Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD), defined as such only in the mid-20th century, continued to gain great interest due to its clinical heterogeneity and biological complexity.

It is considered the second most common respiratory disease in the world, with a progressive increase in its prevalence.

Although asthma is more prevalent, COPD is associated with greater morbidity and mortality). Due to its high prevalence and progressive nature, its pathophysiology and early diagnosis have gained great interest to improve long-term results.

Until recently, understanding of disease progression came from the work of Charles Fletcher and Richard Peto, who measured the FEV1 of 800 men from west London, aged 30 to 59, every 6 months for 8 years from 1961. They observed a continuous and slow decrease in FEV1 that seemed to accelerate with aging.

Non-smokers lost FEV1 slowly over time and almost never developed airflow obstruction. Smokers were “susceptible” or “nonsusceptible.”

Non-susceptible smokers had a decline in FEV1 similar to that of non-smokers while susceptible smokers had a more rapid decline in FEV1 that progressed to airflow obstruction. Therefore, the dominant paradigm was that exposure to particulate matter, usually in the form of cigarette smoke, causes acceleration of the typical age-related decline in lung function in those susceptible to this effect.

This meaning was not questioned until contemporary cohort studies offered new perspectives on the trajectories of lung function throughout life.

Lange et al. used data from 3 cohorts of observational studies to identify 2 different trajectories that can lead to COPD. Some subjects achieved normal lung function in early adulthood followed by a rapid decline in FEV1, while others never achieved normal lung function and developed COPD despite normal age-related decline in FEV1 during adulthood.

Furthermore, many cohort studies have identified trajectories of lung function from birth or childhood to early adulthood, which may reflect the influence of potentially modifiable factors such as preterm birth, smoke exposure, recurrent lung infections, and persistent asthma during childhood, which could be the focus of interventions to maximize lung growth and reduce the risk of COPD in old age. This new understanding of lung function trajectories has led to studies of early pathophysiological changes in COPD to identify patients with early disease who may derive greatest benefit from intervention.

The earliest histological change detectable after exposure to cigarette smoke is the epigenetic reprogramming of basal epithelial cells, essential for effective lung defense and epithelial remodeling after lung injury.

Due to epigenetic reprogramming of these cells, the distal airways exhibit squamous metaplasia, ciliary dysfunction, basal and goblet cell hyperplasia, and mucus hypersecretion, thus creating a local inflammatory milieu prone to damage and infection. Indeed, a gene expression analysis of respiratory epithelial samples collected from healthy non-smokers, healthy smokers, and smokers with COPD demonstrated reprogramming of the distal airways to more closely resemble the proximal airways in smokers, especially those with COPD.

We highlight that distal-to-proximal reprogramming may be mediated by epidermal growth factor signaling in small airway basal cells, which could represent a new therapeutic target.

Epithelial reprogramming induced by chronic exposure to cigarette smoke also changes the volume as well as the water and mucin content of the airway surface fluid. The normal structure and function of this physiological interface prevents airway obstruction, inflammation, and infection by effectively removing mucus.

Mucin polymers, which are high molecular weight carbohydrates produced by goblet cells, have been found at higher concentrations in sputum samples from smokers with COPD compared to healthy controls and were associated with the clinical phenotype of bronchitis. chronicle. Therefore, mucin concentration in the airways may serve as a diagnostic biomarker and identify a potential therapeutic target.

In the healthy lung, small airway cells secrete dimeric immunoglobulin (Ig) A into the mucosal lumen from the polymeric Ig receptor. Cleavage of this receptor at the luminal surface releases secretory IgA still bound to a portion of the receptor called the secretory component. Secretory IgA helps prevent bacterial invasion of the respiratory epithelium.

Smoking reduces the expression of the polymeric Ig receptor leading to a localized deficiency of secretory IgA in the small airways. In the absence of secretory IgA, bacteria can invade respiratory epithelial cells. The resulting activation of nuclear factor kB initiates and maintains airway inflammation.

Differences in lung microbial community structures may also help explain why not all smokers develop COPD but rather which specific microbes cause the disease. The progression and timing are important questions that remain unanswered.

These findings suggest that bacterial invasion may be a trigger leading to airway remodeling. It may be a key early pathological lesion that precedes the development of emphysema.

While it was originally thought that the small airways contributed very little to the overall resistance of the lungs, later work in the late 1960s and early 1970s demonstrated that the small airways are, in fact, the major site of greatest resistance. of the airways in people with COPD, and that these changes can occur in the absence of other morphological lung disease.

Furthermore, histological and computed tomography (CT) data suggest that distal airway narrowing, and ultimately its dysfunction, are present in mild disease, even before the development of overt emphysema.

COPD remains underdiagnosed and misdiagnosed.

An analysis of the National Health and Nutrition Examination Surveys (NHANES) demonstrated that >70% of participants with chronic airway obstruction on spirometry did not have a formal diagnosis of COPD. In another analysis of 5 health plans, only 32% of patients with a new COPD diagnosis had undergone spirometry to confirm their diagnosis.

In 2016, the US Preventive Services Task Force confirmed a previous recommendation against screening asymptomatic adults due to a lack of evidence that screening improves long-term clinical outcomes.

One caveat is that some COPD patients may underestimate their symptoms because they avoid activities that induce symptoms or attribute them to lack of physical condition or advanced age.

Therefore, unlike population screening using spirometry, various methods of finding COPD cases have been adopted. One of them combines a 5-item questionnaire called CAPTURE (COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and Exacerbation Risk) by measuring maximum expiratory flow. This pragmatic, low-cost approach, which is currently being applied in a primary care population for screening, was sensitive and specific in identifying patients at risk for COPD who could then be further evaluated with spirometry.

The definition of COPD requires post-bronchodilation spirometry demonstrating fixed airflow and obstruction, defined as a FEV1/forced vital capacity (FVC) ratio <0.70. However, whether this is the best option to define obstruction is still debated. Using a fixed FEV1/FVC cutoff, the definition of airflow obstruction has been recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The American Thoracic Society and the European Respiratory Society recommend using the lower limit of normal (LLN) of FEV1/FVC, based on the age, race, sex and height of the population.

Although the fixed limit is easier to apply, it may give more false negative results in younger patients, who may benefit from early intervention, and more false positive results in older patients, who may receive unnecessary treatment. A large prospective cohort study from Denmark (6-year follow-up) showed that individuals with FEV1/FVC LIN but ≥0.70 had a median age of 45 years and a higher risk of pneumonia, heart failure, and overall mortality compared to those without. airflow obstruction.

Based on these and other studies, the optimal FEV1/FVC cut-off point (fixed vs. LLIN) to define airflow obstruction in clinical practice remains a topic of debate, but is clearly influenced by age. The 2001 GOLD report designated patients with VEEF1/CVF >0.70 but chronic respiratory diseases as GOLD 0.

Symptoms (chronic cough, sputum production, and mucous hypersecretion) classified as GOLD 0 are those that are at risk of developing airflow obstruction in the future. GOLD 0 remained a controversial classification and was eventually removed from subsequent reports as these patients do not represent the majority of those who develop obstruction. Despite the removal of GOLD 0, smokers without airflow obstruction but with chronic respiratory symptoms were found to experience significant respiratory morbidity.

A subgroup of these smokers with FEV1/FVC ≥0.7 but FEV <80% of predicted is currently being investigated, known as preserved ratio altered spirometry (mPRIS). The Rotterdam Study showed that one third of participants with PRISm transitioned to COPD during the 4.5 years of follow-up, and that the presence of PRISm and COPD GOLD 2–4 was a significant predictor of overall mortality. Studies are required for this group to find specific therapeutic strategies to delay or prevent COPD.

To better characterize and understand smoking-related aspects of lung disease in the absence of airflow obstruction, research is focused on respiratory symptoms and exacerbations and abnormal findings on chest CT. Among smokers with FEV1/FVC >0.70, the SPIROMICS study showed that those with a high symptom burden were more likely to experience respiratory exacerbations, lower exercise tolerance, and signs of airway thickening on chest CT, compared to those with a low symptom burden.

It is notable that 42% of the symptomatic group were already taking inhaled bronchodilators and that 23% were receiving them in combination with corticosteroids, despite the fact that there were no indications for such a prescription due to the lack of airflow obstruction.

There is increasing evidence that CT changes can identify patients with airflow obstruction among current and former smokers. There is also evidence that a large number of permanent smokers with FEV1/FVC ≥0.70 have radiological signs of lung disease (significant emphysema or airway wall thickening), as well as more dyspnea, less exercise tolerance, and more respiratory dysfunction compared to those who never smoked.

Taken together, these results suggest that current guidelines requiring airflow obstruction for the diagnosis of COPD may not be adequate to describe the spectrum of symptomatic lung diseases related to smoking and other guidelines with a broader definition may be required. including the presence of changes on chest CT.

A promising method using CT to identify people at highest risk of disease progression has emerged, using an analytical technique designed to identify small airway abnormalities.

Parametric response mapping (PRM) is an image processing technique that uses dynamic registration of paired inspired and expired CT images to classify areas of the lung as normal or emphysematous or non-emphysematous air trapping, known as functional lung disease. small airways. In smokers without airflow obstruction or with mild to moderate airflow obstruction, functional small airway disease MRP was more closely associated with decline in FEV1 over 5 years of follow-up than emphysematous MRP.

Importantly, MRP metrics have been validated with human lung tissue harvested from patients with advanced COPD at the time of lung transplantation, to show that MRP of functional small airway disease correlates with bronchiole loss. terminals, as well as with narrowing, thickening and obstruction of the surviving terminal bronchioles.

These results support the hypothesis that small airway loss occurs before emphysema or a significant decline in lung function is detectable, and that these changes can be identified using chest CT with appropriate imaging techniques. As such, MRP of small airway disease may be a good biomarker to study and early identify COPD.

Another area of ​​ongoing research is serum biomarkers. New biomarkers are sought that are modifiable, are independently associated with hard clinical outcomes, and result in meaningful clinical changes. A focus of research has been the inflammatory milieu of COPD, with many different inflammatory markers having been identified as potential targets.

C-reactive protein has been identified as an important predictor of COPD hospitalizations and mortality, independent of lung function.

It has been shown to help guide antibiotic use in outpatient COPD exacerbations. Elevated fibrinogen levels are similarly associated with increased risk of severe COPD exacerbations, resulting in hospitalization and mortality. Blood eosinophils are related to exacerbations and response to inhaled corticosteroids (ICS). sRAGE (soluble receptor for advanced glycation end product) is another promising biomarker that appears to play an important mechanistic role in the pathogenesis of emphysema.

When thinking about the concept of early COPD or pre-COPD, the importance of age must be considered. Mild disease in an 80-year-old smoker may present a different risk than the same level of severity in a 40-year-old smoker. Therefore, a definition of early COPD that incorporates age has been proposed. Requires patients to be <50 years old and have a history of smoking ≥10 pack years. They also need ≥1 of the following:

a) Evidence of airflow obstruction, defined as strictest FEV1/FVC1/FVC <0.70

b) CT findings compatible with COPD (visual emphysema, air trapping or bronchial thickening) or

c) Rapid decrease in FEV1 (≥60 ml/year).

A recent analysis of a general population study in Copenhagen found a prevalence of early COPD (FEV1/CVFFC1 >350 ml over 5 years) as well as the highest hazard ratio for overall mortality. Unclear whether this definition would be useful in primary or rural care settings or in the absence of resources such as spirometry or chest CT. On the other hand, it may be that certain aspects of symptoms or specific CT abnormalities have value more predictive than others, which are not accounted for in this construction.

> Pharmacotherapy

According to gold recommendations , initial treatment for most patients with symptomatic COPD usually includes a bronchodilator, such as a long-acting muscarinic antagonist (LAMA).

A double-blind trial of nearly 6,000 participants with moderate to severe COPD and a smoking history of ≥10 pack-years compared the effect of tiotropium with placebo on long-term function. Although tiotropium did not slow the decline in FEV1, it did improve health-related quality of life and was associated with fewer COPD exacerbations after 4 years of follow-up.

Another placebo-controlled study of tiotropium showed that tiotropium was superior in improving post-bronchodilator FEV1 at 24 months in patients with mild to moderate COPD, reduced the annual decline in FEV1, and yielded a lower rate of exacerbations. Although tiotropium did not improve FEV1 decline, in those with severe disease, it may benefit lung function in the early or mild stages of the disease.

Regardless of disease severity, the usefulness of LAMAs in improving symptoms, increasing exercise capacity, and reducing the frequency of exacerbations has been well established in patients with COPD, supporting their use as first-line therapy for patients particularly lung function, increase mortality, worsening health and increasing cardiac events. It is very important to prevent exacerbations. The history of exacerbations and symptom burden is a guide to pharmacological treatment.

In recent years, the effectiveness of various inhaler therapies has been clinically evaluated in order to reduce COPD exacerbation rates. The FLAME study showed that the LAMA/LABA (indacaterol-glycopyrronium) combination was more effective than LABA/CSI (salmeterol-fluticasone). Data from the IMPACT trial on the COPD treatment pathway showed that the triple combination LAMA/LABA/ICS (umeclidinium-vilanterol/fluticasone) was better than furoate-vilanterol in preventing COPD exacerbations in patients with a history of exacerbations and at least moderate obstruction on spirometry.

The 3-inhalant regimen reduced the rate of moderate or severe exacerbations compared with either dual therapy.

Unlike the FLAME study, the IMPACT showed a greater reduction in exacerbations with LABA/CSI than with LAMA/LABA. To reconcile these discrepant data, it should be noted that in the FLAME study, 4 prior weeks of tiotropium monotherapy were required, which could have been beneficial for patients who were stable without receiving ICS.

Currently, for the GOLD D patient population (high symptom burden and increased risk of exacerbations), LAMA, LAMA/LABA, and LABA/CSI are potential options for initial therapy, reserving triple therapy for those with persistent exacerbations despite initial therapy. Triple therapy also reduced overall mortality compared with LAMA/LABA.

Previously, there was little evidence to guide doctors when to reduce ICS use in patients without frequent exacerbations, in whom the benefit would not be as clear. The SUNSET study examined the safety and efficacy of ICS in tapering triple therapy in COPD, enrolling patients with stable COPD (FEV1 40-80% of predicted) receiving long-term triple therapy, with ≤1 exacerbation previous annual moderate or severe.

Participants experienced a significant decrease in V[EF1 (26 ml) after de-escalation from LAMA/LABA triple therapy, although no change in exacerbation rate was observed. In particular, patients with blood eosinophilia (≥300 cells/μl) had greater declines in lung function and experienced more exacerbations after ICS was discontinued. A post hoc analysis of the WISDOM trial on ICS discontinuation and exacerbations also showed a similar association between ICS use, exacerbation rate, and eosinophil count, as there were more exacerbations after ICS discontinuation.

Furthermore, a secondary analysis of eosinophil count as a continuous variable in the IMPACT study showed no difference in exacerbation reduction between the use of LAMA/LABA/ICS and LAMA/LABA in eosinophil count <100 cells. /μl, but there were progressively greater treatment effects in the ICS regimens, with higher levels of eosinophils. These findings regarding eosinophils have been incorporated into the 2019 GOLD guidelines, which to guide treatment escalation and tapering integrate serum eosinophil level, dyspnea, and exacerbation history, highlighting that inhaler use is moving toward a more precision-based approach.

Given this association between eosinophilia and COPD exacerbations, trials have evaluated the IL5 monoclonal antibodies mepolizumab and benralizumab, which are currently approved by the US FDA for eosinophilic asthma. Results have been discordant, with only one study clearly showing lower rates of exacerbations.

Oral medications have become commonly used among patients with frequent exacerbations despite maximal inhaler treatment, and in those with eosinophil counts <100 cells/μl, who are less likely to benefit from ICS. Azithromycin has been shown to reduce exacerbations when administered as prophylaxis to patients with COPD and increased risk of exacerbations. The research showed little effect of the treatment in active smokers, which supports its use only in ex-smokers, monitoring the QT interval, electrocardiogram and hearing, due to its adverse effects.

Another possible concern is antibiotic resistance.

Roflumilast, a phosphodiesterase-4 inhibitor, has been shown to reduce exacerbations and is indicated for patients with recurrent exacerbations, FEV1 <50% predicted, and the chronic bronchitis phenotype. Loss of muscle mass has been associated with mortality and exacerbation risk among patients with COPD.

In a recent placebo-controlled trial involving patients with sarcopenic COPD, bimagrumab, a monoclonal antibody that blocks activin type II receptors, produced an increase in thigh muscle volume and total lean body mass up to 1 week. 24, but did not improve physical function. It is still unclear whether this increase in muscle mass could translate into a decrease in respiratory morbidity and mortality.

Pulmonary rehabilitation is a comprehensive longitudinal intervention that integrates aerobic exercises, muscle strength training, and educational programs to improve the physical and psychological status and well-being of patients with chronic respiratory diseases. PR has been shown to increase functional capacity, improve health-related quality of life, and reduce hospitalizations. Still, pulmonary rehabilitation remains underutilized, likely due to lack of awareness among providers, payers, and patients, as well as lack of access.

A large observation arising from a recent cohort study of Medicare beneficiaries who were discharged after hospitalization for COPD showed that initiation of respiratory rehabilitation within 90 days of hospital discharge 1 year later was associated with lower overall mortality compared to later onset or no onset. While <2% of the nearly 200,000 patients included in the analysis initiated rehabilitation within 90 days of discharge, these findings should encourage increased utilization and funding of pulmonary rehabilitation.

Lung volume reduction surgery is one of the few surgical treatment options for patients with COPD. Its premise is that removal of the diseased, emphysematous lung allows reexpansion of the comparatively healthy adjacent lung. Reducing lung volume has been shown to confer a mortality benefit in patients with upper lobe predominant emphysema and poor exercise tolerance despite completing pulmonary rehabilitation. Although it is one of the few therapies shown to provide benefits in COPD, it remains underused, likely due to accreditation restrictions, misconceptions among physicians about the benefits and risks of the procedure, and its strict eligibility criteria.

Endobronchial valves have become a possible alternative for patients who do not qualify for lung volume reduction surgery. The LIBERATE and IMPROVE studies showed improvement of lung function in severe heterogeneous emphysema using the expiration valve system. These recent multicenter randomized controlled trials evaluated 2 different types of endobronchial valves and compared them with optimal medical treatment.

Inclusion criteria were: severe obstruction on spirometry, evidence of significant hyperinflation on lung volume measurements, heterogeneous distribution of emphysema determined by quantitative CT analysis, and little or no collateral ventilation in the target and ipsilateral lobes.

Both trials reported improvement in FEV1 and residual volume in their respective endobronchial valve arms. At 6 and 12 months of follow-up, improvement in respiratory health status and 6-minute walk distance were also observed. These studies have led to the FDA approval of the use of these devices in patients with COPD.

There is a high risk of pneumothorax associated with valve placement, although post-procedure pneumothorax produced no difference in clinical outcomes at 6 and 12 months.

Targeted pulmonary denervation uses radiofrequency bronchoscopic ablation to alter the pulmonary parasympathetic nervous system, which mediates smooth muscle tone, reflex bronchoconstriction, mucus hypersecretion, and airway inflammation.

While a small double-blind randomized controlled trial showed a reduction in respiratory adverse events in patients with moderate to severe symptomatic COPD, a larger randomized trial evaluated denervation to reduce COPD exacerbations.

Bronchial rheoplasty is another bronchoscopic procedure that applies non-thermal pulsed electric fields to the airways to eliminate mucus-producing cells in patients with chronic bronchitis. In small, uncontrolled trials it has been shown to reduce respiratory symptoms as well as goblet cell hyperplasia.

More than 1,000 lung transplants are performed each year on patients with severe COPD. It is the most common indication for lung transplantation worldwide and the second most common in the US.

The most recent guidelines from the International Society of Heart and Lung Transplantation recognize that the timing of referral for transplantation is challenging because the clinical course of COPD is often prolonged and short- and medium-term survival is greater than in other lung diseases. .

Patients with COPD and without contraindications for transplant, who have a BODE index (body mass index, airflow obstruction, severe dyspnea, exercise capacity) of 5 to 6 with progressive disease, FEV1 <25% of predicted hypoxia or Significant hypercapnia should be referred to a transplant center for evaluation.

One of the first interventions for severe hypoxemia was the administration of supplemental oxygen, which improved COPD survival. The 1980 NOTT nocturnal oxygen therapy trial demonstrated that supplemental oxygen therapy improved survival in those with severe hypoxemia at rest, pulmonary hypertension, heart failure, or hematocrit >55%.

The 2016 LOTT trial of long-term oxygen therapy showed benefits in less severe hypoxemia. The NOTT evaluated the use of oxygen in moderate hypoxemia at rest or in exercise-induced desaturations and found that supplemental oxygen had no effect on any of the outcomes measured, including mortality and time to first hospitalization.

Non-invasive ventilation has been shown to improve survival in patients with COPD exacerbations and acute hypercapnic respiratory failure.

However, its routine role in outpatients with stable COPD and chronic hypercapnia has not yet been fully characterized. However, not all studies found the same benefits.

A recent review identified adherence as a major problem and noted that quality of life and survival appear to improve only when chronically elevated CO2 is effectively reduced.

COPD is a common respiratory disease associated with significant clinical heterogeneity and high morbidity and mortality.

New treatment options, ranging from inhaled and oral pharmacological treatments to surgical and bronchoscopic interventional treatments, have opened the door to a personalized therapeutic approach for patients with COPD.

Continued advances in the understanding of pathobiology, diagnosis and treatment focused on susceptible patients, applied early in the course of the disease, have the potential to improve long-term clinical outcomes and help identify disease-modifying therapies.