**6.5. Diagnosis of COPD**

The current standard for COPD diagnosis is spirometry. Lung spirometry measures the vol‐ ume of exhaled air, thus providing a functional assessment of airway obstruction. Two key spirometric values are FEV1 (forced expiratory volume), the volume of exhaled air over the first second of forced expiration, and FVC (forced vital capacity) or the total volume of air exhaled during forced expiration. These values are interpreted as a ratio (FEV1/FVC) where‐ by a decreasing value indicates increasing airway obstruction. A ratio less than 0.70 after bronchodilator treatment is diagnostic for COPD. [38],[39] Clinical indications for spiromet‐ ric evaluation include age greater than 40 years, family history of COPD, past exposure to inhaled irritants, chronic cough and sputum production and dyspnea. [22]

#### **6.6. Traditional COPD therapeutics**

Pharmacological therapy of COPD is rooted in combating the symptoms that present sec‐ ondary to the tissue damage described above. Currently drug therapy is limited to a small cadre of drug classes. Therapeutic agents include bronchodilators, glucocorticoste‐ roids and phosphodiesterase inhibitors. Bronchodilators are the mainstay of COPD thera‐ py. Β 2 receptor agonists act on bronchial smooth muscle, promoting relaxation and airway dilation. Both long acting (daily therapy) and short acting (acute exacerbation) formulations are used. [40] Anticholinergics, or acetylcholine antagonists complement the airway dilating mechanism of β-agonists by blocking parasympathetic muscarinic recep‐ tors that otherwise cause bronchial smooth muscle contraction. [41] Inhaled glucocorti‐ costeroids aid in controlling inflammation, but are typically only used in conjunction with other drug classes. Oral, or systemic, glucocorticoid therapy is reserved for acute exacerbations because of chronic immunosuppression and undesirable side-effect profiles from long-term daily use. [42]

class III mutations, the CFTR is fully formed and traffics correctly to the cell membrane but does not function properly upon reaching it. Class IV mutations are similar to that of class III but they are solely malfunctions in the opening of the channel. Class V mutations result in less than normal amounts of CFTR, although what is made functions correctly. Finally, class VI mutations are similar to that of class V but they are unique in that what CFTR pro‐ tein is made is degraded too quickly and there is a functional deficit in the necessary amount of CFTR present on the apical membrane. [50]Typically genotypes in classes I-III have worse phenotypic presentations and higher mortality. Like genotype, sex is also a mor‐ tality predictor; males have a higher survival rate than females until the age of 20. [51],[52]

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As noted above, CF presents with numerous extra-pulmonary symptoms, but only pulmo‐ nary complications will be addressed herein. Pulmonary manifestations of CF can be under‐

(1) The underlying genetic defect in CF results in either a dysfunctional or absent CFTR channel. The submucosal glands in the distal airways express CFTR, a protein that spans the membrane of epithelial cells. It employs a cAMP-mediated, PKA activated mechanism to conduct chloride ions across the lipid bilayer. Other functions of CFTR that have been de‐ scribed are affected with varying degrees based on the type of mutation (congenital bilateral absence of the vas deferens). How those secondary functions are altered may explain the phenotypic severity in CF, but dysregulation and dysfunction in chloride conductance is the

(2) Ineffective secretion of chloride anions (and unregulated absorption of sodium ions) leads to a reduced volume of airway surface liquid (ASL) due to the diminished electro‐ lyte content in the airway and very little osmotic pull. In turn, this alters the consistency of airway mucus to a thick, desiccated, hyper-viscous layer that adheres to the airway

(3) The adherent mucus creates plaques that obstruct the airways and disrupt the mucocili‐ ary clearance mechanism. The detrimental effect of poor mucus clearance is two-fold. First, lung function, as measured by spirometry, declines due to the physical obstruction of the airways. Clogged with mucus plugs, the small airways conduct air less efficiently. Second,

(4) The airways are thus persistently colonized by multiple species of bacteria, namely Pseu‐ damonas aeruginosa, Burkholderia cepacia, Hemophila influezae and Staphylococcus aur‐

stood as a stepwise melding of the following pathologic processes:

**7.4. Pathophysiology**

**1.** Defective CFTR

epithelium. [53]

**2.** Reduced ASL height

**3.** Disrupted mucociliary clearance

**5.** Neutrophil dominated inflammation

primary pathology of the CFTR in CF.

the adherent mucus becomes a nidus for infection. [54]

**4.** Colonization/chronic infection/exacerbation
