Chronic obstructive pulmonary disease (COPD) is an underdiagnosed lung disease characterized by persistent inflammation and airflow obstruction. COPD is preventable and treatable, but not fully reversible (Rabe 2007; GOLD 2011; Bednarek 2008; CDC 2011; NIH MedlinePlus 2012; Kardos 2006; American Thoracic Society 2004).

COPD is the fourth-leading cause of death in most industrialized countries and is predicted to become third by 2020 (Cosio 2009). This increase is due primarily to a global epidemic of tobacco smoking, a leading risk factor for COPD (WHO 2008).

COPD encompasses two main conditions (GOLD 2011; NIH NHLBI 2010, Fischer 2011):

• Emphysema, which damages and enlarges the alveoli - the tiny sacs where oxygen transfer takes place in the lungs; and
• Chronic bronchitis, in which a chronic cough accompanies persistent inflammation of the airways.

The goal of COPD treatment is to slow or prevent disease progression, improve exercise tolerance, improve health status, prevent and treat exacerbations, and reduce mortality. Smoking cessation is the most crucial step to prevent COPD or delay its progression (GOLD 2011; NIH-NHLBI 2006).

Conventional therapies such as inhaled corticosteroids, inhaled anticholinergics, and beta2-agonists are helpful in treating COPD (Ferri 2012). However, inhaled corticosteroids may increase the risk of pneumonia (Spencer 2011) and osteoporosis (Leib 2011), and inhaled anticholinergics may increase the risk of death (Singh 2011).

After reading this protocol, you will understand what causes COPD, how therapy can relieve symptoms, and how lifestyle changes can reduce exacerbations. You will also learn about novel therapies and natural compounds that can target some key mechanisms that drive COPD progression, including inflammation and oxidative stress.

Chronic Obstructive Pulmonary Disease (COPD) is a slowly progressing disease that often develops over decades as a result of chronic exposure to inhaled irritants, which trigger an inflammatory response in the lungs (Rabe 2007). In a typical case, a patient will experience declining lung function for many years before being diagnosed with COPD and receiving therapy. During this time, the lungs are undergoing several changes characteristic of COPD (Crawford 2008).

Three pathologic processes play a significant role in COPD-related lung damage: (1) oxidative stress, (2) inflammation, and (3) an imbalance in enzymes (e.g., proteases ) involved in cell injury and repair (Fischer 2011).

The bulk of lung tissue is composed of alveoli - tiny air sacs where the exchange of oxygen and carbon dioxide takes place. Having a large surface area and blood supply makes the lungs susceptible to oxidative injury caused by reactive oxygen species (ROS) and free radicals either in air pollutants or released through metabolic processes. Cigarette smoke itself contains numerous oxidizing agents (Loukides 2011).

As a first line of defense, the lungs produce antioxidants such as glutathione, catalases, and peroxidases to detoxify the reactive species. However, in COPD, increased oxidant burden and/or decreased antioxidant defense causes an imbalance (oxidative stress) between the amount of ROS and the body's ability to neutralize them (Stanojkovic 2011). Oxidative stress can cause the air sacs to become less elastic, and the extracellular matrix of the lungs to become damaged (Loukides 2011; Fischer 2011).

The underlying cause of COPD damage is an inflammatory response mounted by the immune system. Chronic exposure to an irritant (e.g., cigarette smoke) causes inflammatory cells (e.g., neutrophils, macrophages, eosinophils) to gather in the airspaces of the lung. In response to the toxins, macrophages release inflammatory chemicals and begin to recruit more immune-system cells, which in turn release more inflammatory chemicals as well as protease enzymes that degrade the extracellular matrix (Fischer 2011; GOLD 2011; Mosenifar 2011).

The two main disease types encompassing COPD are emphysema and chronic bronchitis (Fischer 2011).

Emphysema

• Emphysema occurs when alveoli enlarge and cluster. This process destroys the air sacs where gas exchange occurs. As tissue walls become damaged and disintegrate, the alveoli expand and coalesce into larger, thinner-walled air sacs (i.e., blebs or bullae). As the walls lose their elasticity, the lung tissues become less efficient gas chambers. Gas exchange for oxygen and carbon dioxide worsens as the disease progresses. With weakened air sacs, the airway collapses during expiration (breathing out) causing airway obstruction (Crawford 2008; GOLD 2011).

Chronic Bronchitis

• As inflammatory cells migrate to the midsize airways, mucus glands in the lungs become enlarged, causing more mucus production and cough. Over time, the bronchial walls thicken, airways narrow (becoming deformed), and airflow becomes more limited (Crawford 2008; GOLD 2011). A number of airway changes occur, including hypertrophy (increase in size) of smooth muscle cells, fibrosis (formation of scar tissue) in the airway walls, and infiltration of inflammatory cells. The term for the lung damage and inflammation of the mucus membrane in the airways is chronic bronchitis. Chronic bronchitis is diagnosed by the presence of cough and sputum production for at least 3 months in each of two consecutive years (GOLD 2011).

Because changes in the lungs develop incrementally, symptoms appear gradually and may be present for many years before medical treatment is initiated. Progressive and chronic coughing, sputum production, and shortness of breath (dyspnea) are the characteristic symptoms of COPD.

A majority of people with COPD also suffer from other medical conditions (e.g., heart disease, osteoporosis, anemia, metabolic syndrome, diabetes, depression, respiratory infections, wasting of the skeletal muscles, and lung cancer) that can affect prognosis (GOLD 2011; Divo 2012). Poor lung function and poor nutrition may also exacerbate muscle weakness, abnormalities in fluid and electrolyte balance, and depression (GOLD 2011; Decramer 2012).

Smoking is a primary risk factor for COPD, accounting for up to 75% of all COPD cases globally. Genetics, occupational exposures to gases & fumes, and exposure to biofuel account for the remaining cases (Salvi 2009; ICSI 2011). People exposed to more than one risk factor can develop COPD earlier, or have more severe symptoms and exacerbations (GOLD 2011).

Smoking

More than half of all long-term smokers will develop COPD (Mannino 2007; IOM 2011). Moreover, life-long cigarette smokers have a significantly higher rate of decline in lung function, are more likely to develop COPD with age, and more frequently die of COPD compared to non-smokers (Rennard 2006; Kohansal 2009).

Secondhand smoke is an independent risk factor for COPD (Eisner 2010; Jordan 2011). Evidence shows that COPD risk doubled among never-smokers exposed to secondhand tobacco smoke for more than 20 hours/week (Jordan 2011).

Occupational Exposure

Occupational exposure is another risk factor in the development of COPD. Studies show that toxic gases in the workplace, such as chemical dust and fumes in factories, can increase the risk of COPD (Mannino 2007; Salvi 2009) and severe exacerbations of COPD (Rodriguez 2008).

Biomass Fuel

Globally, and especially in low- to middle-income countries, another important risk factor for COPD may be exposure to air pollutants such as solid or biomass fuels (e.g., coal, straw, animal dung, and wood) (Mannino 2007; Salvi 2009). Of these fuels, wood smoke, followed by mixed biomass smoke, is the most notable COPD risk factor (Kurmi 2010).

Asthma (Bronchial Hyperresponsiveness)

Childhood asthma is a risk factor for the development of COPD later in life, and asthma in the elderly shares many similarities with COPD (e.g., shortness of breath, wheezing, coughing, decline in lung function and treatment options) (Eisner 2010; Mannino 2011; GOLD 2011). Also, airway obstruction becomes more severe with long-term asthma. Therefore, it is necessary for doctors to distinguish the two conditions in order to properly diagnose and manage them (Tzortzaki 2011).

Clinically distinguishing asthma and COPD is typically straightforward among middle-age and younger people. However, in the elderly, especially those who smoke, differentiating between the two conditions can be difficult using standard clinical lung function assessments. More comprehensive diagnostic testing, including allergy testing, CT scanning of the lungs, and advanced biomarker analyses that characterize COPD vs. asthma based upon the profile of inflammatory mediators in the blood, allow modern clinicians to confidently categorize most patients (Tzortzaki 2011, Hanania 2011).

Treatment response can also aid in the differentiation of the two conditions. For example, asthma is typically significantly reversible using bronchodilators, while COPD is only minimally reversible (Tzortzaki 2011).

Alpha-1-Antitrypsin Deficiency

Alpha-1-antitrypsin deficiency is a rare (up to 3% of COPD patients), inherited cause of COPD, occurring primarily in individuals of northern European descent. This genetic defect causes the body to produce a decreased amount of the protein alpha-1-antitrypsin, which normally prevents neutrophil elastase from damaging the alveoli. Emphysema typically develops by early middle age in people with severe alpha-1-antitrypsin deficiency, especially in those who smoke (Merck Manual 2008; American Lung Assc. 2011; Fregonese 2008; Ferri 2012).

Physicians typically consider COPD in patients with chronic cough, sputum production, shortness of breath, decreased exercise tolerance, and a history of exposure to tobacco smoke (GOLD 2011).

Early in the disease, physical examination(s) may be normal. Later in the disease, however, the classic "barrel chest" may occur due to residual air trapped in the lungs, leading to their hyperinflation. In addition, the increased effort required to exhale can produce wheezing, while pursed lips or grunting respirations may signal efforts to keep the airways open by increasing pressure at the beginning of expiration (Crawford 2008; GOLD 2011; ICSI 2011). Also, severe to very severe COPD commonly results in fatigue, weight loss and anorexia (GOLD 2011).

Spirometry is the gold standard for diagnosing and monitoring progression of COPD. This breathing test includes forced expiratory volume in one second (FEV1) - the greatest volume of air that can be breathed out in the first second of a large breath, and the forced vital capacity (FVC) - the greatest volume of air that can be breathed out in a whole large breath. In healthy people, at least 70% of the FVC comes out in the first second (i.e., the FEV1/FVC ratio is >70%). In fact, the FEV1/FVC ratio <70% is a diagnostic characteristic of COPD (Nathell 2007; GOLD 2011).

Other tests (e.g., x-rays, computed tomography, and magnetic resonance imaging) may be performed if complications such as pneumonia are suspected.

The serum alpha-1-antitrypsin level may also be measured to detect alpha-1-antitrypsin deficiency. This testing may be especially considered for individuals of northern European descent with a personal history of COPD before age 50, family history of COPD or emphysema, and limited exposure to inhalants or irritants (Serapinas 2012; American Lung Assc. 2011; Merck Manual 2008).

Exacerbations of COPD often develop following a viral upper respiratory or tracheal infection. Assessment of COPD exacerbations is based upon the degree of airflow limitation, duration or worsening of new symptoms, and number of previous episodes. Clinical tests (e.g., electrocardiography, blood count, and presence of infections) may also be performed to assess the severity of an exacerbation (GOLD 2011).

There is no cure for COPD. However, both pharmacologic and lifestyle management strategies can help improve health status and physical function (GOLD 2011; Collins 2012).

According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), effective COPD management has the following goals (GOLD 2011):

• Preventing disease progression
• Relieving symptoms
• Improving exercise tolerance and health status
• Preventing and treating complications and exacerbations
• Reducing mortality

Pharmacologic Therapy

Bronchodilators

Bronchodilators are the first-line therapy for mild COPD. Bronchodilators relax airway smooth muscles, making it easier to breathe. Treatment may begin with a rescue bronchodilator used "as needed" during mild episodes of COPD. In more severe COPD, combination bronchodilator therapy (i.e., a rescue bronchodilator combined with a controller [long-acting] bronchodilator) may help relieve symptoms (ICSI 2011; GOLD 2011).

Bronchodilators include the following:

1. Beta2-agonists. Short-acting beta2-adrenergic agonists (SABAs) (e.g., albuterol and levalbuterol) are rescue medications used "as-needed" to relieve acute symptoms by relaxing airway smooth muscles (Barnes 2002). The effect(s) of SABAs are immediate, but usually wear off within 4 to 6 hours. Long-acting beta2-adrenergic agonists (LABAs) (e.g., salmeterol and indacaterol) are effective for 12 or more hours (GOLD 2011). LABAs can significantly reduce exacerbations and improve respiratory health, but do not reduce hospitalization or mortality (Calverley 2007). Side effects of beta-2-agonists include increased heart rate and blood pressure, trembling, and cardiac arrhythmias (Littner 2011).
2. Anticholinergics (e.g., ipratropium and tiotropium) prevent contraction of airway smooth muscle and can reduce exacerbations as well as improve symptoms and health status (Barnes 2004; Tashkin 2008; GOLD 2011). The main side effect of anticholinergics is dry mouth. A comprehensive review showed that tiotropium mist inhaler is associated with a 50% increased risk of death in people with COPD (Singh 2011). Another study showed the use of anticholinergic inhalers increased risk of acute urinary retention among COPD patients with benign prostatic hyperplasia (BPH) (i.e., benign enlargement of the prostate) (Stephenson 2011).
3. Methylxanthines (e.g., theophylline) are a group of alkaloids commonly used for their effects as mild stimulants and bronchodilators (Minor 1994). They are not as well tolerated as inhaled LABAs. Side effects include headache, insomnia, nausea, heartburn, and abnormal cardiac rhythms (which have potential to be fatal in some individuals) (GOLD 2011).

Corticosteroids

Inhaled steroid medications (e.g., fluticasone and budenoside) reduce airway inflammation and frequency of exacerbation(s). They can be effective in severe COPD, especially that which co-occurs with asthma (Barnes 2010b; Roche 2011). At low doses, regular use can improve symptoms, lung function, and quality of life. Side effects include hoarse voice, cough, and oral fungal infection (Irwin 2006). Inhaled corticosteroids may also increase the risk of pneumonia and impair bone health (Barnes 2010b; Spencer 2011).

Combining inhaled corticosteroids with a LABA significantly reduces morbidity and mortality in COPD when compared to steroids alone, although much of the benefit may be due to the LABA (Barnes 2010b; Nannini 2007). Oral corticosteroids (e.g., prednisone, prednisolone), due to their adverse effects (e.g., muscle weakness and respiratory failure), are not recommended for long-term use in patients with COPD (GOLD 2011).

Surgery and Other Treatments

Oxygen therapy. Long-term oxygen therapy may be recommended for severe COPD when oxygen levels during rest fall below the normal threshold twice over a three-week period, or if there is evidence of pulmonary hypertension or failure. Stable but very severe COPD may require ventilator support to improve survival (GOLD 2011).

Surgery. Surgery is a viable treatment in a small subset of carefully selected patients with severe COPD (Van Raemdonck 2010; Gulati 2013).

• Bullectomy. In a bullectomy procedure, large air sacs (bullae) that have been damaged by emphysema are removed. Surgical removal of these bullae can help restore lung volume and allow the remaining healthy parts of the lung to function better.
• Lung volume reduction surgery (LVRS). In LVRS damaged tissue of the lung(s) is removed. LVRS can improve lung function, overall health status, and survival; however, it is indicated only for a small portion of patients with end-stage COPD who no longer respond to more conservative measures (Clarenbach 2015; Criner 2018). LVRS, while being a high-risk procedure with a high frequency of adverse effects and increased mortality risk in the short-term, is associated with a survival benefit long-term (van Agteren 2016).
• Lung transplantation. Lung transplantation can improve quality of life and survival for those with very severe, end-stage COPD. However, the survival benefit is typically limited, and complications can include an increased risk of lung cancer (and other cancers, due to the subsequent need for lifelong therapy with immunosuppressive drugs) (GOLD 2011; Lane 2015; Olland 2018).

Endobronchial valve. In 2018, the FDA approved a novel device called the Zephyr Endobronchial Valve (EBV) for the treatment of COPD. The Zephyr EBV, which is placed into the airway during a minimally invasive bronchoscopic procedure, directs airflow toward healthy lung tissue and away from lung tissue damaged by emphysema. This improves overall lung efficiency. The EBV has been clinically shown to be comparable to LVRS for FEV1 and six-minute walk distance but has a 38% lower mortality risk and less overall adverse effects (PulmonX 2018).

The multi-center, randomized, controlled LIBERATE trial compared the Zephyr EBV device with standard care. One hundred twenty-eight trial participants with severe emphysema underwent an EBV-placement procedure, and 62 patients received standard care and served as controls. The main endpoint in the trial was an improvement in lung function (as measure by FEV1) of at least 15%. Forty-eight percent of subjects in the EBV group achieved this endpoint at 12 months post-intervention versus only 17% of control subjects. The Zephyr EBV also resulted in significant improvement in clinical measures of functional ability and respiratory health.

Lung collapse (pneumothorax) is one possible complication of the EBV device. It occurred in roughly 25% of subjects in the LIBERATE trial who received the device. Fortunately, the majority of cases occurred soon after the procedure and were managed successfully; the development of pneumothorax did not prevent long-term benefit from the procedure (Criner 2018).

Since COPD increases susceptibility to lower respiratory tract infections, preventive vaccines, such as pneumococcal and influenza vaccinations, are recommended in all COPD cases (ICSI 2011). Data show long-term use of antibiotics does not affect the frequency of exacerbations. Unless used to treat bacterial infections, antibiotics are not recommended for long-term COPD therapy (GOLD 2011).

Lifestyle And Dietary Management

Smoking Cessation

Quitting smoking is the most important step to prevent or slow down the progress of COPD. Comprehensive smoking cessation programs include counseling, organized "quit" plans, and when necessary, nicotine replacement therapy (e.g., gum, skin patches, and other methods). The National Network of Tobacco Cessation Quit lines at 1-800-QUITNOW (1-800-784-8669) can provide smokers in every state access to information and support to quit smoking (NCI 2012). Avoiding secondhand smoke and air pollutants that contribute to COPD symptoms and exacerbations of the disease are also beneficial (GOLD 2011).

Although tobacco smoking cessation can help slow disease progression and prevent exacerbations in some cases of severe or very severe COPD, with cardiovascular and respiratory benefits becoming evident within one year of cessation, lung function will not be completely restored by stopping smoking (Godtfredsen 2011).

Pulmonary Rehabilitation

Exercise Programs. Air passage obstruction in COPD causes the lungs and heart to work harder to carry oxygen throughout the body. General muscle wasting also becomes a risk as COPD progresses. Exercise programs can strengthen chest muscles and facilitate breathing, reduce depression and anxiety related to COPD, and improve recovery along with health status after hospitalization (de Blasio 2012). Multidisciplinary pulmonary rehabilitation programs provide well-monitored exercise programs.

Breathing exercises. Breathing exercises induce relaxation and make breathing easier. Pursed-lip breathing stimulates relaxation, increases oxygen intake and prevents shortness of breath. It has been shown to increase exercise and walking endurance, as well as shorten recovery time(s) in patients with moderate to severe COPD (Faager 2008). Breathing exercises are an important part of a COPD rehabilitation program. Respiratory therapists work closely with physicians to personalize the best regimen for each individual.

Diet and COPD

Progressive weight loss, muscle wasting, and malnutrition are common with moderate to severe COPD (Collins 2012; de Blasio 2012). Nutritional support can contribute to weight gain and muscle mass restoration in COPD (Collins 2012). In a three-year, randomized, controlled COPD trial, higher intake of antioxidant-rich foods (i.e., fresh fruits and vegetables) resulted in significantly improved pulmonary function while an unrestricted diet resulted in lung function decline (Keranis 2010). Further, a large study showed that a healthy diet (i.e., fruits, vegetables, fish and whole-grains) was associated with lower risk of COPD (Varraso 2010).

Despite use of current treatments, lung function continues to decline in long-term COPD. Therefore, new classes of drugs and/or non-pharmacological therapies to reduce disease progression are needed (Barnes 2010a; Matera 2012a). Several novel drug therapies are being developed that may offer benefit to people with COPD.

New bronchodilators

Indacaterol (Arcapta Neohaler®), an ultra-long-acting beta2-agonist, was FDA approved in July 2011 (FDA 2012). It is a bronchodilator with rapid-onset action that remains effective for 24 hours or longer. In clinical trials, a once-daily treatment of indacaterol significantly improved shortness of breath and lung function, exercise endurance, and lung hyperinflation compared to placebo among COPD patients. Also, fewer subjects receiving indacaterol experienced COPD worsening compared to placebo (McKeage 2012; Steiropoulos 2012; Roig 2009).

Glycopyrronium bromide, a novel anticholinergic with rapid-onset action that lasts for 24 hours, is being investigated as a new COPD treatment (EMA 2012). In a clinical trial among COPD patients, significant improvement in forced expiratory volume (FEV1) occurred 5 minutes after dosing and continued to be evident through week 26 of treatment (D'Urzo 2011).

Anti-inflammatory Agents

Phosphodiesterase-4 (PDE-4) inhibitors can be used to reduce airway inflammation and exacerbations in severe to very severe COPD with a history of exacerbation and chronic bronchitis. A majority of clinical trials used roflumilast (Daxas®) and cilomilast (Ariflo®), second-generation oral PDE-4 inhibitors. Roflumilast, in particular, is approved in the United States, Canada, and European Union (Diamant 2011). Adverse side effects of PDE-4 inhibitors are nausea, diarrhea, weight loss, sleep problems, and headache (Diamanti 2011).

A safety concern with the anti-inflammatory agents under development is their ability to affect innate immunity, potentially increasing the risk of lung infection and perhaps cancer among people predisposed to COPD (Barnes 2008).

Statins

Statins, which treat cardiovascular disease by lowering cholesterol and combatting inflammation, may have potential as a therapy for COPD exacerbations (Matera 2012b; Bartziokas 2011). Statins possess a variety of biological functions including modulation of the inflammatory response, as well as tissue remodeling pathways, both of which are of potential benefit in treating COPD. Analysis of a large randomized trial on statins and cardiovascular disease found that treatment with pravastatin (Pravachol®) reduced exacerbations and death due to COPD (Heart Protection Study 2005). Another randomized trial found that pravastatin use for 6 months improved exercise performance in COPD (Lee 2008). A prospective trial reported that statin treatment in the first year after hospitalization for COPD exacerbation reduced risk and severity of exacerbations and improved quality of life (Bartziokas 2011).

Vitamin D

The mechanism by which vitamin D affects the pathogenesis of COPD is unclear. However, studies show that vitamin D can modulate the activity of various immune cells (Herr 2011), inhibit inflammatory responses (Hopkinson 2008), and regulate airway smooth muscles (Banerjee 2012).

A review of molecular and animal experiments showed that vitamin D regulates airway contraction, inflammation, and remodeling in airway smooth muscles characteristic of COPD (Banerjee 2012). A cross-sectional study found that higher plasma levels of vitamin D are associated with increased bone mineral density and exercise capacity in people with COPD (Romme 2012). Evidence also showed that high dose vitamin D supplementation improved respiratory muscle strength and exercise capacity in people with COPD (Hornikx 2011).

A study among 414 smokers with COPD showed that vitamin D deficiency is highly prevalent in this population, and correlates with disease severity. The study also found that genetic determinants for low vitamin D levels were associated with an increased risk of COPD (Janssens 2010).

Other COPD intervention studies are underway to examine the effect(s) of 3,000 – 6,000 IU of vitamin D3 on rehabilitation (NCT01416701), as well as time to first upper respiratory infection and first moderate-to-severe exacerbation (NCT00977873) (clinicaltrials.gov 2012).

Antioxidants: Vitamins A, C, and E

Vitamin A plays a role in proper lung development (in the embryonic stage) and repair of damaged lung tissue. Animal models showed that mice with low vitamin A levels were more likely to develop emphysema after 3 months of exposure to cigarette smoke compared to mice with normal vitamin A levels (Van Eijl 2011). In one study, high dietary vitamin A intake (greater than 2,770 IU daily) was associated with a 52% reduction in risk of COPD (Hirayama 2009).

Vitamin E levels are low in smokers, increasing their susceptibility to free radical damage (Bruno 2005). A 10-year, randomized, population-based trial of 38,597 healthy women reported that supplementing with 600 IU of vitamin E reduced the risk of chronic lung disease by 10% (Agler 2011).

A review of population studies reported that low levels of vitamins E and C were associated with more wheezing, phlegm, and dyspnea. Levels of vitamins E and A were significantly lower during acute exacerbations of COPD compared to stable COPD (Tsiligianni 2010). A case-control study showed that people with COPD had significantly lower serum levels of vitamins A, C, E, and carotenoids compared to healthy controls. The COPD group also had higher white blood cell DNA damage and consumed fewer vegetables and fruits than the healthy group (Lin 2010).

N-acetylcysteine (NAC)

N-acetylcysteine (NAC), a glutathione precursor, can dissolve mucus (mucolytic properties) and repair damage caused by reactive oxygen species (Sadowska 2007; Sadowska 2012).

A comprehensive review of studies reported that oral NAC lowered the risk of exacerbations and improved symptoms in patients with chronic bronchitis compared to placebo (Stey 2000). NAC (600 mg) given twice daily for two months reduced the oxidant burden in the airways of people with stable COPD (De Benedetto 2005). Experimental and clinical studies also showed that NAC can reduce symptoms, exacerbations, and slow declining lung function in COPD (Dekhuijzen 2006).

Treating moderate-to-severe COPD with 1,200 mg of oral NAC daily for 6 weeks improved performance on lung function tests after exercise. NAC treatment also reduced air trapping in the lungs compared to placebo (Stav 2009). Clinical evidence indicates that administering 1,200 to 1,800 mg of NAC daily counteracts oxidative stress among subjects with COPD (Foschino 2005; De Benedetto 2005). In contrast, a large multi-center COPD trial reported no difference between NAC and placebo in the decline of lung function. However, those taking NAC who were not on corticosteroids appeared to have fewer exacerbations (Decramer 2005).

A clinical trial is underway to investigate the effect of adding 1,200 mg of NAC daily to standard treatment to reduce air trapping and exacerbations in stable COPD (NCT01136239).

Ginseng

Ginseng has traditionally been used in Chinese medicine to treat a wide range of respiratory symptoms (An 2011). A review of twelve small randomized studies showed that ginseng may be a potential adjunct therapy in patients with COPD. Oral ginseng formula combined with pharmacotherapy improved respiratory symptoms and quality of life, and reduced exacerbation of COPD compared to placebo, non-ginseng formula, or pharmacotherapy alone (An 2011). These results confirmed a previous study on the effects of 200 mg of ginseng extract daily on pulmonary function tests (Gross 2002). Pulmonary function and exercise capacity were significantly improved among people with moderate-to-severe COPD taking ginseng extract compared to placebo. A 2011 article reported that there is a large, multi-center, randomized, controlled study underway to evaluate the safety and efficacy of 200 mg of standardized root extract of Panax ginseng daily for 24 weeks among people with moderate COPD (Xue 2011).

Coenzyme Q10

Coenzyme Q10 (CoQ10) is a powerful antioxidant (Quinzii 2010). Indirect evidence shows potential benefit of supplementation in people with COPD who have low CoQ10 levels (Tanrikulu 2011).

A case-control study showed that CoQ10 levels were lower and oxidative stress markers increased during exacerbation of COPD, indicating an imbalance in antioxidant defense during those periods. The authors suggest supplementation with CoQ10 may reduce COPD exacerbation (Tanrikulu 2011).

A study of the effects of CoQ10 on the exercise performance of athletes and non-athletes showed that plasma levels of CoQ10 increased after 2 weeks of supplementation. Participants who supplemented with COQ10 also experienced less fatigue and increased muscle performance compared to placebo (Cooke 2008). These results support a previous study wherein CoQ10 supplementation (90 mg daily for 8 weeks) improved exercise performance in people with COPD (Fujimoto 1993).

Omega-3 Fatty Acids

Omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have many important functions throughout the body. Greater omega-3 intake may ameliorate certain aspects of COPD including, but not limited to, potentially helping to limit and resolve inflammatory processes in patients. Omega-3 fatty acids act as precursors to anti-inflammatory compounds, and dietary supplementation with omega-3 fatty acids has resulted in decreased production of proinflammatory compounds (eg, prostaglandin E2) (Pizzini 2018).

On the other hand, omega-6 fatty acids are overconsumed in the Western diet. Omega-6 fats are generally regarded as pro-inflammatory, particularly when consumed in excess. A balanced ratio of omega-6 to omega-3’s is believed to be around or less than 4:1 as this resembles the ratio achieved in the diet of our ancestors (Mariamenatu 2021; Shetty 2020). The typical Western diet can result in an omega-6 to omega-3 ratio of 10:1 or higher (Lemoine 2020).

In a study of COPD patients that were clinically stable for at least 3 months after discharge from the hospital, higher dietary intake of omega-3 fatty acids was associated with lower levels of proinflammatory biomarkers, whereas higher dietary intake of omega-6 fatty acids was associated with higher levels of proinflammatory biomarkers (de Batlle 2012). A small cross-sectional study of former smokers with moderate-to-severe COPD found that higher reported intake of omega-3 fatty acids was associated with lower risk of severe COPD exacerbations, better quality of life, and fewer respiratory symptoms. This same study also showed that higher omega-6 intake was associated with an increased risk of COPD morbidity (Lemoine 2020).

Clinical trials have not shown that omega-3 fatty acid supplementation can reverse the underlying characteristics of COPD. Nevertheless, one trial found that omega-3 fatty acid supplementation may improve some conditions associated with COPD, like muscle wasting and dysfunction linked to reduced protein homeostasis. In this clinical trial, 32 normal-weight individuals with moderate-to-severe COPD were randomized to receive either 2 or 3.5 grams of omega-3 fatty acids (EPA + DHA) or placebo for four weeks. The response to a protein meal was measured pre- and post-intervention. Results indicated a dose-dependent improvement in protein metabolism and improved prandial anabolic response in both omega-3 groups. Total lean mass also increased in the high-dose omega-3 group compared with placebo (Engelen 2022).

Boswellia serrata

Cell culture and animal studies report that boswellic acids, specifically acetyl-11-keto-beta-boswellic acid (AKBA), from boswellia serrata can inhibit two enzymes involved in inflammation: 5-lipoxygenase (5-LOX) and cathepsin G (catG) (Siddiqui 2011; Abdel-Tawab 2011). 5-LOX stimulates the manufacture of pro-inflammatory leukotrienes and promotes the migration of inflammatory cells to the inflamed body area. 5-LOX has been shown to cause bronchoconstriction and promote inflammation (Siddiqui 2011). Cathepsin is a protein-degrading enzyme that attracts T cells and other leukocytes (white blood cells) at the sites of injury (Abdel-Tawab 2011). Animal studies showed that synthetic cathepsin inhibitors reduced smoke-induced airway inflammation (Maryanoff 2010) as well as airway hyperresponsiveness and inflammation (Williams 2009).

Studies in asthma suggest an anti-inflammatory role for Boswellia serrata in pulmonary disease. For instance, a randomized controlled trial showed that daily treatment with Boswellia serrata extract (BSE) increased the lung function of people with asthma compared to a control group (Gupta 1998).

Aegle marmelos

Aegle marmelos, commonly known as bael, is a southeast Asian plant that has been used traditionally in Ayurvedic herbal medicine to treat a wide array of conditions, including diarrhea, diabetes, peptic ulcers, and respiratory infections (Sharma 2022; Manandhar 2018). It is rich in free radical-scavenging, antimicrobial, and anti-inflammatory phytochemicals, such as carotenoids, flavonoids, and phenolic compounds (Sharma 2022; Venthodika 2021). Preclinical evidence suggests treatment with Aegle marmelos extract may relax tracheal tissue, inhibit enzymes involved in the inflammatory response, and suppress histamine-induced airway inflammation (Arul 2004; Yugandhar 2018; Rajaram 2018). Because of its antioxidant ability, Aegle marmelos is thought to have a potential role in treating oxidative stress associated with chronic degenerative diseases like COPD (Venthodika 2021). In addition, a combination of Aegle marmelos plus Boswellia serrata was found in a clinical study to improve parameters of lung function such as peak expiratory flow rate and forced expiratory volume (Yugandhar 2018).

Andrographolide

Andrographolide is a compound extracted from the andrographis plant (Andrographis paniculata). Andrographis has a long history of use in parts of Asia for treating sore throat, colds, and flu (Jayakumar 2013). A number of preclinical studies have shown isolated andrographolide may protect lung tissue from inflammatory and oxidative damage due to cigarette smoke exposure (Zhang 2020; Xia 2019; Guan 2013). Andrographolide was also found to reduce lung inflammation and increase expression of antioxidant enzymes in laboratory animals with COPD and infected with Haemophilus influenzae, the most frequent cause of lung infection and a major contributor to exacerbation in people with COPD (Tan 2016; Short 2021). Furthermore, a laboratory study found andrographolide restored corticosteroid sensitivity in mice exposed to cigarette smoke and immune cells from people with COPD that had become resistant to corticosteroid therapy, suggesting andrographolide may have a role in supporting COPD treatment with steroids (Liao 2020).

Saffron

Saffron (stigma of Crocus sativus) is a culinary and medicinal herb known for its bright red-orange color. The saffron carotenoids crocin and crocetin have demonstrated anti-inflammatory, oxidative stress-reducing, anti-degenerative, antidepressant, and other effects that could benefit COPD patients (Cerdá-Bernad 2022). In a placebo-controlled trial in 46 COPD patients, treatment with 30 mg crocin daily for 12 weeks decreased measures of oxidative stress, increased total antioxidant capacity, and improved exercise capacity (Ghobadi 2022). Animal research also supports the use of crocin in COPD: In one study that used an animal model of COPD, crocin decreased the number of immune cells and infiltration in the lungs, reduced levels of inflammatory cytokines in the lungs and brain, and decreased signs of depression, such as weight loss, appetite, and periods of immobility during physical tests (Xie 2019). Furthermore, crocin has been shown to mitigate cigarette smoke-induced inflammation, oxidative stress, and cardiac dysfunction in laboratory animals with COPD (Xie 2019; Dianat 2018).

Resveratrol

Resveratrol, a molecule found in red wine, grapes, and Japanese knotweed, has antioxidant and anti-inflammatory properties that may protect against COPD and asthma (Wood 2010). A cell culture study found that resveratrol inhibited the release of all measured inflammatory mediators (cytokines) from immune cells extracted from the alveoli of smokers and non-smokers with COPD. In contrast, the corticosteroid dexamethasone did not inhibit the release of some cytokines in smokers with COPD (Knobloch 2011). Moreover, while resveratrol attenuated the release of inflammatory mediators in airway smooth muscle cells, it preserved signaling of a protein called vascular endothelial growth factor (VEGF), which may be protective against emphysema. Meanwhile, although corticosteroids significantly reduced inflammatory mediators, they also suppressed VEGF signaling (Knobloch 2010). In another study, resveratrol inhibited inflammatory cytokine release from alveolar macrophages in smokers and non-smokers with COPD in a dose-dependent manner (Culpitt 2003).

Zinc

The concentration of zinc is lower-than-normal in people with COPD; the level is even lower in severe cases (Herzog 2011). A clinical trial showed that critically ill people with COPD spent significantly less time on mechanical ventilation after receiving an intravenous cocktail of selenium, manganese and zinc, compared to those who did not (El-Attar 2009). Another study demonstrated that treatment with 22 mg of zinc picolinate for 8 weeks significantly increased the levels of an important antioxidant, superoxide dismutase, in COPD patients (Kirkil 2008).

L-carnitine

Respiratory infections increase the frequency and severity of exacerbations. L-carnitine modulates immune function, supports fatty acid and glucose metabolism, and may prevent wasting syndrome (Manoli 2004; Ferrari 2004; Alt Med Rev 2005; Silverio 2011). In one clinical trial, 2 grams of L-carnitine daily improved exercise tolerance and the strength of respiratory muscles in people with COPD. Blood lactate level, which is associated with muscle fatigue, was also reduced with L-carnitine supplementation (Borghi-Silva 2006; Cooke 1983).

Essential Amino Acids and Whey Protein

COPD is associated with muscle wasting and weight loss (i.e., sarcopenia, cachexia), especially in elderly people; and a higher degree of wasting predicts mortality in this population (Franssen 2008; Slinde 2005). Supplementation with essential amino acids, which are central to anabolic processes that help sustain muscle mass with advancing age, may help combat wasting in aging people with COPD (Dal Negro 2010). In a 12-week study involving 32 COPD patients aged 75 (mean) with impaired lung function, supplementation with 8 grams of essential amino acids daily lead to gains of body weight and fat free mass, as well as improved physical function and several biomarkers compared to placebo (Dal Negro 2010). Whey protein is a good source of essential amino acids and evidence indicates that whey protein may support muscle protein synthesis even more so than its constituent essential amino acids among an aging population (Katsanos 2008).

Melatonin

Poor sleep quality is prevalent among individuals with COPD, and oxidative stress is a significant contributor to lung deterioration and disease progression (Gumral 2009; Nunes 2008). Since the hormone melatonin is both a powerful antioxidant and a regulator of the sleep-wake cycle, it has received interest within the COPD research community for its potential to target these two important aspects of the disease (Pandi-Perumal 2012; Srinivasan 2009). Observational data indicate that melatonin levels decline and oxidative stress increases during COPD exacerbations (Gumral 2009). Clinical trials have shown that administering 3 mg of melatonin to COPD patients improves sleep quality and attenuates oxidative stress (de Matos Cavalcante 2012; Shilo 2000; Nunes 2008).