will be driven by an increase in the number of patients reporting acute exacerbations of COPD.

It is anticipated that the global market for high-flow nasal cannula will expand as a result of an increase in the number of patients suffering from acute exacerbations of COPD. This disorder is a long-term inflammatory lung disease that can cause the outflow of air from the lungs to become restricted. Excessive exposure to irritating gasses or particulate matter, like that which is found in cigarette smoke, is one of the primary contributors to the development of COPD in a patient. Mucus production, coughing, wheezing, and difficulty breathing are some of the associated symptoms. According to the findings of many research, those who have COPD are at an increased risk of developing lung cancer, more serious forms of heart disease, and other life-threatening disorders. More than 3.23 million people are said to have passed away as a direct result of having chronic obstructive pulmonary disease, as stated in the figures that were published by the World Health Organization (WHO). It is regarded as the third most important factor in causing death across the entire world. The term "acute exacerbations" refers to the rapid deterioration of COPD symptoms that can lead to considerable difficulties breathing. Alterations in the meteorological conditions, respiratory infections, and resistance to medical treatment are some of the factors that have been identified as potential causes for the abrupt increase. When this occurs, the high-flow nasal cannula is the primary treatment method that is implemented since it provides an important amount of oxygen until the symptoms are cured.

The rising levels of air pollution around the world will drive up demand.

Air pollution is a problem that affects the entire world. It is a concern for the health of the general population because rising levels of fine particulate matter in the air combined with the release of harmful gasses can trigger exciting respiratory conditions in patients while also inducing breathing issues in newborns or people who have no previous history of having issues with their breathing. People who breathe in air that has been polluted, for example, put their health at risk since the air is of low quality and does not contain adequate amounts of oxygen. This can lead to a variety of major health problems. In the event that air pollution keeps getting worse, the size of the worldwide high-flow nasal cannula market is expected to expand.

High-flow Nasal Cannula Market: Factors That Are Holding It Back

Because of the high cost of equipment and subsequent therapy, market expansion will be restricted.

A high-flow nasal cannula comes at a significant financial investment. For instance, the price of a typical high-flow nasal cannula begins at around $2,000 and can go higher depending on the functionality and other characteristics of the device. In addition to this, a study that was released by the National Institute of Health (NIH) showed that the anticipated cost of using a high-flow nasal cannula in the United States was somewhere in the neighborhood of USD 368 per patient. In addition, the total cost of treatment is significantly greater than originally estimated due to the inclusion of additional charges that are linked with the process, such as the cost of staying in the hospital, having insurance coverage, receiving complementary medical treatments, and paying for various other fees. It is expected that the expansion of the high-flow nasal cannula sector will be hampered by the high cost of both the equipment and the treatment as a whole.

Opportunities Available in the High-flow Nasal Cannula Market

The increasing availability of cutting-edge high-flow nasal cannulas is expected to generate more opportunities for growth.

Since the impact of COVID-19, more efforts have been made into the development of superior-performance high-flow nasal cannulas that fulfill the needs of patients as well as the expectations placed on medicine. This has resulted in a welcome increase in the number of sophisticated alternatives that are currently available on the market. For instance, the Intersurgical i-floTM high flow nasal cannula that was designed by Intersurgical, a provider of complete respiratory systems, places an emphasis on the task at hand as well as the patient's level of comfort. It is an adult single-use patient interface that comes with a variety of features that are exclusive to themselves.

Increasing spending on healthcare around the world to provide more hospitals and clinics with access to high-flow nasal cannulas.

A jump in global healthcare expenditures has been caused by an increase in the number of patients as well as an increase in the demand for equal access to medical care. These costs have been absorbed by regional governments as well as private healthcare corporations. The need for high-flow nasal cannulas is expected to be a driving force behind the expansion of the global market in the years to come, thanks to the rise in the number of new medical facilities being constructed all over the world.

The Challenges Facing the High-flow Nasal Cannula Market

Due to the stringent guidelines, effective resource management is required to create growth challenges.

The industry of high-flow nasal cannulas is subject to stringent guidelines and regulatory procedures, which can vary significantly depending on where in the world you are. There is no room for error with these gadgets because they are essential to the health of the patient. Companies that are active in this area may face difficulties if they are unable to effectively manage essential resources such as time and money while also conforming to ever-changing compliance regulations.

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Report Scope

Report Attribute Details
Market Size in 2022 USD 7.45 billion
Projected Market Size in 2030 USD 18.65 billion
CAGR Growth Rate 12.18% CAGR
Base Year 2022
Forecast Years 2023-2030
Key Market Players Teleflex Incorporated, Fisher & Paykel Healthcare, Becton, Dickinson and Company (BD), Vapotherm, Drive DeVilbiss Healthcare, ResMed, Flexicare Medical Limited, Hamilton Medical, Invacare Corporation, Salter Labs, Precision Medical Inc., Besmed Health Business Corp., Smiths Medical, Great Group Medical Co. Ltd., Inogen Inc., and others.
Key Segment By End-User, By Application, By Component, and By Region
Major Regions Covered North America, Europe, Asia Pacific, Latin America, and the Middle East &, Africa
Purchase Options Request customized purchase options to meet your research needs. Explore purchase options

High-flow Nasal Cannula Market: Segmentation Analysis

The market for high-flow nasal cannulas around the world may be broken down into four different categories: end-user, application, component, and geography.

Long-term care centers, hospitals, ambulatory care services, and other types of medical facilities are the end-user categories that are used to segment the global market. The hospital sector experienced the most expansion in 2022 due to the fact that hospitals are often regarded as the primary site of initial care for any and all medical disorders. They are prepared to deal with severe cases of respiratory problems because to their high-quality equipment. Increasing expenditures in healthcare facilities may result in stronger market segmentation growth. Around 697 public hospitals might be found across Australia in the year 2021.

Carbon monoxide toxicity, acute respiratory failure, bronchiectasis, chronic obstructive pulmonary disease (COPD), sleep apnea, and other conditions are some of the applications that have led to the segmentation of the high-flow nasal cannula sector into several subcategories.

On the basis of the component, the global market may be broken down into nasal cannulas, air humidifiers, single-heated tubes, air/oxygen blenders, and other categories. As of 2022, the nasal cannulas segment accounted for more than 60.1% of the total market. This was mostly due to the increasing number of patients who were diagnosed with respiratory disorders. During the time covered by the projections, important segmental drivers could include the increasing prevalence of asthma and COPD.

The global High-flow Nasal Cannula market is segmented as follows:

By End-User

By Application

  • Carbon Monoxide Toxicity
  • Acute Respiratory Failure
  • Bronchiectasis
  • Chronic Obstructive Pulmonary Disease (COPD)
  • Sleep Apnea
  • Others

By Component

Browse the full “High-Flow Nasal Cannula Market By End-User (Long-Term Care Centers, Hospitals, Ambulatory Care Services, And Others), By Application (Carbon Monoxide Toxicity, Acute Respiratory Failure, Bronchiectasis, Chronic Obstructive Pulmonary Disease (COPD), Sleep Apnea, And Others), By Component (Nasal Cannulas, Air Humidifiers, Single Heated Tubes, Air/Oxygen Blenders, And Others), And By Region - Global And Regional Industry Overview, Market Intelligence, Comprehensive Analysis, Historical Data, And Forecasts 2023 – 2030" Report At

Competitive Landscape

Some of the main competitors dominating the global High-flow Nasal Cannula market include - 

  • Teleflex Incorporated
  • Fisher & Paykel Healthcare
  • Becton
  • Dickinson and Company (BD)
  • Vapotherm
  • Drive DeVilbiss Healthcare
  • ResMed
  • Flexicare Medical Limited
  • Hamilton Medical
  • Invacare Corporation
  • Salter Labs
  • Precision Medical Inc.
  • Besmed Health Business Corp.
  • Smiths Medical
  • Great Group Medical Co. Ltd.
  • Inogen Inc.

 Key Insights from Primary Research:

  • According to the analysis shared by our research forecaster, the High-flow Nasal Cannula market is likely to expand at a CAGR of around 12.18% during the forecast period (2023-2030).            
  • In terms of revenue, the High-flow Nasal Cannula market size was valued at around US$ 7.45 billion in 2022 and is projected to reach US$ 18.65 billion by 2030.
  • The high-flow nasal cannula market is projected to grow at a significant rate due to the rising number of patients reporting acute exacerbations of COPD.
  • Based on end-user segmentation, hospitals was predicted to show maximum market share in the year 2022.
  • Based on component segmentation, nasal cannulas was the leading segment in 2022.
  • On the basis of region, North America was the leading revenue generator in 2022.

Have Any Query? Ask Our Experts:

Key questions answered in this report:

  • What is the market size and growth rate forecast for High-flow Nasal Cannula industry?
  • What are the main driving factors propelling the High-flow Nasal Cannula Market forward?
  • What are the leading companies in the High-flow Nasal Cannula Industry?
  • What segments does the High-flow Nasal Cannula Market cover?
  • How can I receive a free copy of the High-flow Nasal Cannula Market sample report and company profiles?

Key Offerings:

  • Market Size & Forecast by Revenue | 2023−2030
  • Market Dynamics – Leading Trends, Growth Drivers, Restraints, and Investment Opportunities
  • Market Segmentation – A detailed analysis By End-User, By Application, By Component, and By Region
  • Competitive Landscape – Top Key Vendors and Other Prominent Vendors

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Regional Analysis:

North America to register higher growth during the assessment timeframe

The global high-flow nasal cannula market is expected to be led by North America by 2030. In 2022, the region generated over 50% of the global sales. Factors such as the presence of a robust medical infrastructure, the existence of key medical device manufacturers and suppliers, and increasing demand for non-invasive medical treatments for respiratory conditions contribute to regional dominance. In February 2021, Masimo, a US-based global medical technology company, announced the US launch of softFlow®. It is a novel pulmonary care therapy using a high-flow nasal cannula. North America was one of the most significantly impacted regions during COVID-19 prompting official authorities to take serious actions toward preventing such incidents in the future. Asia-Pacific is expected to grow at a steady pace. Increasing healthcare expenditure, rising air pollution rate, and growing investments in the development of new medical centers to meet the needs of the surging population could act as main regional growth drivers.

By Region

  • North America
    • U.S.
    • Canada
    • Rest of North America
  • Europe
    • France
    • UK
    • Spain
    • Germany
    • Italy
    • Rest of Europe
  • Asia Pacific
    • China
    • Japan
    • India
    • South Korea
    • Rest of Asia Pacific
  • The Middle East & Africa
    • Saudi Arabia
    • South Africa
    • Rest of the Middle East & Africa
  • Latin America
    • Brazil
    • Argentina
    • Rest of Latin America

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September 29, 2023

5 min read


Healio Interviews

Wodicka reports receiving support from NIH (Grant No. UL1TR002529) “Indiana Clinical and Translational Sciences Institute.” Kraman and Pasterkamp report no relevant financial disclosures.

We were unable to process your request. Please try again later. If you continue to have this issue please contact [email protected].

Key takeaways:

  • Devices that monitor wheeze, snoring, coughing or crackles remotely can allow for faster treatment.
  • For children, these devices have the potential to catch lung diseases/conditions early on in life.

With advancements in artificial intelligence and patient-monitoring technology, properly diagnosing individuals who report wheezing, snoring, coughing or crackles is expected to get easier, according to a review published in CHEST.

As Healio previously reported, artificial intelligence (AI) has the ability to determine whether someone has pneumonia through cough recordings and a smart mask has been developed to detect differences in breathing, coughing and speaking for diagnoses of respiratory diseases.

Quote from Hans Pasterkamp

These technologies, as well as several others, can positively impact patients though remote tracking of respiratory sounds that allow for a quicker diagnosis and treatment. According to the review, long-term recording of respiratory sounds can also evaluate treatment adequacy, and this is particularly beneficial for patients with a cough or those who snore and use CPAP.

To learn more about smart devices that measure respiratory sounds and the impact they will have on care provided by pulmonologists, Healio spoke with review authors Steve S. Kraman, MD, FCCP, professor emeritus in the department of internal medicine at the University of Kentucky, Hans Pasterkamp, MD, FRCPC, professor emeritus in the department of pediatrics and child health at the University of Manitoba, and George R. Wodicka, PhD, Vincent P. Reilly Professor of biomedical engineering at Purdue University’s Weldon School of Biomedical Engineering.

Healio: Why has it only recently become possible to monitor/manage respiratory sounds via smart devices?

Steve S. Kraman

Kraman, Pasterkamp and Wodicka: This technology has been around for decades, and the potential usefulness has been recognized as well. For instance, cough counters and wheeze detectors have been presented in meetings such as the International Lung Sounds Association. What was missing from these devices was that they weren’t “smart” in the sense that a clinician could use them without extensive training. They were also big, heavy and often composed of various parts connected by cables. They looked like someone’s hobby rather than a commercially attractive medical device. Recently, the advent of cheap, subminiature, efficient electronic devices has made it possible to build acoustic recorders and analyzers into packages as small as a patch that can be affixed to the chest wall and send data wirelessly to a smart phone for storage and processing for (perhaps) transmission via Wi-Fi and internet to a server in a hospital of doctor’s office. All this capability and more is already present in the cell phones carried by most of the world’s people. All that is left is for engineers to use current technology to design and commercialize these gadgets, which is already happening.

Healio: You wrote that four sounds — wheeze, snoring, cough and crackles — offer the most promise in this technology. To which diseases/conditions can each of these sounds be linked?

George R. Wodicka

Kraman, Pasterkamp and Wodicka: Wheeze, linked to COPD and asthma, is easily heard using a stethoscope in the clinic. But is asthma controlled during sleep? Adults can report that they wake up coughing and wheezing but a young child cannot. A stick-on wheeze detector or even an app running on a smart phone next to the bed could detect and measure the length and number of episodes and send the report directly to the physician’s office. The patient’s medications could then be modified to assure better nighttime coverage.

Snoring is linked to obstructive sleep apnea. Detection of loudness, pattern and rate of snoring as well as background breathing noises can give important hints about the possibility of obstructive sleep apnea. This could be done with an app on a smartphone at virtually no cost.

Cough is linked to asthma, rhinitis, gastric reflux, viral and post-viral coughs. The Hyfe company has designed a smart phone app that counts coughs and is working with Merck to distribute it for free. It can be downloaded and used by anyone. It is not FDA-approved yet, but the aim of the app is for a patient to track the rate and pattern of coughing day-to-day to document changes over time and whether a specific treatment is working. Chronic cough is one of the most frequent problems encountered by pulmonologists in the clinic and this or similar devices could become useful in objectively determining the cough pattern and whether a cough is improving or worsening.

Crackles are linked to COPD, bronchiectasis, heart failure and pulmonary fibrosis. Crackles are quite faint but can be detected by a stick-on microphone and would likely be of most use in detecting nocturnal heart failure.

Healio: How could these devices specifically help children with wheeze, snoring, cough or crackles? Could these devices possibly prevent the development of lung diseases/conditions in children?

Pasterkamp: The ability to remotely monitor children and babies with respiratory illnesses may be the most crucial use of these smart devices. Children often have most of these abnormal respiratory sounds at some point, particularly during their early years of life. Separating wheezing as an early indicator of asthma from similar sounds that are simply reflecting “snotty lungs” is a challenge that smart devices are more likely to manage than reports by parents or a brief auscultation at the doctor’s office. Coughing is common during childhood due to the frequency of respiratory viral infections. Most of these coughs disappear within a couple of weeks. However, young children may have respiratory infections so frequently that reporting by parents may not clarify what is recurrent vs. persistent or even chronic. Again, recording by smart devices, perhaps even with characterization of the type of cough that could point to underlying causes, is promising an advancement in the management of young patients.

Additionally, snoring during sleep when they have obstructed noses is common in young kids. However, documentation of regular snoring, particularly with acoustic patterns that suggest obstructive apneas, will be valuable to direct further investigations and treatments that could prevent cardiovascular and neurodevelopmental consequences of sleep apnea/hypopnea.

Healio: You mention that studies on these devices do not appear in medical journals. Why is that, and what can be done so that more pulmonologists and primary care practitioners hear about advancements in smart devices/AI for respiratory monitoring?

Kraman, Pasterkamp and Wodicka: Most of these machines and apps using AI are coming from engineering labs in academia and companies hoping to commercialize their products. They tend to publish in engineering journals unlikely to be seen by physicians. Private companies may not publish at all to protect their proprietary designs. They can advertise widely but that is expensive. We published our review paper in a widely read and highly regarded medical journal to make chest physicians aware of these developments.

Healio: Are there any challenges that remain to be overcome before these devices can be used widely?

Kraman, Pasterkamp and Wodicka: Certainly. For a medical device to be widely adopted and financially profitable, there must be clinical trials that support its safety and efficacy, hopefully leading to FDA clearance. Such studies are expensive, especially for a start-up. Physicians and hospital administrators must be persuaded that the newly marketed devices will provide meaningful advantages in patient care at reasonable cost and that insurers will see the benefits of covering the use of these devices.

Healio: When can pulmonologists expect to see these devices in routine clinical practice?

Kraman, Pasterkamp and Wodicka: It has already started. Electronic stethoscopes are now beginning to be paired with AI to help analyze abnormal heart sounds and at least one company, Eko, offers a 3-lead ECG built into the stethoscope head.

The Hyfe cough counter app is already being offered free to anyone and is being used in ongoing and planned clinical studies. The Leicester Cough Monitor (Sennheiser), available in the U.K., and VitaloJAK (Vitalograph), available in the U.S. and U.K., are also commercially available for cough counting.

StethoMe (StethoMe sp. z o.o.) for detection of wheeze in the European Union and Feelix (Sonavi Labs) in the U.S. for detection of crackles and wheeze have recently become commercially available. Many more are mentioned in our paper.


For more information:

Steve S. Kraman, MD, FCCP, can be reached at [email protected].

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The consequences of the Covid-19 pandemic have brought to light an impending health emergency: the worsening of pulmonary health, especially after experiencing Covid, compounded by the increasing effects of climate change and air pollution.

As survivors grapple with the aftermath of the virus, a growing number face persistent respiratory challenges, emphasising the urgent need for targetted interventions and a holistic approach to post-Covid lung care.

Rise of pulmonary illness 

Speaking to South First, Dr Ravindra Mehta, a leading pulmonologist in the country from Bengaluru, who recently set up VAAYU Pulmonary Wellness and Rehabilitation Centre — a unique centre for holistic care for pulmonary health — says, “Post Covid-19, there are several patients coming in with what is called interstitial lung disease (ILD), also known as pulmonary fibrosis.”

Interstitial lung disease refers to a group of about 100 chronic lung disorders characterized by inflammation and scarring. (NHLBI)
Interstitial lung disease refers to a group of about 100 chronic lung disorders characterized by inflammation and scarring. (NHLBI)

Is this disease specific to post-Covid conditions? Dr Mehta responds, “This disease, which has been around for many years, has come to focus only after Covid-19, when survivors of severe Covid infections were found to have this disease and people came to know about it.”

Explaining further about ILD, he says that it is caused due to inflammation and scarring of the lung tissue, where a spongy lung becomes scarred and leads to stiffening. With symptoms of shortness of breath and coughing, it is, ultimately, a progressive disease which can be life-threatening.

“Some ILDs can be compared to cancers as they can do more damage in a short span of time than cancer. There are several patients coming in with not just ILDs but lung diseases due to various environmental insults, including air pollution, infections, and allergens,” says Dr Mehta.

He adds, “Asthma and COPD are among the world’s biggest health concerns today. Post-Covid, there has been an explosion of lung diseases and there is an immediate need for innovative methods to treat lung diseases.”

Adding to this, Dr Shivalinga Swamy, Pulmonologist at Trustwell Hospital, says, “Post-Covid lung fibrosis has become a major debilitating respiratory illness, where survival is not more than five years. Treatment for this is absolutely essential.”

Also read: Post-Covid individuals face elevated 1-year mortality risk: ICMR

Various other Covid complications

Pulmonologists tell South First that long-term effects of Covid-19 infection could include new medical conditions like hypertension, lung fibrosis, and asthma, among several other manifestations.

Representative pic. (Creative Commons)
Lung complications are now more commonly seen in patients who have had Covid-19. (Creative Commons)

Doctors claim that they are seeing more patients coming in with bronchiectasis, which is characterised by the widening and damage of the airways, leading to a build-up of excess mucus that can make the lungs more vulnerable to infection.

“In our clinical practice, we’re seeing a spectrum of post-acute respiratory effects in individuals who have had Covid-19. People are coming in with post-Covid asthma, which is a major comorbidity affecting day-to-day life. There has also been an increased risk of developing pulmonary embolism,” says Dr Swamy.

The doctors emphasise that the extent of damage varies from person to person and monitoring lung well-being and seeking immediate medical attention for any kind of respiratory symptom is key.

Also read: Study says no evidence of Covid vaccines increasing heart attack risk

Need for pulmonary rehabilitation

Doctors attest to the fact that these respiratory complications mandate continuous monitoring and comprehensive management.

Vaayu Chest and Sleep Specialists, clinic which works towards holistic pulmonary rehabilitation. This clinic is set up in Bengaluru.
VAAYU Chest and Sleep Specialists. (Supplied)

Though there are several clinical trials and abundant research ongoing to better understand and treat post-Covid pulmonary complications, doctors say that patients often require a multidisciplinary approach, including pulmonary rehabilitation, medications to manage symptoms, and adjustments to a new lifestyle.

A pulmonary rehabilitation programme is a comprehensive and structured approach to improving lung health and overall well-being of individuals with chronic respiratory conditions, such as chronic obstructive pulmonary disease (COPD), interstitial lung disease, bronchiectasis, etc.

The programme is specifically tailored to help patients manage their symptoms, enhance their lung function, increase exercise tolerance, and improve their overall quality of life.

Dr Mehta explains that this is exactly the reason why he set up the VAAYU Rehabilitation and Wellness Centre, “Pulmonary rehabilitation is not seen in major force in the city and in the country. So our aim was to start one of Bengaluru’s most qualified and skill-based pulmonary rehabilitation services. We have the best expertise here.”

Also read: 12 key symptoms commonly associated with long Covid-19

Pulmonary rehabilitation programme

The key components of a pulmonary rehabilitation programme typically includes exercise training, where supervised exercise sessions are conducted to improve cardiovascular fitness, and endurance and muscle strength is worked on. Here, there are awareness and disease management sessions on the patient’s specific lung condition, symptoms, medications, and inhaler techniques are taught as well.

There are other techniques to manage and cope with shortness of breath, fatigue, and other symptoms, which are all explained in great detail as part of the programme.

Along with behavioural modification, activities of daily living, assessment, important screening tests, and accurate diagnosis is also part of the rehabilitation programme, explains Dr Mehta.

Dr Mehta adds that individualised treatment plans are key to addressing the varied manifestations of post-Covid lung disease. These plans may include pulmonary rehabilitation, respiratory therapies, medications, and lifestyle modifications, tailored to each patient’s unique needs and circumstances.

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The respiratory system, often taken for granted, is a vital component of our overall health. Responsible for the exchange of oxygen and carbon dioxide, it plays a crucial role in sustaining life. However, this complex system is susceptible to a range of conditions that can hinder its functionality. As we mark World Lung Day 2023 on September 25, let's explore the common warning signs of lung disease and the steps to maintain optimal lung health.

2 things you need to know

  • Recognise warning signs for lung disease - early detection matters.
  • Lifestyle choices impact lung health: Avoid smoking and pollution.

Recognising Early Warning Signs

Dr. Sachin Kumar, Senior Consultant in Pulmonology and Critical Care Medicine at Sakra World Hospital, sheds light on the common symptoms that individuals should be vigilant about. He states, "The early signs of lung disease, including reduced energy levels, can also manifest as symptoms like breathing difficulties, shortness of breath, persistent cough, coughing up blood or mucus, and discomfort when breathing. Additionally, recurrent lung infections such as acute bronchitis or pneumonia can be indicative of underlying lung problems. Recognizing these early warning signs and recurring infections is vital for early intervention in lung-related health issues."

(World Lung Day 2023 explores the common warning signs of lung disease | Image: iStock)

Lifestyle and Lung Health

Dr Viswesvaran Balasubramanian, Consultant in Interventional Pulmonology and Sleep Medicine at Yashoda Hospitals, explains how lifestyle choices can impact lung health: "Smoking and exposure to air pollution are linked to various lung disorders, including asthma, chronic obstructive lung diseases, and bronchiectasis. They can also lead to interstitial lung disease and increase the risk of lung cancer. Early-life exposure to smoking and air pollution can result in suboptimal lung development."

Debunking Lung Health Myths

Addressing misconceptions about lung health, Dr. Sachin Kumar dispels some common myths:  "Firstly, smoking is often considered the sole cause of lung disease, but other factors matter. Secondly, quitting smoking may help but may not fully reverse the damage. Thirdly, while fresh air is important, medical treatment is often necessary. Fourthly, lung diseases can develop silently without obvious symptoms. Finally, lung cancer doesn't discriminate by gender; many women who never smoked are affected."

Protecting and Maintaining Lung Health

To safeguard lung health, Dr. Sachin Kumar advises, "Refrain or quit smoking. Minimise exposure to pollutants and engage in regular physical activity. Consume a well-rounded diet and ensure adequate hydration. Embrace proper hygiene practices and effectively manage stress. Stay up-to-date on vaccinations and reduce indoor pollutant sources. Regularly schedule check-ups, particularly if you have risk factors."

Dr. Viswesvaran Balasubramanian emphasises the importance of seeking medical advice promptly if concerning symptoms arise: "Inhaling healthy air, aerobic exercises, avoidance of smoking and air pollution, vaccination against pneumonia, and adopting good hygiene measures can improve your lung health. Any new onset of difficulty in breathing, cough with blood in sputum, or chest pain warrants immediate medical consultation with your pulmonologist, as it may indicate a possibility of underlying lung infection like tuberculosis or malignancy."

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