Chronic Bronchitis and its association with COPD and smoking

By Dr. Maria Benito

 

Chronic bronchitis (CB) is a disease typically characterized by chronic coughing and sputum from the airways, chest tightness, and dyspnea; although it is often considered as an age-related illness, CB occurs not only in older individuals but also in younger people. A minimum of three months of persistent coughing in each of two successive years without any other causes explaining the chronic cough is used to diagnose CB, linked to greater airway disease. Pulmonary function tests, chest X-ray, and computed tomography (CT) scan –in addition to the symptoms– are used for the diagnosis of CB.

 

It is well accepted that CB is associated with multiple clinical consequences, which include speeding up lung function decline, impaired quality of life, additional number of hospital admissions, and increased mortality. However, more specific studies have shown the association between CB and all-cause mortality in subjects under 50 years of age, but not among subjects older than 50.

 

One of the controversies in this pathology is the prospect of being reverisible. CB is by definition a chronic condition, but there are some data pointing to the possibility that it can resolve in some smokers and develop in others. Nonetheless, the clinical characteristics associated with a change in the presence of CB have not been described.

 

As one of the several phenotypes of chronic obstructive pulmonary disease (COPD), CB increases the risk of exacerbations in subjects with COPD. In those COPD patients with CB, it has been shown a significantly higher bronchial wall areas and thickness diameter compared to subjects without CB.

 

Although it is clear the connection between COPD and CB, it is fair to say that not all COPD patients develop CB; only those without airflow obstruction develop CB. However, there is no doubt that predisposing factors in combination with exposures lead to CB. Thus, a predictive multivariate model shows that COPD subjects with radiographic and clinical histories showing airway wall thickness in combination with deterioration of lung function, smoking history, allergic symptoms, and gastroesphageal reflux are prone to suffer CB.

 

There is a growing body of evidence in literature describing environmental risk factors, and recent data have revealed a possible genetic predisposition, especially in women, associated with CB.

 

Although CB is commonly considered to occur in elderly patients, outcomes related to the age of onset are unclear. Thus, studies describe that patients with early CB onset have a longer history, younger death age, poorer health status, and lower incidence of comorbidities.

 

The most important known risk factor for CB is cigarette smoking; the exposure to airborne particles may also contribute to the development of CB, associated with a decline in lung function, development of airway obstruction, increased risk for respiratory infection, and rise in respiratory and cardiovascular mortality. All these factors increase the medical cost and the burden in the healthcare sytem.

 

Persistent and newly developed CB is clearly linked to smoking –either reinstated or continuated– and aggravation of respiratory symptoms, highlighting the importance of continuously assessing chronic cough and sputum production in smokers to identify, as soon as possible, those in worse conditions or with an increased deterioration in the lung function, since the early onset CB increases the risk of developing irreversible airflow limitation and mortality.

 

CB is surprisingly common in the general population. The rage of CB prevalence in adults is estimated between 3.5-27%, which may reflect the variability in definition of CB –patients with chronic phlegm versus patients with chronic cough and phlegm– and also the possible inclusion of subjects with bronchiectasis. However, there is a consensus regarding the numbers affected by CB, which dramatically increase with smoking, as many studies have confirmed the relationship between smoking and CB, with or without associated COPD. Thus, statistics reveal that CB affects up to 22% of non-smokers and between 14-74% of patients with COPD. In these COPD pateints, CB is associated with worse outcomes, including an increasing exacerbation frequency, respiratory hospitalizations, poorer quality of life, greater lung function decline, and increased mortality. It is difficult to calculate the prevalence and incidence of CB because they rely on physician diagnosis rather than the classical symptom-based diagnostic criteria.

 

In a study over 30 years, researchers found that the incidence of CB was 42% in continuous smokers, 26% in ex-smokers, and 22% in never smokers, while a recent large cross sectional study of current or ex-smokers showed a CB prevalence of 34.6%.

 

A study with twins assessing the contribution of genetic factors in the development of CB showed a moderate 40% heritability. The gender more affected by CB seems to be controversial, since some studies pointing at men and others as women as the population most affected. Although unclear, it has been speculated that the reasons for the higher prevalence of CB in females may be due to gender differences in symptom –women report more dyspnea and cough while men recount more phlegm symptoms– or hormonal influences. Increased susceptibility to respiratory disease among female smokers relative to male smokers may have a genetic origin too.

 

Although the primary risk factor of CB is smoking, exposure to ambient air pollution may also contribute. Thus, other possible risk factors include occupational exposures, biomass fuels, dusts, chemical fumes, and air pollution –which aggravates CB symptoms and exacerbations–, in addition to childhood asthma, and perhaps gastroesophageal reflux disease.

 

The pathologic origin of CB is the chronic inflammation of the epithelial airways and the narrowing of the non-alveolated conducting airways. It is believed that –through upregulation of transcription factors and generation of reactive oxygen species and oxidative stress– the pollutants trigger pro-inflammatory cascades within airway epithelial cells. Air pollution increases systemic biomarkers of inflammation in COPD subjects, and greater levels of fibrinogen and systemic C-reactive protein in COPD patients with CB have been shown.

 

The relationship between short-term air pollution exposure, acute respiratory symptoms and hospitalizations is well established, but there is no clear eveidence to prove the relationship with long-term exposure.

 

It is still unclear whether CB is a reversible condition. It is possible that CB can resolve in some smokers and develop newly in others, but the clinical characteristics associated with a change in the presence of CB have not been defined. A recent study has shown that CB is not necessarily a chronic condition and can vary over time depending on the smoking status –increasing the likelihood of developing CB when smoking and rising the chances of resolution when quitting cigarettes–, with the greater deterioration in quality of life and increase in dyspnea in subjects who newly develop CB.

 

Chronic bronchitis can frequently occurs after years of cigarette smoking being the age of onset determined by the interaction of gene polymorphisms and environmental factors. Some studies have also shown the association between passive smoking during childhood, and accelerated decline in lung function and lower respiratory symptoms in adulthood.

 

Both, the concentration level and the size of pollutants seem to be relatively important in long-term exposure. Studies have revealed that pollutants PM_2.5 and PM₁₀ –that is, particulate matter <2.5 μm and <10 μm in diameter– did not differ much in their association with CB. However, exposure to higher concentrations of PM₁₀ was significantly associated with CB, chronic cough, and chronic phlegm, particularly in elderly adults, and the drop in PM₁₀ exposure over time was associated with a reduction in chronic cough and phlegm.

 

Treatments for CB include bronchodilator medications –which help to relieve bronchitis symptoms by relaxing and opening the air passages in the lungs–; steroids –that lessen the swelling that narrows the airways–; and oxygen therapy in serious cases when the lungs are seriously damaged. The last resource is surgery –to remove specific areas of damaged lung where air sacs are alveoli are destroyed–, and lung transplant in extreme cases, usually when comorbidity of CB with other pathology exist.

 

Treatment for COPD and CB includes both pharmacologic and non-pharmacologic strategies. Macrolide antibiotics –with anti-inflammatory properties– have been used to decrease COPD exacerbations; they also reduce neutrophil-elastase induced mucus stasis, suggesting benefit in CB. Bronchodilators –β₂-adrenoceptor (β₂-AR) agonists, anticholinergics and theophylline–, and a combination therapy of inhaled corticosteroid plus long-acting β₂-AR agonists are common therapies for COPD. Cyclic adenosine monophosphate (cAMP) –one of the most important second messengers–, plays a key role in relaxing airway smooth muscles and suppressing inflammation, and is an attractive and promising pharmaceutical target in the treatment of chronic respiratory diseases. Phosphodiesterases (PDEs) are enzymes that hydrolyze cyclic nucleotides and help control its signals. Roflumilast –a selective PDE4 inhibitor– is currently used as an add-on treatment for patients with severe COPD associated with bronchitis and a history of frequent exacerbations withbeneficial effects in the treatment of CB.

 

Research highlights the importance of uncovering potential new mechanisms involved in smoking-related lung disease and pollution exposure. Likewise, it is important to strengthen the evidence-based for CB and to harmonize the diagnosis of this disease. Additionally, the discovery of new targets for treatments in respiratory diseases, particularly focused on COPD, might results in beneficial therapies for CB.

 

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