2175Bronchiectasis CHAPTER 290

FIGURE 290-1 Representative chest CT image of severe bronchiectasis. This

patient’s CT demonstrates many severely dilated airways, seen both longitudinally

(arrowhead) and in cross-section (arrow).

TREATMENT

Bronchiectasis

Treatment of infectious bronchiectasis is directed at the control of

active infection and improvements in secretion clearance and bronchial hygiene so as to decrease the microbial load within the airways

and minimize the risk of repeated infections.

ANTIBIOTIC TREATMENT

Antibiotics targeting the causative or presumptive pathogen (with

Haemophilus influenzae and P. aeruginosa isolated commonly)

should be administered in acute exacerbations, usually for a minimum of 7–10 days and perhaps for as long as 14 days. Decisions

about treatment of NTM infection can be difficult, given that these

organisms can be colonizers as well as pathogens and the prolonged

treatment course often is not well tolerated. Consensus guidelines

have advised that diagnostic criteria for true clinical infection

with NTM should be considered in patients with symptoms and

radiographic findings of lung disease who have at least two sputum

samples positive on culture; at least one bronchoalveolar lavage

(BAL) fluid sample positive on culture; a biopsy sample displaying

histopathologic features of NTM infection (e.g., granuloma or a

positive stain for acid-fast bacilli) along with one positive sputum

culture; or a pleural fluid sample (or a sample from another sterile extrapulmonary site) positive on culture. MAC strains are the

most common NTM pathogens, and the recommended regimen

for HIV-negative patients infected with macrolide-sensitive MAC

includes a macrolide combined with rifampin and ethambutol.

Consensus guidelines recommend macrolide susceptibility testing

for clinically significant MAC isolates.

BRONCHIAL HYGIENE

The numerous approaches used to enhance secretion clearance in

bronchiectasis include hydration and mucolytic administration,

aerosolization of bronchodilators and hyperosmolar agents (e.g.,

hypertonic saline), and chest physiotherapy (e.g., postural drainage,

traditional mechanical chest percussion via hand clapping to the

chest, or use of devices such as an oscillatory positive expiratory

pressure flutter valve or a high-frequency chest wall oscillation

vest). Pulmonary rehabilitation and a regular exercise program

may assist with secretion clearance as well as with other aspects of

bronchiectasis, including improved exercise capacity and quality of

life. The mucolytic dornase (DNase) is recommended routinely in

CF-related bronchiectasis but not in non-CF bronchiectasis, given

concerns about lack of efficacy and potential harm in the non-CF

population.

ANTI-INFLAMMATORY THERAPY

It has been proposed that control of the inflammatory response

may be of benefit in bronchiectasis, and relatively small-scale trials

have yielded evidence of alleviated dyspnea, decreased need for

inhaled β-agonists, and reduced sputum production with inhaled

glucocorticoids. However, no significant differences in lung function or bronchiectasis exacerbation rates have been observed. Risks

of immunosuppression and adrenal suppression must be carefully

considered with use of anti-inflammatory therapy in infectious

bronchiectasis. Nevertheless, administration of oral/systemic glucocorticoids may be important in treatment of bronchiectasis due to

certain etiologies, such as ABPA, or of noninfectious bronchiectasis

due to underlying conditions, especially that in which an autoimmune condition is believed to be active (e.g., rheumatoid arthritis

or Sjögren’s syndrome). Patients with ABPA also may benefit from

a prolonged course of treatment with the oral antifungal agent

itraconazole.

REFRACTORY CASES

In select cases, surgery can be considered, with resection of a focal

area of suppuration. In advanced cases, lung transplantation can be

considered.

■ COMPLICATIONS

In more severe cases of infectious bronchiectasis, recurrent infections

and repeated courses of antibiotics can lead to microbial resistance to

antibiotics. In certain cases, combinations of antibiotics that have independent toxicity profiles may be necessary to treat resistant organisms.

Recurrent infections can result in injury to superficial mucosal

vessels, with bleeding and, in severe cases, life-threatening hemoptysis.

Management of massive hemoptysis usually requires intubation to

stabilize the patient, identification of the source of bleeding, and protection of the nonbleeding lung. Control of bleeding often necessitates

bronchial artery embolization and, in severe cases, surgery.

■ PROGNOSIS

Outcomes of bronchiectasis can vary widely with the underlying

etiology and comorbid conditions and also may be influenced by

the frequency of exacerbations and (in infectious cases) the specific

pathogens involved (with worse outcomes associated with P. aeruginosa

colonization). Increasing attention is being given to defining clinical

subphenotypes of bronchiectasis in light of heterogeneous clinical,

radiographic, and microbial features and to developing screening tools

for the assessment of quality of life and disease severity. In one study,

the decline of lung function in patients with non-CF bronchiectasis

was similar to that in patients with COPD, with the forced expiratory

volume in 1 s (FEV1

) declining by 50–55 mL per year as opposed to

20–30 mL per year for healthy controls.

■ PREVENTION

Reversal of an underlying immunodeficient state (e.g., by administration of gamma globulin for immunoglobulin-deficient patients) and

vaccination of patients with chronic respiratory conditions (e.g., influenza and pneumococcal vaccines) can decrease the risk of recurrent

infections. Patients who smoke should be counseled about smoking

cessation.

After resolution of an acute infection in patients with recurrences

(e.g., ≥3 episodes per year), the use of suppressive antibiotics to minimize the microbial load and reduce the frequency of exacerbations has

been proposed. Although there is less consensus about this approach

in non-CF-associated bronchiectasis than in CF-related bronchiectasis,

small studies have supported benefits of selected therapies. Possible

suppressive treatments include (1) administration of an oral antibiotic (e.g., ciprofloxacin) daily for 1–2 weeks per month; (2) use of a

rotating schedule of oral antibiotics (to minimize the risk of development of drug resistance); (3) administration of a macrolide antibiotic (see below) daily or three times per week (with mechanisms of

possible benefit related to non-antimicrobial properties, such as antiinflammatory effects and reduction of gram-negative bacillary

2176 PART 7 Disorders of the Respiratory System

■ CLINICAL FEATURES

Cystic fibrosis (CF) is an autosomal recessive exocrinopathy affecting

multiple epithelial tissues. The gene product responsible for CF (the

cystic fibrosis transmembrane conductance regulator [CFTR]) serves

as an anion channel in the apical (luminal) plasma membranes of epithelial cells and regulates volume and composition of exocrine secretion. An increasingly sophisticated understanding of CFTR molecular

genetics and membrane protein biochemistry has facilitated CF drug

discovery, with a number of recently approved agents that have transformed the clinical outlook for many with the disease.

Respiratory Manifestations The major morbidity and mortality associated with CF is attributable to pulmonary compromise,

291 Cystic Fibrosis

Eric J. Sorscher

biofilms); (4) inhalation of aerosolized antibiotics (e.g., tobramycin

inhalation solution) for select patients on a rotating schedule (e.g.,

30 days on, 30 days off), with the goal of decreasing the microbial

load without eliciting the side effects of systemic drug administration;

other studies examining inhaled aztreonam and inhaled ciprofloxacin

formulations have shown conflicting results, suggesting there might

be subpopulations of patients with bronchiectasis who might benefit

from specific therapies; and (5) intermittent administration of IV antibiotics (e.g., “clean-outs”) for patients with more severe bronchiectasis

and/or resistant pathogens. In relation to macrolide therapy (point 3

above), a number of double-blind, placebo-controlled, randomized

trials have been published in non-CF bronchiectasis and support a

benefit of long-term macrolides (6–12 months of azithromycin or erythromycin) in decreasing rates of bronchiectasis exacerbation, mucus

production, and decline in lung function. However, two of these studies

and a meta-analysis also reported increased macrolide resistance in

commensal pathogens, dampening enthusiasm for universal use of

macrolides in this setting and raising the question of whether there

might be select non-CF bronchiectasis patients with higher morbidity

for whom benefits of long-term macrolides might outweigh the risks

of emergence of antibiotic resistance. In particular, development of

macrolide-resistant NTM is a potential concern, making treatment of

those pathogens much more difficult. Furthermore, patients with different patterns of microbial colonization may not all experience similar

benefits with macrolide therapy. Therefore, before chronic macrolide

therapy is considered, it is advisable to rule out NTM infection and

carefully consider each patient’s scenario closely, obtaining an electrocardiogram to rule out a prolonged QT interval that might place the

patient at increased risk of arrhythmias.

In addition, ongoing consistent attention to bronchial hygiene can

promote secretion clearance and decrease the microbial load in the

airways.

■ FURTHER READING

Chalmers JD, Chotirmall SH: Bronchiectasis: New therapies and

new perspectives. Lancet Respir Med 6:715, 2018.

Henkle E et al: Characteristics and health-care utilization history of

patients with bronchiectasis in US Medicare enrollees with prescription drug plans, 2006-2014. Chest 154:1311, 2018.

Mac Aogáin M et al: Distinct “immunoallertypes” of disease and high

frequencies of sensitization in non-cystic fibrosis bronchiectasis. Am

J Respir Crit Care Med 199:842, 2019.

Wang D et al: Meta-analysis of macrolide maintenance therapy for prevention of disease exacerbations in patients with noncystic fibrosis

bronchiectasis. Medicine (Baltimore) 98:e15285, 2019.

characterized by copious hyperviscous and adherent secretions that

obstruct small and medium-sized airways. CF respiratory secretions

are exceedingly difficult to clear, and a complex bacterial flora that

includes Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa (among other pathogens, see below) is routinely

cultured from CF sputum. Microbiome analysis has identified dozens

of other bacterial species in CF lungs, although a relationship of these

less well-characterized organisms to disease progression has not been

determined. Robust pulmonary inflammation in the setting of inspissated mucus and chronic bacterial infection leads to collateral tissue

injury and further aggravates respiratory decline. Organisms such as P.

aeruginosa exhibit a stereotypic mode of pathogenesis; a sentinel and

early colonization event often engenders lifelong pulmonary infection

by the same genetic strain. Over a period of many years, P. aeruginosa

evolves in CF lungs to adopt a mucoid phenotype (attributable to

release of alginate exoproduct) that confers selective advantage for the

pathogen and poor prognosis for the host.

Pancreatic Findings The complete name of the disease, cystic

fibrosis of the pancreas, refers to profound tissue destruction of the

exocrine pancreas, with fibrotic scarring and/or fatty replacement,

cyst formation, loss of acinar tissue, and ablation of normal pancreatic

architecture. As in the lung, tenacious exocrine secretions (sometimes

termed concretions) obstruct pancreatic ducts and impair production

and flow of digestive enzymes to the duodenum. The sequelae of exocrine pancreatic insufficiency include chronic malabsorption, poor

growth, fat-soluble vitamin insufficiency, high levels of blood immunoreactive trypsinogen (a test used in newborn screening), and loss of

pancreatic islet cell mass. CF-related diabetes mellitus is a manifestation

in >30% of adults with the disease and likely multifactorial in nature

(attributable to progressive destruction/dysfunction of the endocrine

pancreas and, in some cases, insulin resistance or other features).

Additional Organ System Damage As in CF lung and pancreas,

thick and inspissated secretions compromise numerous exocrine tissues. Obstruction of intrahepatic bile ducts and parenchymal fibrosis

are commonly observed in pathologic specimens, with multilobular

cirrhosis in 4–15% of patients with CF and significant hepatic insufficiency as a resulting manifestation among many adults. Contents of

the intestinal lumen are often difficult to excrete, leading to meconium

ileus (a presentation in 10–20% of newborns with CF) or distal intestinal obstructive syndrome in older individuals. Men typically exhibit

complete involution of the vas deferens and infertility (despite functioning spermatogenesis), and ~99% of males with CF are infertile. The

etiology of this dramatic anatomic defect in the male genitourinary system is not understood but may represent a developmental abnormality

secondary to improper epithelial secretion in the vas or associated

structures. Males with CF can conceive children through in vitro fertilization. Abnormalities of female reproductive tract secretions are likely

contributors to a higher incidence of infertility among women with

the disease. Radiographic evidence of sinusitis occurs in most patients

with CF and is associated with organisms similar to those recovered

from lower airways, suggesting the sinus may serve as a reservoir for

bacterial seeding.

■ PATHOGENESIS

Cystic Fibrosis Transmembrane Conductance Regulator

CFTR is an integral membrane protein that functions as an epithelial

anion channel. The ~1480-amino-acid molecule encodes a passive

conduit for chloride and bicarbonate transport across plasma membranes of epithelial tissues, with direction of ion flow dependent on the

electrochemical driving force. Gating of CFTR involves conformational

cycling between an open and closed configuration and is augmented by

hydrolysis of adenosine triphosphate (ATP). Anion flux mediated by

CFTR does not involve active transport against a concentration gradient but utilizes the energy provided from ATP hydrolysis as a central

feature of ion channel mechanochemistry and gating.

CFTR is situated in the apical plasma membranes of acinar and

other epithelial cells where it regulates the amount and composition

2177Cystic Fibrosis CHAPTER 291

■ DIAGNOSIS

During the past decade, newborn screening has led to most CF

diagnoses, with confirmation through CFTR mutation analysis

and sweat electrolyte measurements as cardinal tests. DNA-based

of secretion by exocrine glands. In numerous epithelia, chloride and

bicarbonate release via CFTR is followed passively by flow of water

through other pathways, aiding mobilization and clearance of exocrine

products. Along respiratory mucosa, CFTR is necessary to provide

sufficient depth of the periciliary fluid layer (PCL), allowing normal

ciliary extension and mucociliary transport. CFTR-deficient airway

cells exhibit depleted PCL, causing ciliary collapse and failure to clear

overlying mucus (Video 291-1). In airway submucosal glands, CFTR

is expressed in acini and may participate both in the formation of

mucus and extrusion of glandular secretion onto the airway surface

(Fig. 291-1). In other exocrine glands characterized by abrogated

mucus transport (e.g., pancreatic acini and ducts, as well as bile canaliculi, and intestinal secretions), similar pathogenic mechanisms have

been implicated. In these tissues, a driving force for apical chloride

and/or bicarbonate secretion is believed to promote CFTR-mediated

fluid and electrolyte release into the lumen, which confers proper

rheology of mucins and other exocrine products. Failure of this mechanism disrupts normal hydration and transport of glandular secretion

and is widely viewed as a proximate cause of obstruction, with concomitant tissue injury.

Pulmonary Inflammation and Remodeling The CF airway is

characterized by an aggressive, unrelenting, neutrophilic inflammatory response with release of proteases and oxidants leading to airway

remodeling and bronchiectasis. Intense pulmonary inflammation is

largely driven by chronic respiratory infection. Macrophages and other

cells resident in CF lungs augment elaboration of proinflammatory

cytokines, which contribute to innate and adaptive immune reactivity.

CFTR-dependent abnormalities of airway surface fluid composition

(e.g., pH) have been reported as contributors to impaired bacterial killing in CF lungs. The role of CFTR as a direct mediator of inflammatory

responsiveness and/or pulmonary remodeling represents an important

and topical area of investigation.

■ MOLECULAR GENETICS

DNA sequencing of CFTR from patients (and others) worldwide has

revealed >1600 allelic mutations; several hundred of these have been

well characterized as disease-causing variants. Distinguishing the

single nucleotide transversions or other polymorphisms with causal

relevance can sometimes present a significant challenge. The CFTR2

resource (www.cftr2.org/) helps delineate gene variants with a clear

etiologic role.

CFTR defects known to elicit disease are often categorized based on

molecular mechanism. For example, the common F508del mutation

(nomenclature denotes omission of a single phenylalanine residue

[F] at CFTR position 508) leads to a folding abnormality recognized

by cellular quality control pathways. CFTR encoding F508del retains

partial ion channel function, but protein maturation is arrested in the

endoplasmic reticulum, and CFTR fails to arrive at the plasma membrane. Instead, F508del CFTR is misrouted and undergoes endoplasmic

reticulum–associated degradation via the proteasome. CFTR mutations

that disrupt protein maturation are termed class II defects and are by

far the most common genetic abnormalities. F508del alone accounts for

~70% of defective CFTR alleles in the United States, where ~90% of individuals with CF carry at least one F508del mutation. (See Video 291-1).

Other gene defects include CFTR ion channels properly trafficked

to the apical cell surface but unable to open and/or gate. Such channel

proteins include G551D (a glycine to aspartic acid replacement at CFTR

position 551), which leads to an inability to transport Cl–

 or HCO3

–

 (a

class III abnormality). Individuals with at least one G551D allele represent ~4% of patients with CF. CFTR nonsense mutations such as

G542X, R553X, or W1282X (premature termination codon replaces glycine, arginine, or tryptophan at positions 542, 553, or 1282, respectively)

are among the common class I defects, in addition to large deletions or

other major disruptions of the gene. The W1282X mutation, for example, is prevalent among individuals of Ashkenazi descent and a predominant CF genotype in Israel. Additional categories of CFTR mutation

include defects in the ion channel pore (class IV), RNA splicing (class

V), and increased plasma membrane turnover (class VI) (Fig. 291-2).

A

B

C

D

FIGURE 291-1 Extrusion of mucus secretion onto the epithelial surface of airways in

cystic fibrosis (CF). A. Schematic of the surface epithelium and supporting glandular

structure of the human airway. B. The submucosal glands of a patient with CF are filled

with mucus, and mucopurulent debris overlies the airway surfaces, essentially burying

the epithelium. C. A higher magnification view of a mucus plug tightly adhering to the

airway surface, with arrows indicating the interface between infected and inflamed

secretions and the underlying epithelium to which the secretions adhere. (Both B

and C were stained with hematoxylin and eosin, with the colors modified to highlight

structures.) Infected secretions obstruct airways and, over time, dramatically disrupt

the normal architecture of the lung. D. CFTR is expressed in surface epithelium and

serous cells at the base of submucosal glands in a porcine lung sample, as shown

by the dark staining, signifying binding by CFTR antibodies to epithelial structures

(aminoethylcarbazole detection of horseradish peroxidase with hematoxylin

counterstain). (From SM Rowe, S Miller, EJ Sorscher: Cystic Fibrosis. N Engl J Med

352:1992, 2005. Copyright © 2005 Massachusetts Medical Society. Reprinted with

permission from Massachusetts Medical Society.)

2178 PART 7 Disorders of the Respiratory System

CFTR

Cl–

Class III Class VI Class IV

Accelerated

turnover

Golgi

complex

Proteosome

Class II

Endoplasmic

reticulum

Class I Class V Nucleus

FIGURE 291-2 Categories of CFTR mutations. Classes of defects in the CFTR

gene include the absence of synthesis (class I); defective protein maturation and

premature degradation (class II); disordered gating/regulation, such as diminished

adenosine triphosphate (ATP) binding and hydrolysis (class III); defective

conductance through the ion channel pore (class IV); a reduced number of CFTR

transcripts due to a promoter or splicing abnormality (class V); and accelerated

turnover from the cell surface (class VI). (From SM Rowe, S Miller, EJ Sorscher:

N Engl J Med 352:1992, 2005.)

evaluation typically surveys numerous disease-associated mutations;

panels that identify up to ~330 CFTR variants are available through

a variety of public health laboratories or commercial sources. For

difficult cases, complete CFTR exonic sequencing together with

analysis of splice junctions and key regulatory elements can be

obtained.

Sweat electrolytes following pilocarpine iontophoresis continue to

comprise an essential diagnostic element, with levels of chloride markedly elevated in CF compared to non-CF individuals. The sweat test

result is highly specific and served as a mainstay of diagnosis for many

decades prior to availability of CFTR genotyping. Notably, hyperviscosity of eccrine sweat is not a clinical feature of the disease. Sweat

ducts function to reabsorb chloride from a primary sweat secretion

produced by the glandular coil. Malfunction of CFTR leads to diminished chloride uptake from the ductular lumen, and sweat emerges on

the skin with elevated levels of chloride. For the unusual situation in

which both CFTR genotype and sweat electrolytes are inconclusive, in

vivo measurement of ion transport across the nasal airways can serve

as a specific test for CF and is used by a number of referral centers. For

example, elevated (sodium-dependent) transepithelial charge separation

across airway epithelial tissue and persistent failure of isoproterenoldependent chloride secretion (via CFTR) represent bioelectric findings

specific for the disease. Measurements of CFTR activity in excised rectal mucosal biopsies can also be obtained.

■ COMPLEXITY OF A CF PHENOTYPE

Prior to the advent of newborn screening, CF classically presented

in childhood with chronic productive cough, malabsorption including steatorrhea, and failure to thrive. The disease is most common

among whites (~1 in 3300 live births) and much less frequent among

African-American (~1 in 10,000) or Asian populations (~1 in 33,000).

Several “severe” defects that impair CFTR activity (including F508del,

G551D, and truncation alleles) are predictive of pancreatic insufficiency,

which is clinically evident in ~90% of individuals with the disease. These

few genotype-phenotype correlations notwithstanding, genotype is, in

general, a poor predictor of overall respiratory prognosis.

A spectrum of CFTR-related conditions with features resembling

classic CF has been well described. In addition to multiorgan involvement, forme frustes, such as isolated congenital bilateral absence of

the vas deferens or pancreatitis (without other organ system findings),

are strongly associated with CFTR mutations in at least one allele.

Although CF is a classic monogenic disease, the importance of nonCFTR gene modifiers and proteins that regulate ion flux, inflammatory

pathways, and airway remodeling has been appreciated as influencing

clinical course. For example, the magnitude of transepithelial sodium

reabsorption in CF airways, which helps control periciliary fluid depth

and composition, is strongly influenced by CFTR and represents a

molecular target for intervention.

■ CFTR MODULATORS

Potentiation of Mutant CFTR Gating A major effort directed

toward high-throughput analysis of large compound libraries (including

millions of individual agents) has identified effective new approaches

to CF therapy. The first approved compound in this class, ivacaftor,

robustly potentiates CFTR channel opening and stimulates ion transport. Ivacaftor overcomes the G551D CFTR gating defect, and individuals carrying this mutation exhibit pronounced improvement in lung

function, weight gain, and other clinical benefit following oral therapy.

Sweat chloride values are significantly reduced by the drug. Prior to ivacaftor, no clinical intervention of any sort had been shown to normalize

the CF sweat phenotype. In addition to G551D, ivacaftor has been

approved in the United States for 96 other CFTR variants. Multiyear

administration studies indicate durable respiratory improvement. Ivacaftor has been viewed as the harbinger of a new era for CF therapeutics

directed at treating the most fundamental causes of this disease.

Correction of the F508del Processing Abnormality Lumacaftor and tezacaftor, two U.S. Food and Drug Administration (FDA)–

approved “corrector” molecules that repair CFTR misfolding (as distinct

from CFTR gating “potentiators” such as ivacaftor), partially overcome

defective F508del CFTR biogenesis. The drugs promote cell surface

localization of F508del CFTR. Formulations of lumacaftor or tezacaftor

(together with ivacaftor to augment channel opening) typically confer modest improvement in pulmonary function among individuals

homozygous for F508del (~45% of the U.S. CF population). Elexacaftor,

a next-generation corrector that operates through a different mechanism

of action, is FDA-approved in combination with tezacaftor and ivacaftor

for patients with CF encoding at least one F508del variant (irrespective

of the other CFTR mutations), as well as for a series of less common

CFTR defects. This triple combination therapy (TCT) may, therefore,

benefit >90% of individuals with the disease. Marked enhancement of

forced expiratory volume in 1 s (FEV1

), fewer respiratory exacerbations,

improved quality of life, and diminished sweat chloride have all been

demonstrated in patients following TCT, leading to designation as

“highly effective modulator treatments” (HEMTs). For example, among

patients carrying one F508del together with a CFTR minimal function

variant, FEV1

 (% predicted) was improved by ~14% over a 4- to 24-week

treatment period. Monitoring liver function of patients started on TCTs

and attention to pharmacologic interactions, including effects mediated

by CYP3A, are required. (See Video 291-2A,B).

Personalized Molecular Therapies The advent of CFTR modulators with robust clinical impact has engendered new optimism

regarding care of patients with CF. Based on the large number of

2179Cystic Fibrosis CHAPTER 291

disease-causing CFTR mutations, together with the ability to group

these into molecular categories (Fig. 291-2), CF has been deemed a

condition ideally suited for personalized (i.e., mechanistically tailored)

drug treatment. That being said, many CFTR variants clearly exhibit

multiple molecular abnormalities (across more than one mechanistic

subclass), and modulator compounds can therefore provide benefit

across numerous disease subcategories. CFTR drug discovery—while

highly successful—might, therefore, be viewed as less “personalized”

or “precise” than originally envisioned. Moreover, clinical data indicate

that a subset of individuals with F508del respond poorly to TCTs.

Understanding the multifactorial determinants mediating favorable

drug response and risk of toxicity (e.g., genomic loci other than CFTR,

epigenetic/environmental features, complex CFTR alleles with numerous polymorphisms) constitutes a major objective for future research

in the field.

Other Challenges Involving CF Precision Therapy The

high cost of modulator compounds has often restricted third-party

reimbursement to include only the specific genotypes for which FDA

or other regulatory approval has been obtained. As a consequence,

modulator access to potentially efficacious agents among patients with

very rare CFTR defects, and off-label prescribing, are largely precluded.

Moreover, clinical trials intended to expand the drug label can be

difficult to arrange based on the small numbers of patients carrying

ultra-rare alleles. In vitro models rigorously shown to predict clinical

modulator response have proven useful in this setting (e.g., studies of

primary airway or other well-validated epithelial monolayers, organoid

cultures) and are being advanced as a potential means to expand regulatory approval for uncommon variants.

Progress in CF drug discovery is emblematic of what might

be accomplished in other refractory inherited conditions using an

approach grounded in molecular mechanism and unbiased compound

library screening. Genetic manipulation (CFTR gene transfer, certain

types of genome editing, etc.) and airway progenitor cell treatments

comprise experimental strategies less dependent on a specific (i.e.,

personalized) CFTR mutation. Such approaches will require efficient,

durable, and safe in vivo delivery, with particular emphasis on CF lung

disease.

■ THERAPEUTICS DIRECTED TOWARD CF

SEQUELAE

Chronic Outpatient Management, Including Relationship to

Modulators Standard care for patients with CF is intensive, with

outpatient regimens that include exogenous pancreatic enzymes taken

with meals, nutritional supplementation, anti-inflammatory medication, bronchodilators, and chronic or periodic administration of oral or

aerosolized antibiotics (e.g., as maintenance therapy for patients with P.

aeruginosa). Recombinant DNAse aerosols (degrade DNA strands that

contribute to mucus viscosity) and nebulized hypertonic saline (serves

to augment PCL depth, activate mucociliary clearance, and mobilize inspissated airway secretions) are administered routinely. Chest

physiotherapy several times each day is a standard means to promote

clearance of airway mucus. Among adults with CF, malabsorption,

chronic inflammation, and endocrine abnormalities can lead to poor

bone mineralization, requiring treatment with vitamin D, calcium, and

other measures. The time, complexity, and expense of home care are

considerable and take a significant toll on patients and their families.

Chronic sequelae of CF have received particular attention in the era

of highly effective modulator treatment, since patients with established

CF lung disease given TCT or other formulations continue to exhibit

respiratory infection and inflammation despite clinical improvement.

Moreover, impact of CFTR modulators has not been well characterized

for many extrapulmonary manifestations of the disease. Improved

treatments that address ongoing respiratory infection/inflammation,

nutritional deficits, hepatic and endocrine abnormalities, mucostasis,

or other features that persist despite modulator treatment remain a

priority. Opportunities to define better these aspects of CF and simplify

therapeutic regimens among patients recently started on TCT are the

focus of several multicenter trials.

Pulmonary Exacerbation Severe CF respiratory exacerbation is

commonly managed by hospital admission for parenteral antibiotics

and frequent chest physiotherapy directed against (often multidrugresistant) bacterial pathogens. Aggressive intervention in this setting

can restore a large component of lung function, but ongoing and

cumulative loss of pulmonary reserve has traditionally reflected natural

history of the disease. Poor prognostic indicators such as sputum culture containing Burkholderia cepacia complex, mucoid P. aeruginosa,

or atypical mycobacteria are rigorously monitored in the CF patient

population. An increasing incidence of methicillin-resistant S. aureus

has also been observed and may be associated with poor outcomes.

Typical inpatient antibiotic coverage includes combination drug therapy with an aminoglycoside and β-lactam for at least 14 days. Maximal

improvement in lung function is often achieved by 8–10 days in that

setting, although optimal duration of therapy is a subject of continuing investigation. Many families elect parenteral antibiotic treatment

at home, but additional studies are needed to evaluate specific drug

combinations, duration of therapy, and home versus inpatient management. Other CF respiratory sequelae that may require hospitalization

include hemoptysis and pneumothorax. Hypersensitivity to Aspergillus

(allergic bronchopulmonary aspergillosis) occurs in ~5% of individuals

with the disease and should be considered in the absence of favorable

response to aggressive inpatient treatment. Contributions of viral

infection (including SARS-CoV-2) during acute CF respiratory decline

represent an area of intense clinical interest.

Lung Transplantation For end-stage CF pulmonary failure,

transplantation is a viable therapeutic option with median survival

>9 years among adults with the disease. Determining optimal timing

for surgery presents a substantial challenge in patients with severe respiratory compromise, particularly since the rate of continued functional

decline, as well as individualized mortality risk from transplantation,

can be difficult to predict. FEV1

 measurements <30% predicted, together

with an assortment of other clinical parameters (hospitalization frequency, need for supplemental oxygen, etc.), are employed as thresholds for transplant referral, although patients with conditions such as

significant pulmonary hypertension may merit consultation at higher

FEV1

. Based on clinical outcome and other features, eligible patients

with CF and their families sometimes do not pursue a surgical option.

The decision is best approached through early discussions with health

care providers specializing in both CF clinical management and

transplantation.

■ CF QUALITY IMPROVEMENT

As a direct result of advances in basic research, modulator and other

therapies are transforming CF from a disease that historically led to

death in early childhood to a condition with frequent survival well into

the fourth decade of life and beyond. Although initiating modulator

treatment in young children may extend longevity even further by

forestalling pulmonary damage, this prediction will require formal

evaluation. As modulatory therapies advance, carefully standardized

approaches to management will be essential. Well-defined protocols for

CF care have been widely established, including thresholds for hospital

admission, antibiotic regimens, nutritional guidelines, periodicity of

diagnostic tests, and other clinical parameters. These recommendations are accepted throughout specialized CF care centers and other

accredited programs. Such measures have led to markedly improved

pulmonary function, weight gain, body mass index, and other clinical endpoints among patients with the disease. The same approach

is expected to optimize benefit attributable to CFTR modulation.

Standardized protocols for CF therapy can be accessed at www.cff.org/

treatments/cfcareguidelines/ or through a number of excellent reviews.

■ GLOBAL CONSIDERATIONS

Newborn screening for CF is universal throughout the United States

and Canadian provinces, Australia, New Zealand, and much of Europe,

and facilitates early intervention. Nutritional and other therapies at a

young age are expected to promote quality of life and increase longevity. Global implementation of quality improvement measures and

access to novel therapeutics have become increasing imperatives. For

2180 PART 7 Disorders of the Respiratory System

example, median survival among individuals with CF is <30 years

in much of Latin America (compared to >45 years in the United

States). The less favorable prognosis is attributable in part to lack of

widespread diagnostic capabilities (i.e., newborn screening, sweat

testing, and genetic analysis tailored to ethnic background), together

with insufficient access to leading-edge, interdisciplinary treatment.

Efforts to apply state-of-the-art management to underdiagnosed and

underserved CF patient populations will help improve outcomes and

mitigate CF health disparities in the future.

■ FURTHER READING

Farrell PM et al: The impact of the CFTR gene discovery on cystic

fibrosis diagnosis, counseling, and preventive therapy. Genes 11:401,

2020.

Huang YJ, LiPuma JJ: The microbiome in cystic fibrosis. Clin Chest

Med 37:59, 2016.

Keating D et al: VX-445-tezacaftor-ivacator in patients with cystic

fibrosis and one or two Phe508del alleles. N Engl J Med 379:1612,

2018.

Manfredi C et al: Making precision medicine personal for cystic

fibrosis. Science 365:220, 2019.

Middleton PG et al: Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis

with a single Phe508del allele. N Engl J Med 381:1809, 2019.

Ramos KJ et al: Lung transplant referral for individuals with cystic

fibrosis: Cystic Fibrosis Foundation consensus guidelines. J Cyst

Fibros 18:321, 2019.

Sosnay PR et al: Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet

45:1160, 2013.

Stevens DP, Marshall BC: A decade of healthcare improvement

in cystic fibrosis: Lessons for other chronic diseases. BMJ Qual Saf

23:i1, 2014.

Stoltz DA et al: Origins of cystic fibrosis lung disease. N Engl J Med

372:351, 2015.

VIDEO 291-1 Role of CFTR during airway mucociliary clearance. Initial video

sequences depict establishment of the normal periciliary fluid layer bathing the surface

airway epithelium, with spheres representing chloride and bicarbonate ions secreted

through CFTR and across the apical (mucosal) respiratory surface. Later video

describes failure of CFTR anion transport and resulting depletion of the periciliary

layer, “plastering” of cilia against the mucosal surface, and accumulation of mucus

in the airway with resulting bacterial infection. (Reproduced with permission from

Cystic Fibrosis Foundation.)

VIDEO 291-2AB Pharmacologic modulation of mutant CFTR. Initial video (A)

illustrates CFTR encoding an ion transport gating (class III) defect. The CF gene

product is localized to the plasma membrane but incapable of conducting anions

(yellow spheres) until a potentiator molecule (shown in green) binds and facilitates

channel opening. Later video (B) describes CFTR encoding a maturational

processing (protein biogenesis, class II) defect. The mutant protein is misfolded,

fails to traffic to the cell surface, and is degraded by the proteasome. Binding of

corrector molecules (red spheres) improves folding and facilitates CFTR stabilization

and cell surface localization/function. (Reproduced with permission from Cystic

Fibrosis Foundation.)

Chronic obstructive pulmonary disease (COPD) is defined as a

disease state characterized by persistent respiratory symptoms and

airflow obstruction (https://goldcopd.org/2021-gold-reports/). COPD

includes emphysema, an anatomically defined condition characterized

292 Chronic Obstructive

Pulmonary Disease

Edwin K. Silverman, James D. Crapo,

Barry J. Make

by destruction of the lung alveoli with air space enlargement; chronic

bronchitis, a clinically defined condition with chronic cough and

phlegm; and/or small airway disease, a condition in which small

bronchioles are narrowed and reduced in number. The classic definition of COPD requires the presence of chronic airflow obstruction,

determined by spirometry, that usually occurs in the setting of noxious

environmental exposures—most commonly products of combustion,

cigarette smoking in the United States, and biomass fuels in some other

countries. Host factors such as abnormal lung development and genetics can lead to COPD. Emphysema, chronic bronchitis, and small airway disease are present in varying degrees in different COPD patients.

Patients with a history of cigarette smoking without chronic airflow

obstruction may have chronic bronchitis, emphysema, and dyspnea.

Although these patients are not included within the classic definition of

COPD, they may have similar disease processes. Respiratory symptoms

and other features of COPD can occur in subjects who do not meet a

definition of COPD based only on airflow obstruction determined by

spirometric population thresholds of normality. Investigators in the

COPDGene study recently proposed a multidimensional approach to

COPD diagnosis, which is based on domains of environmental exposures, respiratory symptoms, imaging abnormalities, and physiologic

abnormalities.

COPD is the fourth leading cause of death and affects >10 million

persons in the United States. COPD is also a disease of increasing

public health importance around the world. Globally, there are an estimated 250 million individuals with COPD.

PATHOGENESIS

Airflow obstruction, the physiologic marker of COPD, can result from

airway disease and/or emphysema. Small airways may become narrowed by cells (hyperplasia and accumulation), mucus, and fibrosis,

and extensive small airway destruction has been demonstrated to be

a hallmark of COPD. Although the precise biological mechanisms

leading to COPD have not been determined, a number of key cell

types, molecules, and pathways have been identified from cell-based

and animal model studies. The pathogenesis of emphysema (shown in

Fig. 292-1) is more clearly defined than the pathogenesis of small

airway disease. Pulmonary vascular destruction occurs in concert with

small airway disease and emphysema.

The current dominant paradigm for the pathogenesis of emphysema

comprises a series of four interrelated events: (1) Chronic exposure to

cigarette smoke in genetically susceptible individuals triggers inflammatory and immune cell recruitment within large and small airways

and in the terminal air spaces of the lung. (2) Inflammatory cells release

proteinases that damage the extracellular matrix supporting airways,

vasculature, and gas exchange surfaces of the lung. (3) Structural cell

death occurs through oxidant-induced damage, cellular senescence,

and proteolytic loss of cellular-matrix attachments leading to extensive

loss of smaller airways, vascular pruning, and alveolar destruction. (4)

Disordered repair of elastin and other extracellular matrix components

contributes to air space enlargement and emphysema.

■ INFLAMMATION AND EXTRACELLULAR MATRIX

PROTEOLYSIS

Elastin, the principal component of elastic fibers, is a highly stable

component of the extracellular matrix that is critical to the integrity

of the lung. The elastase:antielastase hypothesis, proposed in the mid1960s, postulated that the balance of elastin-degrading enzymes and

their inhibitors determines the susceptibility of the lung to destruction, resulting in air space enlargement. This hypothesis was based

on the clinical observation that patients with genetic deficiency in α1

antitrypsin (α1

AT), the inhibitor of the serine proteinase neutrophil

elastase, were at increased risk of emphysema, and that instillation

of elastases, including neutrophil elastase, into experimental animals

results in emphysema. The elastase:antielastase hypothesis remains a

prevailing mechanism for the development of emphysema. However,

a complex network of immune and inflammatory cells and additional

biological mechanisms that contribute to emphysema have subsequently

been identified. Upon exposure to oxidants from cigarette smoke, lung

2181Chronic Obstructive Pulmonary Disease CHAPTER 292

Triggers

Effector cells

Biological pathways

Key molecules

Pathobiological result

Macrophages Neutrophils Epithelial cells Lymphocytes

MMP12

SERPINA1

Neutrophil

Elastase

SOD3

HDAC2

NF KappaB Ceramide Elastin

NRF2

Rtp801 TGFBeta

Protease/Antiprotease Oxidant/Antioxidant Apoptosis Lung repair

Extracellular matrix

destruction

Chronic

inflammation

Ineffective

repair Cell death

Cigarette smoke Genetic susceptibility

FIGURE 292-1 Pathogenesis of emphysema. Upon long-term exposure to cigarette smoke in genetically susceptible individuals, lung epithelial cells and T and B

lymphocytes recruit inflammatory cells to the lung. Biological pathways of protease-antiprotease imbalance, oxidant/antioxidant imbalance, apoptosis, and lung repair lead

to extracellular matrix destruction, cell death, chronic inflammation, and ineffective repair. Although most of these biological pathways influence multiple pathobiological

results, only a single relationship between pathways and results is shown. A subset of key molecules related to these biological pathways is listed.

macrophages and epithelial cells become activated, producing proteinases and chemokines that attract other inflammatory and immune

cells. Oxidative stress is a key component of COPD pathobiology; the

transcription factor NRF2, a major regulator of oxidant-antioxidant

balance, and SOD3, a potent antioxidant, have been implicated in

emphysema pathogenesis by animal models. Mitochondrial dysfunction in COPD may worsen oxidative stress. One mechanism of macrophage activation occurs via oxidant-induced inactivation of histone

deacetylase-2 (HDAC2), shifting the balance toward acetylated or open

chromatin, exposing nuclear factor-κB sites, and resulting in transcription of matrix metalloproteinases and proinflammatory cytokines such

as interleukin 8 (IL-8) and tumor necrosis factor α (TNF-α); this leads

to neutrophil recruitment. CD8+ T cells are also recruited in response

to cigarette smoke and release interferon-inducible protein-10 (IP-10,

CXCL-7), which in turn leads to macrophage production of macrophage elastase (matrix metalloproteinase-12 [MMP-12]).

Matrix metalloproteinases and serine proteinases, most notably neutrophil elastase, work together by degrading the inhibitor of the other,

leading to lung destruction. Proteolytic cleavage products of elastin

serve as a macrophage chemokine, and proline-glycine-proline (generated by proteolytic cleavage of collagen) is a neutrophil chemokine—

fueling this destructive positive feedback loop. Elastin degradation

and disordered repair are thought to be primary mechanisms in the

development of emphysema.

There is some evidence that autoimmune mechanisms may promote

the progression of disease. Increased B cells and lymphoid follicles

are present around the airways of COPD patients, particularly those

with advanced disease. Antibodies have been found against elastin

fragments as well; IgG autoantibodies with avidity for pulmonary epithelium and the potential to mediate cytotoxicity have been detected.

Concomitant cigarette smoke–induced loss of cilia in the airway

epithelium and impaired macrophage phagocytosis predispose to

bacterial infection with neutrophilia. In end-stage lung disease, long

after smoking cessation, there remains an exuberant inflammatory

response, suggesting that cigarette smoke–induced inflammation

both initiates the disease and, in susceptible individuals, establishes

a chronic process that can continue disease progression even after

smoking cessation.

Cell Death Cigarette smoke oxidant-mediated structural cell death

occurs via a variety of mechanisms including excessive ceramide

production and Rtp801 inhibition of mammalian target of rapamycin

(mTOR), leading to cell death as well as inflammation and proteolysis. Involvement of mTOR and other cellular senescence markers

has led to the concept that emphysema resembles premature aging of

the lung. Heterozygous gene-targeting of one of the leading genetic

determinants of COPD identified by genome-wide association studies

(GWAS), hedgehog interacting protein (HHIP), in a murine model

leads to aging-related emphysema.

Ineffective Repair The ability of the adult lung to replace lost

smaller airways and microvasculature and to repair damaged alveoli

appears limited. Uptake of apoptotic cells by macrophages normally

results in production of growth factors and dampens inflammation,

promoting lung repair. Cigarette smoke impairs macrophage uptake

of apoptotic cells, limiting repair. It is unlikely that the intricate and

dynamic process of septation that is responsible for alveologenesis

during lung development can be reinitiated in the adult human lung.

PATHOLOGY

Cigarette smoke exposure may affect the large airways, small airways

(≤2 mm diameter), and alveoli. Changes in large airways cause cough

and sputum production, while changes in small airways and alveoli

are responsible for physiologic alterations. Airway inflammation,

2182 PART 7 Disorders of the Respiratory System

destruction, and the development of emphysema are present in most

persons with COPD; however, they appear to be relatively independent

processes, and their relative contributions to obstruction vary from one

person to another. The early stages of COPD, based on the severity of

airflow obstruction (Table 292-1), appear to be primarily associated

with medium and small airway disease with the majority of Global

Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric

airflow obstruction stage 1 and stage 2 subjects demonstrating little or

no emphysema. The early development of chronic airflow obstruction

is driven by small airway disease. Advanced stages of COPD (GOLD

stages 3 and 4) are typically characterized by extensive emphysema,

although there are a small number of subjects with very severe (GOLD

stage 4) obstruction with virtually no emphysema. The subjects at

greatest risk of progression in COPD are those with both aggressive

airway disease and emphysema. Thus, finding emphysema (by chest

computed tomography [CT]) either early or late in the disease process

suggests enhanced risk for disease progression.

■ LARGE AIRWAYS

Cigarette smoking often results in mucus gland enlargement and goblet

cell hyperplasia, leading to cough and mucus production that define

chronic bronchitis, but these abnormalities are not directly related

to airflow obstruction. In response to cigarette smoking, goblet cells

increase not only in number but also in extent through the bronchial

tree. Bronchi also undergo squamous metaplasia, predisposing to

carcinogenesis and disrupting mucociliary clearance. Although not

as prominent as in asthma, patients may have smooth-muscle hypertrophy and bronchial hyperreactivity leading to airflow obstruction.

Neutrophil influx has been associated with purulent sputum during

respiratory tract infections. Independent of its proteolytic activity,

neutrophil elastase is among the most potent secretagogues identified.

■ SMALL AIRWAYS

The major site of increased resistance

in most individuals with COPD is in

airways ≤2 mm diameter. Characteristic cellular changes include goblet cell

metaplasia, with these mucus-secreting

cells replacing surfactant-secreting Club

cells. Smooth-muscle hypertrophy may

also be present. Luminal narrowing can

occur by fibrosis, excess mucus, edema,

and cellular infiltration. Reduced surfactant may increase surface tension at the

air-tissue interface, predisposing to airway narrowing or collapse. Respiratory

bronchiolitis with mononuclear inflammatory cells collecting in distal airway

tissues may cause proteolytic destruction

of elastic fibers in the respiratory bronchioles and alveolar ducts where the

fibers are concentrated as rings around

alveolar entrances. Narrowing and drop-out of small airways precede

the onset of emphysematous destruction. Advanced COPD has been

shown to be associated with a loss of many of the smaller airways and

a similar significant loss of the lung microvasculature.

■ LUNG PARENCHYMA

Emphysema is characterized by destruction of gas-exchanging air spaces,

i.e., the respiratory bronchioles, alveolar ducts, and alveoli. Large numbers of macrophages accumulate in respiratory bronchioles of essentially

all smokers. Neutrophils, B lymphocytes, and T lymphocytes, particularly CD8+ cells, are also increased in the alveolar space of smokers.

Alveolar walls become perforated and later obliterated with coalescence

of the delicate alveolar structure into large emphysematous air spaces.

Emphysema is classified into distinct pathologic types, which

include centrilobular, panlobular, and paraseptal (Fig 292-2). Centrilobular emphysema, the type most frequently associated with cigarette

smoking, is characterized by enlarged air spaces found (initially) in

association with respiratory bronchioles. Centrilobular emphysema is

usually most prominent in the upper lobes and superior segments of

lower lobes and is often quite focal. Panlobular emphysema refers to

abnormally large air spaces evenly distributed within and across acinar

units. Panlobular emphysema is commonly observed in patients with

α1

AT deficiency, which has a predilection for the lower lobes. Paraseptal emphysema occurs in 10–15% of cases and is distributed along the

pleural margins with relative sparing of the lung core or central regions.

It is commonly associated with significant airway inflammation and

with centrilobular emphysema.

PATHOPHYSIOLOGY

Persistent reduction in forced expiratory flow rates is the classic definition of COPD. Hyperinflation with increases in the residual volume

and the residual volume/total lung capacity ratio, nonuniform distribution of ventilation, and ventilation-perfusion mismatching also occur.

■ AIRFLOW OBSTRUCTION

Airflow obstruction, also known as airflow limitation, is typically

determined for clinical purposes by spirometry, which involves maximal forced expiratory maneuvers after the subject has inhaled to total

lung capacity. Key parameters obtained from spirometry include the

volume of air exhaled within the first second of the forced expiratory

maneuver (FEV1

) and the total volume of air exhaled during the entire

spirometric maneuver (forced vital capacity [FVC]). Patients with

airflow obstruction related to COPD have a chronically reduced ratio

of FEV1

/FVC. In contrast to asthma, the reduced FEV1

 in COPD seldom shows large improvements to inhaled bronchodilators, although

improvements up to 15% are common.

■ HYPERINFLATION

Lung volumes are also routinely assessed in pulmonary function

testing. In COPD, there is often “air trapping” (increased residual

volume and increased ratio of residual volume to total lung capacity)

TABLE 292-1 GOLD Criteria for Severity of Airflow Obstruction in

COPD

GOLD STAGE SEVERITY SPIROMETRY

I Mild FEV1

/FVC <0.7 and FEV1

 ≥80% predicted

II Moderate FEV1

/FVC <0.7 and FEV1

 ≥50% but <80%

predicted

III Severe FEV1

/FVC <0.7 and FEV1

 ≥30% but <50%

predicted

IV Very severe FEV1

/FVC <0.7 and FEV1

 <30% predicted

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV1, forced

expiratory volume in 1 s; FVC, forced vital capacity; GOLD, Global Initiative for

Chronic Obstructive Lung Disease.

Source: Reproduced with permission from the Global Strategy for Diagnosis,

Management and Prevention of COPD 2021, ©.

A B C

FIGURE 292-2 CT patterns of emphysema. A. Centrilobular emphysema with severe upper lobe involvement in a

68-year-old man with a 70-pack-year smoking history but forced expiratory volume in 1 s (FEV1

) 81% predicted (GOLD

spirometry grade 1). B. Panlobular emphysema with diffuse loss of lung parenchymal detail predominantly in the lower

lobes in a 64-year-old man with severe α1

 antitrypsin (α1

AT) deficiency. C. Paraseptal emphysema with marked airway

inflammation in a 52-year-old woman with a 37-pack-year smoking history and FEV1

 40% predicted.

2183Chronic Obstructive Pulmonary Disease CHAPTER 292

and progressive hyperinflation (increased total lung capacity) in more

advanced disease. Hyperinflation of the thorax during tidal breathing preserves maximum expiratory airflow, because as lung volume

increases, elastic recoil pressure increases, and airways enlarge so that

airway resistance decreases.

Despite compensating for airway obstruction, hyperinflation can

push the diaphragm into a flattened position with a number of adverse

effects. First, by decreasing the zone of apposition between the diaphragm and the abdominal wall, positive abdominal pressure during

inspiration is not applied as effectively to the chest wall, hindering rib

cage movement and impairing inspiration. Second, because the muscle

fibers of the flattened diaphragm are shorter than those of a more normally curved diaphragm, they are less capable of generating inspiratory

pressures than normal. Third, the flattened diaphragm must generate

greater tension to develop the transpulmonary pressure required to

produce tidal breathing. Fourth, the thoracic cage is distended beyond

its normal resting volume, and during tidal breathing, the inspiratory

muscles must do work to overcome the resistance of the thoracic cage

to further inflation instead of gaining the normal assistance from the

chest wall recoiling outward toward its resting volume.

■ GAS EXCHANGE

Although there is considerable variability in the relationships between

the FEV1

 and other physiologic abnormalities in COPD, certain generalizations may be made. The partial pressure of oxygen in arterial blood

Pao2

 usually remains near normal until the FEV1

 is decreased to below

50% of predicted, and even much lower FEV1

 values can be associated

with a normal Pao2

, at least at rest. An elevation of arterial level of

carbon dioxide (Paco2

) is not expected until the FEV1

 is <25% of predicted and even then may not occur. Pulmonary arterial hypertension

severe enough to cause cor pulmonale and right ventricular failure due

to COPD typically occurs in individuals who have marked decreases in

FEV1

 (<25% of predicted) and chronic hypoxemia (Pao2

 <55 mmHg);

however, some patients develop significant pulmonary arterial hypertension independent of COPD severity (Chap. 283).

Nonuniform ventilation and ventilation-perfusion mismatching

are characteristic of COPD, reflecting the heterogeneous nature of the

disease process within the airways and lung parenchyma. Physiologic

studies are consistent with multiple parenchymal compartments having

different rates of ventilation due to regional differences in compliance

and airway resistance. Ventilation-perfusion mismatching accounts for

essentially all of the reduction in Pao2

 that occurs in COPD; shunting

is minimal. This finding explains the effectiveness of modest elevations

of inspired oxygen in treating hypoxemia due to COPD and therefore

the need to consider problems other than COPD when hypoxemia is

difficult to correct with modest levels of supplemental oxygen.

RISK FACTORS

■ CIGARETTE SMOKING

By 1964, the Advisory Committee to the Surgeon General of the

United States had concluded that cigarette smoking was a major risk

factor for mortality from chronic bronchitis and emphysema. Subsequent longitudinal studies have shown accelerated decline in FEV1

in a dose-response relationship to the intensity of cigarette smoking,

which is typically expressed as pack-years (average number of packs

of cigarettes smoked per day multiplied by the total number of years

of smoking). This dose-response relationship between reduced pulmonary function and cigarette smoking intensity accounts, at least in

part, for the higher prevalence rates of COPD with increasing age. The

historically higher rate of smoking among males is the likely explanation for the higher prevalence of COPD among males; however, the

prevalence of COPD among females is increasing as the gender gap in

smoking rates has diminished in the past 50 years.

Although the causal relationship between cigarette smoking and

the development of COPD has been absolutely proved, there is considerable individual variability in the response to smoking. Pack-years

of cigarette smoking is the most highly significant predictor of FEV1

(Fig. 292-3), but only 15% of the variability in FEV1

 is explained by

pack-years. This finding suggests that additional environmental and/

or genetic factors contribute to the impact of smoking on the development of chronic airflow obstruction. Nonetheless, many patients with

a history of cigarette smoking with normal spirometry have evidence

for worse health-related quality of life, reduced exercise capacity, and

emphysema and/or airway disease on chest CT evaluation; thus, they

have not escaped the harmful effects of cigarette smoking. While they

do not meet the classic definition of COPD based on population normals for FEV1

 and FEV1

/FVC, studies have shown that these subjects

overall have a shift toward lower FEV1

 values, which is consistent with

obstruction on an individual level.

Although cigar and pipe smoking may also be associated with the

development of COPD, the evidence supporting such associations is

less compelling, likely related to the lower dose of inhaled tobacco

by-products during cigar and pipe smoking. The impact of electronic

cigarettes and vaping on the development and progression of COPD

has not yet been determined.

■ AIRWAY RESPONSIVENESS AND COPD

A tendency for increased bronchoconstriction in response to a variety

of exogenous stimuli, including methacholine and histamine, is one of

the defining features of asthma (Chap. 287). However, many patients

with COPD also share this feature of airway hyperresponsiveness. In

older subjects, there is considerable overlap between persons with a

history of chronic asthma and smokers with COPD in terms of airway

responsiveness, airflow obstruction, and pulmonary symptoms. The

origin of asthma is viewed in many patients as an allergic disease while

COPD is thought to primarily result from smoking-related inflammation and damage; however, they likely share common environmental

and genetic factors and the chronic form in older subjects can present

similarly. This is particularly relevant for childhood asthmatic subjects

who become chronic smokers.

Longitudinal studies that compared airway responsiveness to subsequent decline in pulmonary function have demonstrated that increased

0 Pack years (945)

Median

–1 S.D. Mean +1 S.D.

% of Population

20

10

0

0–20 Pack years (578)

20

10

0

21–40 Pack years (271)

20

10

0

41–60 Pack years (154)

61+ Pack years (100)

20

10

0

20

40

10

0

60 80 100

FEV1 (% predicted)

120 140 160

FIGURE 292-3 Distributions of forced expiratory volume in 1 s (FEV1

) values in a

general population sample, stratified by pack-years of smoking. Means, medians,

and ±1 standard deviation of percent predicted FEV1

 are shown for each smoking

group. Although a dose-response relationship between smoking intensity and

FEV1

 was found, marked variability in pulmonary function was observed among

subjects with similar smoking histories. S.D., standard deviation. (Reproduced with

permission from B Burrows: Quantitative relationships between cigarette smoking

and ventilatory function. Am Rev Respir Dis 115:195, 1997.)