Chronic Obstructive Pulmonary Disease

Introduction

Chronic obstructive pulmonary disease (COPD) has been defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), an international collaborative effort to improve awareness, diagnosis, and treatment of COPD, as a disease state characterized by airflow limitation that is not fully reversible (http://www.goldcopd.com/). COPD includes emphysema, an anatomically defined condition characterized by destruction and enlargement of the lung alveoli; chronic bronchitis, a clinically defined condition with chronic cough and phlegm; and small airways disease, a condition in which small bronchioles are narrowed. COPD is present only if chronic airflow obstruction occurs; chronic bronchitis without chronic airflow obstruction is not included within COPD.

COPD is the fourth leading cause of death and affects >16 million persons in the United States. COPD is also a disease of increasing public health importance around the world. GOLD estimates suggest that COPD will rise from the sixth to the third most common cause of death worldwide by 2020.

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 the volume of air exhaled within the first second of the forced expiratory maneuver (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 for the higher prevalence rates for 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 variability in the response to smoking. Although pack-years of cigarette smoking is the most highly significant predictor of FEV1 (Fig. 254-1), 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 airflow obstruction.

Figure 254-1




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. (From R Burrows et al: Am Rev Respir Dis 115:95, 1977; with permission.)



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 byproducts during cigar and pipe smoking.

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. 248). However, many patients with COPD also share this feature of airway hyperresponsiveness. The considerable overlap between persons with asthma and those with COPD in airway responsiveness, airflow obstruction, and pulmonary symptoms led to the formulation of the Dutch hypothesis. This suggests that asthma, chronic bronchitis, and emphysema are variations of the same basic disease, which is modulated by environmental and genetic factors to produce these pathologically distinct entities. The alternative British hypothesis contends that asthma and COPD are fundamentally different diseases: Asthma is viewed as largely an allergic phenomenon, while COPD results from smoking-related inflammation and damage. Determination of the validity of the Dutch hypothesis vs. the British hypothesis awaits identification of the genetic predisposing factors for asthma and/or COPD, as well as the interactions between these postulated genetic factors and environmental risk factors.

Longitudinal studies that compared airway responsiveness at the beginning of the study to subsequent decline in pulmonary function have demonstrated that increased airway responsiveness is clearly a significant predictor of subsequent decline in pulmonary function. Thus, airway hyperresponsiveness is a risk factor for COPD.

Respiratory Infections

These have been studied as potential risk factors for the development and progression of COPD in adults; childhood respiratory infections have also been assessed as potential predisposing factors for the eventual development of COPD. The impact of adult respiratory infections on decline in pulmonary function is controversial, but significant long-term reductions in pulmonary function are not typically seen following an episode of bronchitis or pneumonia. The impact of the effects of childhood respiratory illnesses on the subsequent development of COPD has been difficult to assess due to a lack of adequate longitudinal data. Thus, although respiratory infections are important causes of exacerbations of COPD, the association of both adult and childhood respiratory infections to the development and progression of COPD remains to be proven.

Occupational Exposures

Increased respiratory symptoms and airflow obstruction have been suggested as resulting from general exposure to dust at work. Several specific occupational exposures, including coal mining, gold mining, and cotton textile dust, have been suggested as risk factors for chronic airflow obstruction. However, although nonsmokers in these occupations developed some reductions in FEV1, the importance of dust exposure as a risk factor for COPD, independent of cigarette smoking, is not certain. Among workers exposed to cadmium (a specific chemical fume), FEV1, FEV1/FVC, and DLCO were significantly reduced (FVC, forced vital capacity; DLCO, carbon monoxide diffusing capacity of the lung; Chap. 246), consistent with airflow obstruction and emphysema. Although several specific occupational dusts and fumes are likely risk factors for COPD, the magnitude of these effects appears to be substantially less important than the effect of cigarette smoking.

Ambient Air Pollution

Some investigators have reported increased respiratory symptoms in those living in urban compared to rural areas, which may relate to increased pollution in the urban settings. However, the relationship of air pollution to chronic airflow obstruction remains unproven. Prolonged exposure to smoke produced by biomass combustion—a common mode of cooking in some countries—also appears to be a significant risk factor for COPD among women in those countries. However, in most populations, ambient air pollution is a much less important risk factor for COPD than cigarette smoking.

Passive, or Second-Hand, Smoking Exposure

Exposure of children to maternal smoking results in significantly reduced lung growth. In utero tobacco smoke exposure also contributes to significant reductions in postnatal pulmonary function. Although passive smoke exposure has been associated with reductions in pulmonary function, the importance of this risk factor in the development of the severe pulmonary function reductions in COPD remains uncertain.

Genetic Considerations

Although cigarette smoking is the major environmental risk factor for the development of COPD, the development of airflow obstruction in smokers is highly variable. Severe 1 antitrypsin (1AT) deficiency is a proven genetic risk factor for COPD; there is increasing evidence that other genetic determinants also exist.

1 Antitrypsin Deficiency

Many variants of the protease inhibitor (PI or SERPINA1) locus that encodes 1AT have been described. The common M allele is associated with normal 1AT levels. The S allele, associated with slightly reduced 1AT levels, and the Z allele, associated with markedly reduced 1AT levels, also occur with frequencies >1% in most Caucasian populations. Rare individuals inherit null alleles, which lead to the absence of any 1AT production through a heterogeneous collection of mutations. Individuals with two Z alleles or one Z and one null allele are referred to as PiZ, which is the most common form of severe 1AT deficiency.

Although only 1–2% of COPD patients are found to have severe 1AT deficiency as a contributing cause of COPD, these patients demonstrate that genetic factors can have a profound influence on the susceptibility for developing COPD. PiZ individuals often develop early-onset COPD, but the ascertainment bias in the published series of PiZ individuals—which have usually included many PiZ subjects who were tested for 1AT deficiency because they had COPD—means that the fraction of PiZ individuals who will develop COPD and the age-of-onset distribution for the development of COPD in PiZ subjects remain unknown. Approximately 1 in 3000 individuals in the United States inherits severe 1AT deficiency, but only a small minority of these individuals has been recognized. The clinical laboratory test used most frequently to screen for 1AT deficiency is measurement of the immunologic level of 1AT in serum (see "Laboratory Findings," below).

A significant percentage of the variability in pulmonary function among PiZ individuals is explained by cigarette smoking; cigarette smokers with severe 1AT deficiency are more likely to develop COPD at early ages. However, the development of COPD in PiZ subjects, even among current or ex-smokers, is not absolute. Among PiZ nonsmokers, impressive variability has been noted in the development of airflow obstruction. Other genetic and/or environmental factors likely contribute to this variability.

Specific treatment in the form of 1AT augmentation therapy is available for severe 1AT deficiency as a weekly intravenous infusion (see "Treatment," below).

The risk of lung disease in heterozygous PiMZ individuals, who have intermediate serum levels of 1AT (~60% of PiMM levels), is controversial. Although previous general population surveys have not typically shown increased rates of airflow obstruction in PiMZ compared to PiMM individuals, case-control studies that compared COPD patients to control subjects have usually found an excess of PiMZ genotypes in the COPD patient group. Several recent large population studies have suggested that PiMZ subjects are at slightly increased risk for the development of airflow obstruction, but it remains unclear if all PiMZ subjects are at slightly increased risk for COPD or if a subset of PiMZ subjects are at substantially increased risk for COPD due to other genetic or environmental factors.

Other Genetic Risk Factors

Studies of pulmonary function measurements performed in general population samples have suggested that genetic factors other than PI type influence variation in pulmonary function. Familial aggregation of airflow obstruction within families of COPD patients has also been demonstrated.

Association studies have compared the distribution of variants in genes hypothesized to be involved in the development of COPD in COPD patients and control subjects. However, the results have been quite inconsistent, and no genetic determinants of COPD other than severe 1AT deficiency have been definitively proven using this approach. Genome scan linkage analyses of early-onset COPD families have found evidence for linkage of spirometric phenotypes to several chromosomal regions, but the specific genetic determinants in those regions have yet to be definitively identified.

Natural History

The effects of cigarette smoking on pulmonary function appear to depend on the intensity of smoking exposure, the timing of smoking exposure during growth, and the baseline lung function of the individual; other environmental factors may have similar effects. Although rare individuals may demonstrate precipitous declines in pulmonary function, most individuals follow a steady trajectory of increasing pulmonary function with growth during childhood and adolescence, followed by a gradual decline with aging. Individuals appear to track in their quartile of pulmonary function based upon environmental and genetic factors that put them on different tracks. The risk of eventual mortality from COPD is closely associated with reduced levels of FEV1. A graphic depiction of the natural history of COPD is shown as a function of the influences on tracking curves of FEV1 in Fig. 254-2. Death or disability from COPD can result from a normal rate of decline after a reduced growth phase (curve C), an early initiation of pulmonary function decline after normal growth (curve B), or an accelerated decline after normal growth (curve D). The rate of decline in pulmonary function can be modified by changing environmental exposures (i.e., quitting smoking), with smoking cessation at an earlier age providing a more beneficial effect than smoking cessation after marked reductions in pulmonary function have already developed. Genetic factors likely contribute to the level of pulmonary function achieved during growth and to the rate of decline in response to smoking and potentially to other environmental factors as well.

Figure 254-2




Hypothetical tracking curves of FEV1 for individuals throughout their life spans. The normal pattern of growth and decline with age is shown by curve A. Significantly reduced FEV1 (<65% of predicted value at age 20) can develop from a normal rate of decline after a reduced pulmonary function growth phase (curve C), early initiation of pulmonary function decline after normal growth (curve B), or accelerated decline after normal growth (curve D). (From B Rijcken: Doctoral dissertation, p 133, University of Groningen, 1991; with permission.)



Pathophysiology

Persistent reduction in forced expiratory flow rates is the most typical finding in COPD. 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 limitation, also known as airflow obstruction, is typically determined by spirometry, which involves forced expiratory maneuvers after the subject has inhaled to total lung capacity (see Fig. 246-4). Key phenotypes obtained from spirometry include FEV1 and the total volume of air exhaled during the entire spirometric maneuver (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 responses to inhaled bronchodilators, although improvements up to 15% are common. Asthma patients can also develop chronic (not fully reversible) airflow obstruction. Maximal inspiratory flow can be relatively well preserved in the presence of a markedly reduced FEV1.

Airflow during forced exhalation is the result of the balance between the elastic recoil of the lungs promoting flow and the resistance of the airways limiting flow. In normal lungs, as well as in lungs affected by COPD, maximal expiratory flow diminishes as the lungs empty because the lung parenchyma provides progressively less elastic recoil and because the cross-sectional area of the airways falls, raising the resistance to airflow. The decrease in flow coincident with decreased lung volume is readily apparent on the expiratory limb of a flow-volume curve. In the early stages of COPD, the abnormality in airflow is only evident at lung volumes at or below the functional residual capacity (closer to residual volume), appearing as a scooped-out lower part of the descending limb of the flow-volume curve. In more advanced disease the entire curve has decreased expiratory flow compared to normal.

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) and progressive hyperinflation (increased total lung capacity) late in the 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.

Hyperinflation helps to compensate for airway obstruction. However, 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 (with increased radius of curvature, r) must generate greater tension (t) to develop the transpulmonary pressure (p) required to produce tidal breathing. This follows from Laplace's law, p = 2t/r. Also, because the thoracic cage is distended beyond its normal resting volume, 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 PaO2 usually remains near normal until the FEV1 is decreased to ~50% of predicted, and even much lower FEV1s can be associated with a normal PaO2, at least at rest. An elevation of PaCO2 is not expected until the FEV1 is <25% of predicted and even then may not occur. Pulmonary hypertension severe enough to cause cor pulmonale and right ventricular failure due to COPD occurs only in those individuals who have marked decreases in FEV1 (<25% of predicted) together with chronic hypoxemia (PaO2 <55 mmHg), although earlier in the course some elevation of pulmonary artery pressure, particularly with exercise, may occur (Chap. 244).

Nonuniform ventilation and ventilation-perfusion mismatching are characteristic of COPD, reflecting the heterogeneous nature of the disease process within the airways and lung parenchyma. Nitrogen wash-out while breathing 100% oxygen is delayed due to regions that are poorly ventilated, and the profile of the nitrogen wash-out curve is consistent with multiple parenchymal compartments having different wash-out rates 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 in the patient with COPD.

Pathology

Cigarette smoke exposure may affect the large airways, small airways (2 mm diameter), and alveolar space. Changes in large airways cause cough and sputum, while changes in small airways and alveoli are responsible for physiologic alterations. Emphysema and small airway pathology are both present in most persons with COPD, and their relative contributions to obstruction vary from one person to another.

Large Airway

Cigarette smoking often results in mucous gland enlargement and goblet cell hyperplasia. These changes are proportional to cough and mucus production that define chronic bronchitis, but these abnormalities are not related to airflow limitation. Goblet cells not only increase in number but in extent through the bronchial tree. Bronchi also undergo squamous metaplasia, which not only predisposes to carcinogenesis but also disrupts mucociliary clearance. Although not as prominent as in asthma, patients may have smooth-muscle hypertrophy and bronchial hyperreactivity leading to airflow limitation. Neutrophil influx has been associated with purulent sputum of upper respiratory tract infections that hamper patients with COPD. 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 and replacement of surfactant-secreting Clara cells with mucus-secreting and infiltrating mononuclear inflammatory cells. Smooth-muscle hypertrophy may also be present. These abnormalities may cause luminal narrowing by excess mucus, edema, and cellular infiltration. Reduced surfactant may increase surface tension at the air-tissue interface, predisposing to airway narrowing or collapse. Fibrosis in the wall may cause airway narrowing directly or, as in asthma, predispose to hyperreactivity. 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.

Because small airway patency is maintained by the surrounding lung parenchyma that provides radial traction on bronchioles at points of attachment to alveolar septa, loss of bronchiolar attachments as a result of extracellular matrix destruction may cause airway distortion and narrowing in COPD. Although the significance of alveolar attachments is not resolved, the concept of decreased alveolar attachments leading to small airway obstruction is appealing because it underscores the mechanistic relationship between loss of elastic recoil and increased resistance to airflow in small airways.

Lung Parenchyma

Emphysema is characterized by destruction of gas-exchanging airspaces, i.e., the respiratory bronchioles, alveolar ducts, and alveoli. Their walls become perforated and later obliterated with coalescence of small distinct airspaces into abnormal and much larger airspaces. Macrophages accumulate in respiratory bronchioles of essentially all young smokers. Bronchoalveolar lavage fluid from such individuals contains roughly five times as many macrophages as lavage from nonsmokers. In smokers' lavage fluid, macrophages comprise >95% of the total cell count, and neutrophils, nearly absent in nonsmokers' lavage, account for 1–2% of the cells. T lymphocytes, particularly CD8+ cells, are also increased in the alveolar space of smokers.

Emphysema is classified into distinct pathologic types, the most important being centriacinar and panacinar. Centriacinar emphysema, the type most frequently associated with cigarette smoking, is characterized by enlarged airspaces found (initially) in association with respiratory bronchioles. Centriacinar emphysema is most prominent in the upper lobes and superior segments of lower lobes and is often quite focal. Panacinar emphysema refers to abnormally large airspaces evenly distributed within and across acinar units. Panacinar emphysema is usually observed in patients with 1AT deficiency, which has a predilection for the lower lobes. Distinctions between centriacinar and panacinar emphysema are interesting and may ultimately be shown to have different mechanisms of pathogenesis. However, garden-variety smoking-related emphysema is usually mixed, particularly in advanced cases, and these pathologic classifications are not helpful in the care of patients with COPD.

Pathogenesis

Airflow limitation, the major physiologic change in COPD, can result from both small airway obstruction and emphysema, as discussed above. Pathologic findings that can contribute to small airway obstruction are described above, but their relative importance is unknown. Fibrosis surrounding the small airways appears to be a significant contributor. Mechanisms leading to collagen accumulation around the airways in the face of increased collagenase activity remain an enigma. Although seemingly counterintuitive, there are several potential mechanisms whereby a proteinase can predispose to fibrosis, including proteolytic activation of transforming growth factor (TGF-) and insulin-like growth factor (IGF) binding protein degradation releasing profibrotic IGF. Largely due to availability of suitable animal models, we know much more about mechanisms involved in emphysema than small airway obstruction.

The pathogenesis of emphysema can be dissected into four interrelated events (Fig. 254-3): (1) Chronic exposure to cigarette smoke may lead to inflammatory cell recruitment within the terminal airspaces of the lung. (2) These inflammatory cells release elastolytic proteinases which damage the extracellular matrix of the lung. (3) Loss of matrix-cell attachment leads to apoptosis of structural cells of the lung. (4) Ineffective repair of elastin and perhaps other extracellular matrix components result in airspace enlargement that defines pulmonary emphysema.

Figure 254-3




Pathogenesis of emphysema. Upon long-term exposure to cigarette smoke, inflammatory cells are recruited to the lung; they release proteinases in excess of inhibitors, and if repair is abnormal, this leads to airspace destruction and enlargement or emphysema.



The Elastase:Antielastase Hypothesis

Elastin, the principal component of elastic fibers, is a highly stable component of the extracellular matrix that is critical to the integrity of both the small airways and the lung parenchyma. The elastase:antielastase hypothesis proposed in the mid-1960s states that the balance of elastin-degrading enzymes and their inhibitors determines the susceptibility of the lung to destruction resulting in airspace enlargement. This hypothesis was based on the clinical observation that patients with genetic deficiency in 1AT, the inhibitor of the serine proteinase neutrophil elastase, were at increased risk of emphysema, and that instillation of elastases, including neutrophil elastase, to experimental animals results in emphysema. To this day, the elastase:antielastase hypothesis is the prevailing mechanism for the development of emphysema. However, a complex network of inflammatory cells and additional proteinases that contribute to emphysema have subsequently been identified.

Inflammation and Extracellular Matrix Proteolysis

Macrophages patrol the lower airspace under normal conditions. Upon exposure to oxidants from cigarette smoke, histone deacetylase-2 is inactivated, shifting the balance toward acetylated or loose chromatin, exposing nuclear factor B sites and resulting in transcription of matrix metalloproteinase-9, proinflammatory cytokines interleukin 8 (IL-8), and tumor necrosis factor (TNF-); 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) that 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 also serve as a macrophage chemokine, fueling this destructive positive feedback loop.

Concomitant cigarette smoke-induced loss of cilia in the airway epithelium predisposes to bacterial infection with neutrophilia. Surprisingly, in end-stage lung disease, long after smoking cessation there remains an exuberant inflammatory response, suggesting that mechanisms of cigarette smoke-induced inflammation that initiate the disease differ from mechanisms that sustain inflammation after smoking cessation.

Collagen turnover in COPD is complex. The three collagenases (MMP-1, MMP-8, and MMP-13) that initiate the cleavage of interstitial collagens are also induced in both inflammatory cells and structural cells in COPD. While collagen is disrupted as alveolar units are obliterated, overall there is a net increase in collagen content in the COPD lung, with prominent accumulation in the airway submucosa.

Cell Death

Airspace enlargement with loss of alveolar units obviously requires disappearance of both extracellular matrix and cells. Traditional theories suggest that inflammatory cell proteinases degrade lung extracellular matrix as the primary event, with subsequent loss of cell anchoring leading to apoptosis. Animal models have used endothelial and epithelial cell death as a means to generate transient airspace enlargement. Whether apoptosis is a primary or secondary event in COPD remains to be determined.

Ineffective Repair

The ability of the adult lung to repair damaged alveoli appears limited. Whether the process of septation that is responsible for alveogenesis during lung development can be reinitiated is not clear. In animal models, treatment with all-trans retinoic acid has resulted in some repair. Also, lung resection results in compensatory lung growth in the remaining lung in animal models. In addition to restoring cellularity following injury, it appears difficult for an adult to completely restore an appropriate extracellular matrix, particularly functional elastic fibers.

Clinical Presentation

History

The three most common symptoms in COPD are cough, sputum production, and exertional dyspnea. Many patients have such symptoms for months or years before seeking medical attention. Although the development of airflow obstruction is a gradual process, many patients date the onset of their disease to an acute illness or exacerbation. A careful history, however, usually reveals the presence of symptoms prior to the acute exacerbation. The development of exertional dyspnea, often described as increased effort to breathe, heaviness, air hunger, or gasping, can be insidious. It is best elicited by a careful history focused on typical physical activities and how the patient's ability to perform them has changed. Activities involving significant arm work, particularly at or above shoulder level, are particularly difficult for patients with COPD. Conversely, activities that allow the patient to brace the arms and use accessory muscles of respiration are better tolerated. Examples of such activities include pushing a shopping cart, walking on a treadmill, or pushing a wheelchair. As COPD advances, the principal feature is worsening dyspnea on exertion with increasing intrusion on the ability to perform vocational or avocational activities. In the most advanced stages, patients are breathless doing simple activities of daily living.

Accompanying worsening airflow obstruction is an increased frequency of exacerbations (described below). Patients may also develop resting hypoxemia and require institution of supplemental oxygen.

Physical Findings

In the early stages of COPD, patients usually have an entirely normal physical examination. Current smokers may have signs of active smoking, including an odor of smoke or nicotine staining of fingernails. In patients with more severe disease, the physical examination is notable for a prolonged expiratory phase and expiratory wheezing. In addition, signs of hyperinflation include a barrel chest and enlarged lung volumes with poor diaphragmatic excursion as assessed by percussion. Patients with severe airflow obstruction may also exhibit use of accessory muscles of respiration, sitting in the characteristic "tripod" position to facilitate the actions of the sternocleidomastoid, scalene, and intercostal muscles. Patients may develop cyanosis, visible in the lips and nail beds.

Although traditional teaching is that patients with predominant emphysema, termed "pink puffers," are thin and noncyanotic at rest and have prominent use of accessory muscles, and patients with chronic bronchitis are more likely to be heavy and cyanotic ("blue bloaters"), current evidence demonstrates that most patients have elements of both bronchitis and emphysema and that the physical examination does not reliably differentiate the two entities.

Advanced disease may be accompanied by systemic wasting, with significant weight loss, bitemporal wasting, and diffuse loss of subcutaneous adipose tissue. This syndrome has been associated with both inadequate oral intake and elevated levels of inflammatory cytokines (TNF-). Such wasting is an independent poor prognostic factor in COPD. Some patients with advanced disease have paradoxical inward movement of the rib cage with inspiration (Hoover's sign), the result of alteration of the vector of diaphragmatic contraction on the rib cage as a result of chronic hyperinflation.

Signs of overt right heart failure, termed cor pulmonale, are relatively infrequent since the advent of supplemental oxygen therapy.

Clubbing of the digits is not a sign of COPD, and its presence should alert the clinician to initiate an investigation for causes of clubbing. In this population, the development of lung cancer is the most likely explanation for newly developed clubbing.

Laboratory Findings

The hallmark of COPD is airflow obstruction (discussed above). Pulmonary function testing shows airflow obstruction with a reduction in FEV1 and FEV1/FVC (Chap. 246). With worsening disease severity, lung volumes may increase, resulting in an increase in total lung capacity, functional residual capacity, and residual volume. In patients with emphysema, the diffusing capacity may be reduced, reflecting the parenchymal destruction characteristic of the disease. The degree of airflow obstruction is an important prognostic factor in COPD and is the basis for the GOLD disease classification (Table 254-1). More recently it has been shown that a multifactorial index incorporating airflow obstruction, exercise performance, dyspnea, and body mass index is a better predictor of mortality than pulmonary function alone.

Table 254-1 Gold Criteria for COPD Severity



GOLD Stage Severity Symptoms Spirometry
0 At Risk Chronic cough, sputum production Normal
I Mild With or without chronic cough or sputum production FEV1/FVC <0.7 and FEV1 80% predicted

IIA Moderate With or without chronic cough or sputum production FEV1/FVC <0.7 and 50% FEV1 <80% predicted

III Severe With or without chronic cough or sputum production FEV1/FVC <0.7 and 30% FEV1 <50% predicted

IV Very Severe With or without chronic cough or sputum production FEV1/FVC <0.7 and FEV1 <30% predicted

or

FEV1 <50% predicted with respiratory failure or signs of right heart failure




Note: GOLD, Global Initiative for Chronic Obstructive Pulmonary Disease (COPD).

Source: From Pauwels et al.


While arterial blood gases and oximetry are not sensitive (discussed above), they may demonstrate resting or exertional hypoxemia. Arterial blood gases provide additional information about alveolar ventilation and acid-base status by measuring arterial PCO2 and pH. The change in pH with PCO2 is 0.08 units/10 mmHg acutely and 0.03 units/10 mmHg in the chronic state. Knowledge of the arterial pH therefore allows the classification of ventilatory failure, defined as PCO2 >45 mmHg, into acute or chronic conditions. The arterial blood gas is an important component of the evaluation of patients presenting with symptoms of an exacerbation. An elevated hematocrit suggests the presence of chronic hypoxemia, as does the presence of signs of right ventricular hypertrophy.

Radiographic studies may assist in the classification of the type of COPD. Obvious bullae, paucity of parenchymal markings, or hyperlucency suggest the presence of emphysema. Increased lung volumes and flattening of the diaphragm suggest hyperinflation but do not provide information about chronicity of the changes. Computed tomography (CT) scan is the current definitive test for establishing the presence or absence of emphysema in living subjects (Fig. 254-4). From a practical perspective, the CT scan does little to influence therapy of COPD except in those individuals considering surgical therapy for their disease (described below).

Figure 254-4




Chest CT scan of a patient with COPD who underwent a left single-lung transplant. Note the reduced parenchymal markings in the right lung (left side of figure) as compared to the left lung, representing emphysematous destruction of the lung, and mediastinal shift to the left, indicative of hyperinflation.



Recent guidelines have suggested testing for 1AT deficiency in all subjects with COPD or asthma with chronic airflow obstruction. Measurement of the serum 1AT level is a reasonable initial test. For subjects with low 1AT levels, the definitive diagnosis of 1AT deficiency requires PI type determination. This is typically performed by isoelectric focusing of serum, which reflects the genotype at the PI locus for the common alleles and many of the rare PI alleles as well. Molecular genotyping of DNA can be performed for the common PI alleles (M, S, and Z).

Chronic Obstructive Pulmonary Disease: Treatment

Stable Phase COPD

Only three interventions—smoking cessation, oxygen therapy in chronically hypoxemic patients, and lung volume reduction surgery in selected patients with emphysema—have been demonstrated to influence the natural history of patients with COPD. There is currently suggestive, but not definitive, evidence that the use of inhaled glucocorticoids may alter mortality (but not lung function). All other current therapies are directed at improving symptoms and decreasing the frequency and severity of exacerbations. The institution of these therapies should involve an assessment of symptoms, potential risks, costs, and benefits of therapy. This should be followed by an assessment of response to therapy, and a decision should be made whether or not to continue treatment.

Pharmacotherapy

Smoking Cessation (See Also Chap. 390)

It has been shown that middle-aged smokers who were able to successfully stop smoking experienced a significant improvement in the rate of decline in pulmonary function, returning to annual changes similar to that of nonsmoking patients. Thus, all patients with COPD should be strongly urged to quit and educated about the benefits of quitting. An emerging body of evidence demonstrates that combining pharmacotherapy with traditional supportive approaches considerably enhances the chances of successful smoking cessation. There are two principal pharmacologic approaches to the problem: bupropion, originally developed as an antidepressant medication, and nicotine replacement therapy. The latter is available as gum, transdermal patches, inhaler, and nasal spray. Current recommendations from the U.S. Surgeon General are that all adult, nonpregnant smokers considering quitting be offered pharmacotherapy, in the absence of any contraindication to treatment.

Bronchodilators

In general, bronchodilators are used for symptomatic benefit in patients with COPD. The inhaled route is preferred for medication delivery as the incidence of side effects is lower than that seen with the use of parenteral medication delivery.

Anticholinergic Agents

While regular use of ipratopium bromide does not appear to influence the rate of decline of lung function, it improves symptoms and produces acute improvement in FEV1. Tiotropium, a long-acting anticholinergic, has been shown to improve symptoms and reduce exacerbations. Side effects are minor, and a trial of inhaled anticholinergics is recommended in symptomatic patients with COPD.

Beta Agonists

These provide symptomatic benefit. The main side effects are tremor and tachycardia. Long-acting inhaled agonists, such as salmeterol, have benefits comparable to ipratopium bromide. Their use is more convenient than short-acting agents. The addition of a agonist to inhaled anticholinergic therapy has been demonstrated to provide incremental benefit. A recent report in asthma suggests that those patients, particularly African Americans, using a long-acting agonist without concomitant inhaled corticosteroids have an increased risk of deaths from respiratory causes. The applicability of these data to patients with COPD is unclear.

Inhaled Glucocorticoids

Several trials have failed to find a beneficial effect for the regular use of inhaled glucocorticoids on the rate of decline of lung function, as assessed by FEV1. Patients studied included those with mild to severe airflow obstruction and current and ex-smokers. Patients with significant acute response to inhaled agonists were excluded from these trials. Their use has been associated with increased rates of oropharyngeal candidiasis and an increased rate of loss of bone density. Some analyses suggest that inhaled glucocorticoids reduce exacerbation frequency by ~25%. A more recent meta-analysis suggests that they may also reduce mortality by ~25%. A definitive conclusion regarding the mortality benefits awaits the results of ongoing prospective trials. A trial of inhaled glucocorticoids should be considered in patients with frequent exacerbations, defined as two or more per year, and in patients who demonstrate a significant amount of acute reversibility in response to inhaled bronchodilators.

Oral Glucocorticoids

The chronic use of oral glucocorticoids for treatment of COPD is not recommended because of an unfavorable benefit/risk ratio. The chronic use of oral glucocorticoids is associated with significant side effects, including osteoporosis, weight gain, cataracts, glucose intolerance, and increased risk of infection. A recent study demonstrated that patients tapered off chronic low-dose prednisone (~10 mg/d) did not experience any adverse effect on the frequency of exacerbations, health-related quality of life, or lung function. On average, patients lost ~4.5 kg (~10 lb) when steroids were withdrawn.

Theophylline

Theophylline produces modest improvements in expiratory flow rates and vital capacity and a slight improvement in arterial oxygen and carbon dioxide levels in patients with moderate to severe COPD. Nausea is a common side effect; tachycardia and tremor have also been reported.

Oxygen

Supplemental O2 is the only pharmacologic therapy demonstrated to decrease mortality in patients with COPD. For patients with resting hypoxemia (resting O2 saturation <88% or <90% with signs of pulmonary hypertension or right heart failure), the use of O2 has been demonstrated to have a significant impact on mortality. Patients meeting these criteria should be on continual oxygen supplementation, as the mortality benefit is proportional to the number of hours/day oxygen is used. Various delivery systems are available, including portable systems that patients may carry to allow mobility outside the home.

Supplemental O2 is commonly prescribed for patients with exertional hypoxemia or nocturnal hypoxemia. Although the rationale for supplemental O2 in these settings is physiologically sound, the benefits of such therapy are not well substantiated.

Other Agents

N-acetyl cysteine has been used in patients with COPD for both its mucolytic and antioxidant properties. A prospective trial failed to find any benefit with respect to decline in lung function or prevention of exacerbations. Specific treatment in the form of intravenous 1AT augmentation therapy is available for individuals with severe 1AT deficiency. Despite sterilization procedures for these blood-derived products and the absence of reported cases of viral infection from therapy, some physicians recommend hepatitis B vaccination prior to starting augmentation therapy. Although biochemical efficacy of 1AT augmentation therapy has been shown, a randomized controlled trial of 1AT augmentation therapy has never proven the efficacy of augmentation therapy in reducing decline of pulmonary function. Eligibility for 1AT augmentation therapy requires a serum 1AT level <11 M (approximately 50 mg/dL). Typically, PiZ individuals will qualify, although other rare types associated with severe deficiency (e.g., null-null) are also eligible. Since only a fraction of individuals with severe 1AT deficiency will develop COPD, 1AT augmentation therapy is not recommended for severely 1AT-deficient persons with normal pulmonary function and a normal chest CT scan.

Nonpharmacologic Therapies

General Medical Care

Patients with COPD should receive the influenza vaccine annually. Polyvalent pneumococcal vaccine is also recommended, although proof of efficacy in this patient population is not definitive.

Pulmonary Rehabilitation

This refers to a treatment program that incorporates education and cardiovascular conditioning. In COPD, pulmonary rehabilitation has been demonstrated to improve health-related quality of life, dyspnea, and exercise capacity. It has also been shown to reduce rates of hospitalization over a 6–12-month period.

Lung Volume Reduction Surgery (LVRS)

Surgery to reduce the volume of lung in patients with emphysema was first introduced with minimal success in the 1950s and was reintroduced in the 1990s. The operation may be performed via either a median sternotomy or a thoracoscopic approach. Patients are excluded if they have significant pleural disease, a pulmonary artery systolic pressure >45 mmHg, extreme deconditioning, congestive heart failure, or other severe comorbid conditions. Recent data demonstrate that patients with an FEV1 <20% of predicted and either diffusely distributed emphysema on CT scan or DLCO <20% of predicted have an increased mortality after the procedure and thus are not candidates for LVRS.

The National Emphysema Treatment trial demonstrated that LVRS offers both a mortality benefit and a symptomatic benefit in certain patients with emphysema. The anatomic distribution of emphysema and postrehabilitation exercise capacity are important prognostic characteristics. Patients with upper lobe–predominant emphysema and a low postrehabilitation exercise capacity are most likely to benefit from LVRS.

Lung Transplantation (See Also Chap. 260)

COPD is the single leading indication for lung transplantation (Fig. 254-4). Current recommendations are that candidates for lung transplantation should be <65 years; have severe disability despite maximal medical therapy; and be free of comorbid conditions such as liver, renal, or cardiac disease. In contrast to LVRS, the anatomic distribution of emphysema and the presence of pulmonary hypertension are not contraindications to lung transplantation. Unresolved issues concerning lung transplantation and COPD include whether single- or double-lung transplant is the preferred procedure.

Exacerbations of COPD

Exacerbations are a prominent feature of the natural history of COPD. Exacerbations are commonly considered to be episodes of increased dyspnea and cough and change in the amount and character of sputum. They may or may not be accompanied by other signs of illness, including fever, myalgias, and sore throat. Self-reported health-related quality of life correlates with frequency of exacerbations more closely than it does with the degree of airflow obstruction. Economic analyses have shown that >70% of COPD-related health care expenditures go to emergency department visits and hospital care; this translates to >$10 billion annually in the United States. The frequency of exacerbations increases as airflow obstruction increases; patients with moderate to severe airflow obstruction [GOLD stages III,IV (Table 254-1)] have 1–3 episodes per year.

The approach to the patient experiencing an exacerbation includes an assessment of the severity of the patient's illness, both acute and chronic components; an attempt to identify the precipitant of the exacerbation; and the institution of therapy.

Precipitating Causes and Strategies to Reduce Frequency of Exacerbations

A variety of stimuli may result in the final common pathway of airway inflammation and increased symptoms that are characteristic of COPD exacerbations. Bacterial infections play a role in many, but by no means all, episodes. Viral respiratory infections are present in approximately one-third of COPD exacerbations. In a significant minority of instances (20–35%), no specific precipitant can be identified.

Despite the frequent implication of bacterial infection, chronic suppressive or "rotating" antibiotics are not beneficial in patients with COPD. This is in contrast to their apparent efficacy in patients with significant bronchiectasis. In patients with bronchiectasis due to cystic fibrosis, suppressive antibiotics have been shown to reduce frequency of hospital admissions.

The role of anti-inflammatory therapy in reducing exacerbation frequency is less well studied. Chronic oral glucocorticoids are not recommended for this purpose. Inhaled glucocorticoids did reduce the frequency of exacerbations by 25–30% in some analyses. The use of inhaled glucocorticoids should be considered in patients with frequent exacerbations or those who have an asthmatic component, i.e., significant reversibility on pulmonary function testing or marked symptomatic improvement after inhaled bronchodilators.

Patient Assessment

An attempt should be made to establish the severity of the exacerbation as well as the severity of preexisting COPD. The more severe either of these two components, the more likely that the patient will require hospital admission. The history should include quantification of the degree of dyspnea by asking about breathlessness during activities of daily living and typical activities for the patient. The patient should be asked about fever; change in character of sputum; any ill contacts; and associated symptoms such as nausea, vomiting, diarrhea, myalgias, and chills. Inquiring about the frequency and severity of prior exacerbations can provide important information.

The physical examination should incorporate an assessment of the degree of distress of the patient. Specific attention should be focused on tachycardia, tachypnea, use of accessory muscles, signs of perioral or peripheral cyanosis, the ability to speak in complete sentences, and the patient's mental status. The chest examination should establish the presence or absence of focal findings, degree of air movement, presence or absence of wheezing, asymmetry in the chest examination (suggesting large airway obstruction or pneumothorax mimicking an exacerbation), and the presence or absence of paradoxical motion of the abdominal wall.

Patients with severe underlying COPD who are in moderate or severe distress or those with focal findings should have a chest x-ray. Approximately 25% of x-rays in this clinical situation will be abnormal, with the most frequent findings being pneumonia and congestive heart failure. Patients with advanced COPD, those with a history of hypercarbia, those with mental status changes (confusion, sleepiness), or those in significant distress should have an arterial blood gas measurement. The presence of hypercarbia, defined as a PCO2 >45 mmHg, has important implications for treatment (discussed below). In contrast to its utility in the management of exacerbations of asthma, measurement of pulmonary function has not been demonstrated to be helpful in the diagnosis or management of exacerbations of COPD.

There are no definitive guidelines concerning the need for inpatient treatment of exacerbations. Patients with respiratory acidosis and hypercarbia, significant hypoxemia, or severe underlying disease or those whose living situation is not conducive to careful observation and the delivery of prescribed treatment should be admitted to the hospital.

Acute Exacerbations

Bronchodilators

Typically, patients are treated with an inhaled agonist, often with the addition of an anticholinergic agent. These may be administered separately or together, and the frequency of administration depends on the severity of the exacerbation. Patients are often treated initially with nebulized therapy, as such treatment is often easier to administer in older patients or to those in respiratory distress. It has been shown, however, that conversion to metered-dose inhalers is effective when accompanied by education and training of patients and staff. This approach has significant economic benefits and also allows an easier transition to outpatient care. The addition of methylxanthines (such as theophylline) to this regimen can be considered, although convincing proof of its efficacy is lacking. If added, serum levels should be monitored in an attempt to minimize toxicity.

Antibiotics

Patients with COPD are frequently colonized with potential respiratory pathogens and it is often difficult to identify conclusively a specific species of bacteria responsible for a particular clinical event. Bacteria frequently implicated in COPD exacerbations include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. In addition, Mycoplasma pneumoniae or Chlamydia pneumoniae are found in 5–10% of exacerbations. The choice of antibiotic should be based on local patterns of antibiotic susceptibility of the above pathogens as well as the patient's clinical condition. Most practitioners treat patients with moderate or severe exacerbations with antibiotics, even in the absence of data implicating a specific pathogen.

Glucocorticoids

Among patients admitted to the hospital, the use of glucocorticoids has been demonstrated to reduce the length of stay, hasten recovery, and reduce the chance of subsequent exacerbation or relapse for a period of up to 6 months. One study demonstrated that 2 weeks of glucocorticoid therapy produced benefit indistinguishable from 8 weeks of therapy. The GOLD guidelines recommend 30–40 mg of oral prednisolone or its equivalent for a period of 10–14 days. Hyperglycemia, particularly in patients with preexisting diagnosis of diabetes, is the most frequently reported acute complication of glucocorticoid treatment.

Oxygen

Supplemental O2 should be supplied to keep arterial saturations 90%. Hypoxic respiratory drive plays a small role in patients with COPD. Studies have demonstrated that in patients with both acute and chronic hypercarbia, the administration of supplemental O2 does not reduce minute ventilation. It does, in some patients, result in modest increases in arterial PCO2, chiefly by altering ventilation-perfusion relationships within the lung. This should not deter practitioners from providing the oxygen needed to correct hypoxemia.

Mechanical Ventilatory Support

The initiation of noninvasive positive pressure ventilation (NIPPV) in patients with respiratory failure, defined as PaCO2 >45 mmHg, results in a significant reduction in mortality, need for intubation, complications of therapy, and hospital length of stay. Contraindications to NIPPV include cardiovascular instability, impaired mental status or inability to cooperate, copious secretions or the inability to clear secretions, craniofacial abnormalities or trauma precluding effective fitting of mask, extreme obesity, or significant burns.

Invasive (conventional) mechanical ventilation via an endotracheal tube is indicated for patients with severe respiratory distress despite initial therapy, life-threatening hypoxemia, severe hypercapnia and/or acidosis, markedly impaired mental status, respiratory arrest, hemodynamic instability, or other complications. The goal of mechanical ventilation is to correct the aforementioned conditions. Factors to consider during mechanical ventilatory support include the need to provide sufficient expiratory time in patients with severe airflow obstruction and the presence of auto-PEEP (positive end-expiratory pressure) which can result in patients having to generate significant respiratory effort to trigger a breath during a demand mode of ventilation. The mortality of patients requiring mechanical ventilatory support is 17–30% for that particular hospitalization. For patients age >65 admitted to the intensive care unit for treatment, the mortality doubles over the next year to 60%, regardless of whether mechanical ventilation was required.

Interstitial Lung Diseases: Introduction

Patients with interstitial lung diseases (ILDs) come to medical attention mainly because of the onset of progressive exertional dyspnea or a persistent, nonproductive cough. Hemoptysis, wheezing, and chest pain may be present. Often, the identification of interstitial opacities on chest x-ray focuses the diagnostic approach toward one of the ILDs.

ILDs represent a large number of conditions that involve the parenchyma of the lung—the alveoli, the alveolar epithelium, the capillary endothelium, and the spaces between these structures, as well as the perivascular and lymphatic tissues. This heterogeneous group of disorders is classified together because of similar clinical, roentgenographic, physiologic, or pathologic manifestations. These disorders are often associated with considerable morbidity and mortality, and there is little consensus regarding the best management of most of them.

ILDs have been difficult to classify because > 200 known individual diseases are characterized by diffuse parenchymal lung involvement, either as the primary condition or as a significant part of a multiorgan process, as may occur in the connective tissue diseases (CTDs). One useful approach to classification is to separate the ILDs into two groups based on the major underlying histopathology: (1) those associated with predominant inflammation and fibrosis, and (2) those with a predominantly granulomatous reaction in interstitial or vascular areas (Table 255-1). Each of these groups can be further subdivided according to whether the cause is known or unknown. For each ILD there may be an acute phase, and there is usually a chronic one as well. Rarely, some are recurrent, with intervals of subclinical disease.

Table 255-1 Major Categories of Alveolar and Interstitial Inflammatory Lung Disease



Lung Response: Alveolitis, Interstitial Inflammation, and Fibrosis
Known Cause

Asbestos

Fumes, gases

Drugs (antibiotics, amiodarone, gold) and chemotherapy drugs
Radiation

Aspiration pneumonia

Residual of adult respiratory distress syndrome

Unknown Cause

Idiopathic interstitial pneumonias

Idiopathic pulmonary fibrosis (usual interstitial pneumonia)

Desquamative interstitial pneumonia

Respiratory bronchiolitis-associated interstitial lung disease

Acute interstitial pneumonia (diffuse alveolar damage)

Cryptogenic organizing pneumonia (bronchiolitis obliterans with organizing pneumonia)

Nonspecific interstitial pneumonia

Connective tissue diseases

Systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, systemic sclerosis, Sjögren's syndrome, polymyositis-dermatomyositis

Pulmonary hemorrhage syndromes

Goodpasture's syndrome, idiopathic pulmonary hemosiderosis, isolated pulmonary capillaritis
Pulmonary alveolar proteinosis

Lymphocytic infiltrative disorders (lymphocytic interstitial pneumonitis associated with connective tissue disease)

Eosinophilic pneumonias

Lymphangioleiomyomatosis

Amyloidosis

Inherited diseases

Tuberous sclerosis, neurofibromatosis, Niemann-Pick disease, Gaucher's disease, Hermansky-Pudlak syndrome

Gastrointestinal or liver diseases (Crohn's disease, primary biliary cirrhosis, chronic active hepatitis, ulcerative colitis)

Graft-vs.-host disease (bone marrow transplantation; solid organ transplantation)

Lung Response: Granulomatous
Known Cause

Hypersensitivity pneumonitis (organic dusts) Inorganic dusts: beryllium, silica
Unknown Cause

Sarcoidosis

Langerhans' cell granulomatosis (eosinophilic granuloma of the lung)

Granulomatous vasculitides

Wegener's granulomatosis, allergic granulomatosis of Churg-Strauss
Bronchocentric granulomatosis

Lymphomatoid granulomatosis





Sarcoidosis (Chap. 322), idiopathic pulmonary fibrosis (IPF), and pulmonary fibrosis associated with CTDs (Chaps. 313, 314, 315, 316, 317, 318, and 319) are the most common ILDs of unknown etiology. Among the ILDs of known cause, the largest group comprises occupational and environmental exposures, especially the inhalation of inorganic dusts, organic dusts, and various fumes or gases (Chaps. 249 and 250) (Table 255-2). A clinical diagnosis is possible for many forms of ILD, especially if an occupational and environmental history is aggressively pursued. For other forms, tissue examination, usually obtained by thoracoscopic lung biopsy, is critical to confirmation of the diagnosis. High-resolution computed tomography (HRCT) scanning improves diagnostic accuracy as experience with histologic-image correlation is perfected.

Table 255-2 Estimated Relative Frequency of the Interstitial Lung Diseases



Diagnosis Relative Frequency, %
Idiopathic interstitial pneumonias 40
Idiopathic pulmonary fibrosis 55
Nonspecific interstitial pneumonia 25
Respiratory bronchiolitis—ILD and desquamative interstitial pneumonia 15
Cryptogenic organizing pneumonia 3
Acute interstitial pneumonia <1
Occupational and environmental 26
Sarcoidosis 10
Connective tissue diseases 9
Drug and radiation 1
Pulmonary hemorrhage syndromes <1
Other 13



Source: From DB Coultas, R Hubbard, in JP Lynch III (ed): Lung Biology in Health and Disease. New York, Marcel Dekker, 2004; and S Garantziotis et al: J Clin Invest 114:319, 2004.


Pathogenesis

The ILDs are nonmalignant disorders and are not caused by identified infectious agents. The precise pathway(s) leading from injury to fibrosis is not known. Although there are multiple initiating agent(s) of injury, the immunopathogenic responses of lung tissue are limited, and the mechanisms of repair have common features (Fig. 255-1).

Figure 255-1




Proposed mechanism for the pathogenesis of pulmonary fibrosis. The lung is naturally exposed to repetitive injury from a variety of exogenous and endogenous stimuli. Several local and systemic factors (e.g., fibroblasts, circulating fibrocytes, chemokines, growth factors, and clotting factors) contribute to tissue healing and functional recovery. Dysregulation of this intricate network through genetic predisposition, autoimmune conditions, or superimposed diseases can lead to aberrant wound healing with the result of pulmonary fibrosis. Alternatively, excessive injury to the lung may overwhelm even intact reparative mechanisms and lead to pulmonary fibrosis. (From S Garantziotis, et al: J Clin Invest 114:319, 2004.)



As mentioned above, the two major histopathologic patterns are a granulomatous pattern and a pattern in which inflammation and fibrosis predominate.

Granulomatous Lung Disease

This process is characterized by an accumulation of T lymphocytes, macrophages, and epithelioid cells organized into discrete structures (granulomas) in the lung parenchyma. The granulomatous lesions can progress to fibrosis. Many patients with granulomatous lung disease remain free of severe impairment of lung function, or, when symptomatic, they improve after treatment. The main differential diagnosis is between sarcoidosis (Chap. 322) and hypersensitivity pneumonitis (Chap. 249).

Inflammation and Fibrosis

The initial insult is an injury to the epithelial surface causing inflammation in the air spaces and alveolar walls (Fig. 255-2). If the disease becomes chronic, inflammation spreads to adjacent portions of the interstitium and vasculature and eventually causes interstitial fibrosis. Important histopathologic patterns found in the ILDs include: usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia, respiratory bronchiolitis, organizing pneumonia [bronchiolitis obliterans with organizing pneumonia (BOOP) pattern], diffuse alveolar damage (acute or organizing), desquamative interstitial pneumonia, and lymphocytic interstitial pneumonia. The development of irreversible scarring (fibrosis) of alveolar walls, airways, or vasculature is the most feared outcome in all of these conditions because it is often progressive and leads to significant derangement of ventilatory function and gas exchange.

Figure 255-2




Cellular bases for the pathogenesis of interstitial lung disease. Multiple microinjuries damage and activate alveolar epithelial cells (top left), which in turn induce an antifibrinolytic environment in the alveolar spaces, enhancing wound clot formation. Alveolar epithelial cells secrete growth factors and induce migration and proliferation of fibroblasts and differentiation into myofibroblasts (bottom left). Subepithelial myofibroblasts and alveolar epithelial cells produce gelatinases that may increase basement membrane disruption and allow fibroblast–myofibroblast migration (bottom right). Angiogenic factors induce neovascularization. Both intraalveolar and interstitial myofibroblasts secrete extracellular matrix proteins, mainly collagens. An imbalance between interstitial collagenases and tissue inhibitors of metalloproteinases provokes the progressive deposit of extracellular matrix (top right). Signals responsible for myofibroblast apoptosis seem to be absent or delayed in usual interstitial pneumonia, increasing cell survival. Myofibroblasts produce angiotensinogen that as angiotensin II provokes alveolar epithelial cell death, further impairing reepithelialization. Abbreviations: FGF-2, fibroblast growth factor 2; MMPs, metalloproteinases; PAI-1, PAI-2, plasminogen activator inhibitor 1, 2; PDGF, platelet-derived growth factor; TGF-, transforming growth factor ; TIMPs, tissue inhibitors of metalloproteinases; TNF-, tumor necrosis factor ; VEGF, vascular endothelial growth factor. (From M Selman et al: Ann Intern Med 134:136, 2001; with permission.)



History

Duration of Illness

Acute presentation (days to weeks), while unusual, occurs with allergy (drugs, fungi, helminths), acute interstitial pneumonia (AIP), eosinophilic pneumonia, and hypersensitivity pneumonitis. These conditions may be confused with atypical pneumonias because of diffuse alveolar opacities on chest x-ray. Subacute presentation (weeks to months) may occur in all ILDs but is seen especially in sarcoidosis, drug-induced ILDs, the alveolar hemorrhage syndromes, cryptogenic organizing pneumonia (COP), and the acute immunologic pneumonia that complicates systemic lupus erythematosus (SLE) or polymyositis. In most ILDs the symptoms and signs form a chronic presentation (months to years). Examples include IPF, sarcoidosis, pulmonary Langerhans cell histiocytosis (PLCH) (also known as Langerhans cell granulomatosis, eosinophilic granuloma, or histiocytosis X), pneumoconioses, and CTDs. Episodic presentations are unusual and include eosinophilic pneumonia, hypersensitivity pneumonitis, COP, vasculitides, pulmonary hemorrhage, and Churg-Strauss syndrome.

Age

Most patients with sarcoidosis, ILD associated with CTD, lymphangioleiomyomatosis (LAM), PLCH, and inherited forms of ILD (familial IPF, Gaucher's disease, Hermansky-Pudlak syndrome) present between the ages of 20 and 40 years. Most patients with IPF are older than 50 years.

Gender

LAM and pulmonary involvement in tuberous sclerosis occur exclusively in premenopausal women. Also, ILD in Hermansky-Pudlak syndrome and in the CTDs is more common in women; an exception is ILD in rheumatoid arthritis (RA), which is more common in men. Because of occupational exposures, pneumoconioses also occur more frequently in men.

Family History

Family associations (with an autosomal dominant pattern) have been identified in tuberous sclerosis and neurofibromatosis. An autosomal recessive pattern of inheritance occurs in Niemann-Pick disease, Gaucher's disease, and the Hermansky-Pudlak syndrome. Familial clustering has been increasingly identified in sarcoidosis. Familial lung fibrosis has been associated with mutations in the surfactant protein C gene and is characterized by several patterns of interstitial pneumonia, including nonspecific interstitial pneumonia, desquamative interstitial pneumonia, and UIP.

Smoking History

Two-thirds to 75% of patients with IPF have a history of smoking. Patients with PLCH, desquamative interstitial pneumonia (DIP), Goodpasture's syndrome, respiratory bronchiolitis, and pulmonary alveolar proteinosis are almost always current or former smokers.

Occupation and Environmental History

A strict chronologic listing of the patient's lifelong employment must be sought, including specific duties and known exposures. In hypersensitivity pneumonitis (see Fig. 249-1), respiratory symptoms, fever, chills, and an abnormal chest roentgenogram are often temporally related to a hobby (pigeon breeder's disease) or to the workplace (farmer's lung) (Chap. 249). Symptoms may diminish or disappear after the patient leaves the site of exposure for several days; similarly, symptoms may reappear on returning to the exposure site.

Other Important Past History

Parasitic infections may cause pulmonary eosinophilia, and therefore a travel history should be taken in patients with known or suspected ILD. History of risk factors for HIV infection should be elicited from all patients with ILD because several processes may occur at the time of initial presentation or during the clinical course, e.g., HIV infection, BOOP, AIP, lymphocytic interstitial pneumonitis, or diffuse alveolar hemorrhage.

Respiratory Symptoms and Signs

Dyspnea is a common and prominent complaint in patients with ILD, especially the idiopathic interstitial pneumonias, hypersensitivity pneumonitis, COP, sarcoidosis, eosinophilic pneumonias, and PLCH. Some patients, especially patients with sarcoidosis, silicosis, PLCH, hypersensitivity pneumonitis, lipoid pneumonia, or lymphangitis carcinomatosis, may have extensive parenchymal lung disease on chest x-ray without significant dyspnea, especially early in the course of the illness. Wheezing is an uncommon manifestation of ILD but has been described in patients with chronic eosinophilic pneumonia, Churg-Strauss syndrome, respiratory bronchiolitis, and sarcoidosis. Clinically significant chest pain is uncommon in most ILDs. However, substernal discomfort is common in sarcoidosis. Sudden worsening of dyspnea, especially if associated with acute chest pain, may indicate a spontaneous pneumothorax, which occurs in PLCH, tuberous sclerosis, LAM, and neurofibromatosis. Frank hemoptysis and blood-streaked sputum are rarely presenting manifestations of ILD but can be seen in the diffuse alveolar hemorrhage (DAH) syndromes, LAM, tuberous sclerosis, and the granulomatous vasculitides. Fatigue and weight loss are common in all ILDs.

Physical Examination

The findings are usually not specific. Most commonly, physical examination reveals tachypnea and bibasilar end-inspiratory dry crackles, which are common in most forms of ILD associated with inflammation but are less likely to be heard in the granulomatous lung diseases. Crackles may be present in the absence of radiographic abnormalities on the chest radiograph. Scattered late inspiratory high-pitched rhonchi—so-called inspiratory squeaks—are heard in patients with bronchiolitis. The cardiac examination is usually normal except in the mid or late stages of the disease, when findings of pulmonary hypertension and cor pulmonale may become evident (Chap. 244). Cyanosis and clubbing of the digits occur in some patients with advanced disease.

Laboratory

Antinuclear antibodies and anti-immunoglobulin antibodies (rheumatoid factors) are identified in some patients, even in the absence of a defined CTD. A raised lactate dehydrogenase (LDH) level is a nonspecific finding common to ILDs. Elevation of the serum angiotensin-converting enzyme level is common in sarcoidosis. Serum precipitins confirm exposure when hypersensitivity pneumonitis is suspected, although they are not diagnostic of the process. Antineutrophil cytoplasmic or anti-basement membrane antibodies are useful if vasculitis is suspected. The electrocardiogram is usually normal unless pulmonary hypertension is present; then it demonstrates right-axis deviation, right ventricular hypertrophy, or right atrial enlargement or hypertrophy. Echocardiography also reveals right ventricular dilatation and/or hypertrophy in the presence of pulmonary hypertension.

Chest Imaging Studies

Chest X-Ray

ILD may be first suspected based on an abnormal chest radiograph, which most commonly reveals a bibasilar reticular pattern. A nodular or mixed pattern of alveolar filling and increased reticular markings may also be present. A subgroup of ILDs exhibit nodular opacities with a predilection for the upper lung zones [sarcoidosis, PLCH, chronic hypersensitivity pneumonitis, silicosis, berylliosis, RA (necrobiotic nodular form), ankylosing spondylitis]. The chest x-ray correlates poorly with the clinical or histopathologic stage of the disease. The radiographic finding of honeycombing correlates with pathologic findings of small cystic spaces and progressive fibrosis; when present, it portends a poor prognosis. In most cases, the chest radiograph is nonspecific and usually does not allow a specific diagnosis.

Computed Tomography

High-resolution computed tomography (HRCT) is superior to the plain chest x-ray for early detection and confirmation of suspected ILD (Fig. 255-3). Also, HRCT allows better assessment of the extent and distribution of disease, and it is especially useful in the investigation of patients with a normal chest radiograph. Coexisting disease is often best recognized on HRCT scanning, e.g., mediastinal adenopathy, carcinoma, or emphysema. In the appropriate clinical setting HRCT may be sufficiently characteristic to preclude the need for lung biopsy in IPF, sarcoidosis, hypersensitivity pneumonitis, asbestosis, lymphangitic carcinoma, and PLCH. When a lung biopsy is required, HRCT scanning is useful for determining the most appropriate area from which biopsy samples should be taken.

Figure 255-3




Idiopathic pulmonary fibrosis. High-resolution CT image shows bibasal, peripheral predominant reticular abnormality with traction bronchiectasis and honeycombing. The lung biopsy showed the typical features of usual interstitial pneumonia.



Pulmonary Function Testing

Spirometry and Lung Volumes

Measurement of lung function is important in assessing the extent of pulmonary involvement in patients with ILD. Most forms of ILD produce a restrictive defect with reduced total lung capacity (TLC), functional residual capacity, and residual volume (Chap. 246). Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) are reduced, but these changes are related to the decreased TLC. The FEV1/FVC ratio is usually normal or increased. Lung volumes decrease as lung stiffness worsens with disease progression. A few disorders produce interstitial opacities on chest x-ray and obstructive airflow limitation on lung function testing (uncommon in sarcoidosis and hypersensitivity pneumonitis, while common in tuberous sclerosis and LAM). Pulmonary function studies have proven to have prognostic value in patients with idiopathic interstitial pneumonias, particularly, IPF or nonspecific interstitial pneumonia (NSIP).

Diffusing Capacity

A reduction in the diffusing capacity of the lung for carbon monoxide (DLCO) is a common but nonspecific finding in most ILDs. This decrease is due, in part, to effacement of the alveolar capillary units but, more importantly, to mismatching of ventilation and perfusion (/). Lung regions with reduced compliance due to either fibrosis or cellular infiltration may be poorly ventilated but may still maintain adequate blood flow, and the ventilation-perfusion mismatch in these regions acts like true venous admixture. The severity of the reduction in DLCO does not correlate with disease stage.

Arterial Blood Gas

The resting arterial blood gas may be normal or reveal hypoxemia (secondary to a mismatching of ventilation to perfusion) and respiratory alkalosis. A normal arterial O2 tension (or saturation by oximetry) at rest does not rule out significant hypoxemia during exercise or sleep. CO2 retention is rare and is usually a manifestation of end-stage disease.

Cardiopulmonary Exercise Testing

Because hypoxemia at rest is not always present and because severe exercise-induced hypoxemia may go undetected, it is useful to perform exercise testing with measurement of arterial blood gases to detect abnormalities of gas exchange. Arterial oxygen desaturation, a failure to decrease dead space appropriately with exercise [i.e., a high VD/VT ratio (Chap. 246)], and an excessive increase in respiratory rate with a lower-than-expected recruitment of tidal volume provide useful information about physiologic abnormalities and extent of disease. Serial assessment of resting and exercise gas exchange is an excellent method for following disease activity and responsiveness to treatment, especially in patients with IPF. Increasingly, the 6-min walk test is used to obtain a global evaluation of submaximal exercise capacity in patients with ILD. The walk distance and level of oxygen desaturation tend to correlate with the patient's baseline lung function.

Fiberoptic Bronchoscopy and Bronchoalveolar Lavage (BAL)

In selected diseases (e.g., sarcoidosis, hypersensitivity pneumonitis, DAH syndrome, cancer, pulmonary alveolar proteinosis), cellular analysis of BAL fluid may be useful in narrowing the differential diagnostic possibilities among various types of ILD (Table 255-3). The role for BAL in defining the stage of disease and assessment of disease progression or response to therapy remains poorly understood, and the usefulness of BAL in the clinical assessment and management remains to be established.

Table 255-3 Diagnostic Value of Bronchoalveolar Lavage in Interstitial Lung Disease



Condition Bronchoalveolar Lavage Finding
Sarcoidosis
Lymphocytosis; CD4:CD8 ratio >3.5 most specific of diagnosis

Hypersensitivity pneumonitis
Marked lymphocytosis (>50%)

Organizing pneumonia
Foamy macrophages; mixed pattern of increased cells characteristic; decreased CD4:CD8 ratio

Eosinophilic lung disease
Eosinophils >25%

Diffuse alveolar bleeding
Hemosiderin-laden macrophages, red blood cells

Diffuse alveolar damage, drug toxicity
Atypical hyperplastic type II pneumocytes

Opportunistic infections
Pneumocystis carinii, fungi, cytomegalovirus-transformed cells

Lymphangitic carcinomatosis, alveolar cell carcinoma, pulmonary lymphoma
Malignant cells

Alveolar proteinosis
Milky effluent, foamy macrophages and lipoproteinaceous intraalveolar material (periodic acid–Schiff stain positive)

Lipoid pneumonia
Fat globules in macrophages

Pulmonary Langerhans' cell histiocytosis
Increased CD1+ Langerhans' cells

Electron microscopy demonstrating Birbeck granule in lavaged macrophage (expensive and difficult to perform)

Asbestos-related pulmonary disease
Dust particles, ferruginous bodies

Berylliosis
Positive lymphocyte transformation test to beryllium

Silicosis
Dust particles by polarized light microscopy

Lipoidosis
Accumulation of specific lipopigment in alveolar macrophages





Tissue and Cellular Examination

Lung biopsy is the most effective method for confirming the diagnosis and assessing disease activity. The findings may identify a more treatable process than originally suspected, particularly chronic hypersensitivity pneumonitis, COP, respiratory bronchiolitis–associated ILD, or sarcoidosis. Biopsy should be obtained before initiation of treatment. A definitive diagnosis avoids confusion and anxiety later in the clinical course if the patient does not respond to therapy or suffers serious side effects from it.

Fiberoptic bronchoscopy with multiple transbronchial lung biopsies (four to eight biopsy samples) is often the initial procedure of choice, especially when sarcoidosis, lymphangitic carcinomatosis, eosinophilic pneumonia, Goodpasture's syndrome, or infection is suspected. If a specific diagnosis is not made by transbronchial biopsy, then surgical lung biopsy by video-assisted thoracic surgery or open thoracotomy is indicated. Adequate-sized biopsies from multiple sites, usually from two lobes, should be obtained. Relative contraindications to lung biopsy include serious cardiovascular disease, honeycombing and other roentgenographic evidence of diffuse end-stage disease, severe pulmonary dysfunction, or other major operative risks, especially in the elderly.

Interstitial Lung Disease: Treatment

Although the course of ILD is variable, progression is common and often insidious. All treatable possibilities should be carefully considered. Since therapy does not reverse fibrosis, the major goals of treatment are permanent removal of the offending agent, when known, and early identification and aggressive suppression of the acute and chronic inflammatory process, thereby reducing further lung damage.

Hypoxemia (PaO2 < 55 mmHg) at rest and/or with exercise should be managed by supplemental oxygen. If cor pulmonale develops, diuretic therapy and phlebotomy may occasionally be required (Chaps. 227 and 244).

Drug Therapy

Glucocorticoids are the mainstay of therapy for suppression of the alveolitis present in ILD, but the success rate is low. There have been no placebo-controlled trials of glucocorticoids in ILD, so there is no direct evidence that steroids improve survival in many of the diseases for which they are commonly used. Glucocorticoid therapy is recommended for symptomatic ILD patients with eosinophilic pneumonias, COP, CTD, sarcoidosis, acute inorganic dust exposures, acute radiation pneumonitis, DAH, and drug-induced ILD. In organic dust disease, glucocorticoids are recommended for both the acute and chronic stages.

The optimal dose and proper length of therapy with glucocorticoids in the treatment of most ILDs are not known. A common starting dose is prednisone, 0.5–1 mg/kg in a once-daily oral dose (based on the patient's lean body weight). This dose is continued for 4–12 weeks, at which time the patient is reevaluated. If the patient is stable or improved, the dose is tapered to 0.25–0.5 mg/kg and is maintained at this level for an additional 4–12 weeks depending on the course. Rapid tapering or a shortened course of glucocorticoid treatment can result in recurrence. If the patient's condition continues to decline while on glucocorticoids, a second agent (see below) is often added and the prednisone dose is lowered to or maintained at 0.25 mg/kg per day.

Cyclophosphamide and azathioprine (1–2 mg/kg lean body weight per day), with or without glucocorticoids, have been tried with variable success in IPF, vasculitis, and other ILDs. An objective response usually requires at least 8–12 weeks to occur. In situations in which these drugs have failed or could not be tolerated, other agents, including methotrexate, colchicine, penicillamine, and cyclosporine, have been tried. However, their role in the treatment of ILDs remains to be determined.

Many cases of ILD are chronic and irreversible despite the therapy discussed above, and lung transplantation may then be considered (Chap. 260).

Idiopathic Pulmonary Fibrosis

IPF is the most common form of idiopathic interstitial pneumonia. Separating IPF from other forms of lung fibrosis is an important step in the evaluation of all patients presenting with ILD. IPF has a distinctly poor response to therapy and a bad prognosis.

Clinical Manifestations

Exertional dyspnea, a nonproductive cough, and inspiratory crackles with or without digital clubbing may be present on physical examination. The HRCT lung scans typically show patchy, predominantly basilar, subpleural reticular opacities, often associated with traction bronchiectasis and honeycombing (Fig. 255-3). Atypical findings that should suggest an alternative diagnosis include: extensive ground-glass abnormality, nodular opacities, upper or mid-zone predominance, and prominent hilar or mediastinal lymphadenopathy. Pulmonary function tests often reveal a restrictive pattern, a reduced DLCO, and arterial hypoxemia that is exaggerated or elicited by exercise.

Histologic Findings

Confirmation of the presence of the UIP pattern on histologic examination is essential to confirm this diagnosis. Transbronchial biopsies are not helpful in making the diagnosis of UIP, and surgical biopsy is usually required. The histologic hallmark and chief diagnostic criterion of UIP is a heterogeneous appearance at low magnification with alternating areas of normal lung, interstitial inflammation, foci of proliferating fibroblasts, dense collagen fibrosis, and honeycomb changes. These histologic changes affect the peripheral, subpleural parenchyma most severely. The interstitial inflammation is usually patchy and consists of a lymphoplasmacytic infiltrate in the alveolar septa, associated with hyperplasia of type 2 pneumocytes. The fibrotic zones are composed mainly of dense collagen, although scattered foci of proliferating fibroblasts are a consistent finding. The extent of fibroblastic proliferation is predictive of disease progression. Areas of honeycomb change are composed of cystic fibrotic air spaces that are frequently lined by bronchiolar epithelium and filled with mucin. Smooth-muscle hyperplasia is commonly seen in areas of fibrosis and honeycomb change. A fibrotic pattern with some features similar to UIP may be found in the chronic stage of several specific disorders such as: pneumoconioses (e.g., asbestosis), radiation injury, certain drug-induced lung diseases (e.g., nitrofurantoin), chronic aspiration, sarcoidosis, chronic hypersensitivity pneumonitis, organized chronic eosinophilic pneumonia, and PLCH. Commonly, other histopathologic features are present in these situations thus allowing separation of these lesions from the UIP-like pattern. Consequently, the term UIP is used for those patients in whom the lesion is idiopathic and not associated with another condition.

Patients with IPF may suffer acute deterioration secondary to infections, pulmonary embolism, pneumothorax, or heart failure. These patients also commonly suffer an accelerated phase of rapid clinical decline that is associated with a poor prognosis (so-called acute exacerbations of IPF). These acute exacerbations are defined by: worsening of dyspnea within a few days to 4 weeks; newly developing diffuse radiographic opacities; worsening hypoxemia; and absence of infectious pneumonia, heart failure, and sepsis. The rate of these acute exacerbations ranges from 10–57%, apparently depending on the length of follow-up. During these episodes, the histopathologic pattern of diffuse alveolar damage is often found on the background of UIP.

Idiopathic Pulmonary Fibrosis: Treatment

No therapy has been found to be effective in the management of acute exacerbations of IPF. Often mechanical ventilation is required but is usually not successful, with a hospital mortality rate of up to three-fourths of the patients. In those that survive, a recurrence of acute exacerbation is common and usually results in death at those times.

Lung transplantation should be considered for those patients who experience progressive deterioration despite optimal medical management and who meet the established criteria (Chap. 260).

Nonspecific Interstitial Pneumonia (NSIP)

This condition defines a subgroup of the idiopathic interstitial pneumonias that can be distinguished clinically and pathologically from UIP, desquamative interstitial pneumonia (DIP), AIP, and idiopathic BOOP. Importantly, many cases with this histopathologic pattern occur in the context of an underlying disorder, such as a connective tissue disease, drug-induced ILD, or chronic hypersensitivity pneumonitis. Idiopathic NSIP is a subacute restrictive process with a presentation similar to IPF but usually at a younger age, most commonly in women who have never smoked. It is often associated with a febrile illness. HRCT shows bilateral, subpleural ground-glass opacities, often associated with lower lobe volume loss (Fig. 255-4). Patchy areas of airspace consolidation and reticular abnormalities may be present, but honeycombing is unusual. The key histopathologic features of NSIP are the uniformity of interstitial involvement across the biopsy section, and this may be predominantly cellular or fibrosing. There is less temporal and spatial heterogeneity than in UIP and little or no honeycombing is found. The cellular variant is rare. Unlike patients with IPF (UIP), the majority of patients with NSIP have a good prognosis (5-year mortality rate estimated at <15%) with most showing improvement after treatment with glucocorticoids, often used in combination with azathioprine.

Figure 255-4




Nonspecific interstitial pneumonia. High-resolution CT through the lower lung shows volume loss with extensive ground-glass abnormality, reticular abnormality and traction bronchiectasis. There is sparing on the lung immediately adjacent to the pleura. Histology showed a combination of inflammation and mild fibrosis.



Acute Interstitial Pneumonia (AIP, Hamman-Rich Syndrome)

AIP is a rare, fulminant form of lung injury characterized histologically by diffuse alveolar damage on lung biopsy. Most patients are older than 40 years. AIP is similar in presentation to the acute respiratory distress syndrome (ARDS) (Chap. 262) and probably corresponds to the subset of cases of idiopathic ARDS. The onset is usually abrupt in a previously healthy individual. A prodromal illness, usually lasting 7–14 days before presentation, is common. Fever, cough, and dyspnea are frequent manifestations at presentation. Diffuse, bilateral, air-space opacification is present on chest radiograph. HRCT scans show bilateral, patchy, symmetric areas of ground-glass attenuation. Bilateral areas of air-space consolidation may also be present. A predominantly subpleural distribution may be seen. The diagnosis of AIP requires the presence of a clinical syndrome of idiopathic ARDS and pathologic confirmation of organizing diffuse alveolar damage. Therefore, lung biopsy is required to confirm the diagnosis. Most patients have moderate to severe hypoxemia and develop respiratory failure. Mechanical ventilation is often required. The mortality rate is high (>60%), with most patients dying within 6 months of presentation. Recurrences have been reported. However, those who recover often have substantial improvement in lung function. The main treatment is supportive. It is not clear that glucocorticoid therapy is effective.

Cryptogenic Organizing Pneumonia

Also known as idiopathic BOOP, COP is a clinicopathologic syndrome of unknown etiology. The onset is usually in the fifth and sixth decades. The presentation may be of a flulike illness with cough, fever, malaise, fatigue, and weight loss. Inspiratory crackles are frequently present on examination. Pulmonary function is usually impaired, with a restrictive defect and arterial hypoxemia being most common. The roentgenographic manifestations are distinctive, revealing bilateral, patchy, or diffuse alveolar opacities in the presence of normal lung volume. Recurrent and migratory pulmonary opacities are common. HRCT shows areas of air-space consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening and dilation. These changes occur more frequently in the periphery of the lung and in the lower lung zone. Lung biopsy shows granulation tissue within small airways, alveolar ducts, and airspaces, with chronic inflammation in the surrounding alveoli. Glucocorticoid therapy induces clinical recovery in two-thirds of patients. A few patients have rapidly progressive courses with fatal outcomes despite glucocorticoids.

Foci of organizing pneumonia (i.e., a "BOOP pattern") is a nonspecific reaction to lung injury found adjacent to other pathologic processes or as a component of other primary pulmonary disorders (e.g., cryptococcosis, Wegener's granulomatosis, lymphoma, hypersensitivity pneumonitis, and eosinophilic pneumonia). Consequently, the clinician must carefully reevaluate any patient found to have this histopathologic lesion to rule out these possibilities.

ILD Associated with Cigarette Smoking

Desquamative Interstitial Pneumonia

DIP is a rare but distinct clinical and pathologic entity found exclusively in cigarette smokers. The histologic hallmark is the extensive accumulation of macrophages in intraalveolar spaces with minimal interstitial fibrosis. The peak incidence is in the fourth and fifth decades. Most patients present with dyspnea and cough. Lung function testing shows a restrictive pattern with reduced DLCO and arterial hypoxemia. The chest x-ray and HRCT scans usually show diffuse hazy opacities. Clinical recognition of DIP is important because the process is associated with a better prognosis (10-year survival rate is ~70%) and a better response to smoking cessation and systemic glucocorticoids than IPF.

Respiratory Bronchiolitis–Associated ILD

Respiratory bronchiolitis–associated ILD (RB-ILD) is considered to be a subset of DIP and is characterized by the accumulation of macrophages in peribronchial alveoli. The clinical presentation is similar to DIP. Rales are often heard on chest examination and occur throughout inspiration; sometimes they continue into expiration. The process is seen best on HRCT lung scanning which shows bronchial wall thickening, centrilobular nodules, ground-glass opacity, and emphysema with air trapping. RB-ILD appears to resolve in most patients following smoking cessation alone.

Pulmonary Langerhans Cell Histiocytosis (PLCH)

This is a rare, smoking-related, diffuse lung disease that primarily affects men between the ages of 20 and 40 years. The clinical presentation varies from an asymptomatic state to a rapidly progressive condition. The most common clinical manifestations at presentation are cough, dyspnea, chest pain, weight loss, and fever. Pneumothorax occurs in ~25% of patients. Hemoptysis and diabetes insipidus are rare manifestations. The radiographic features vary with the stage of the disease. The combination of ill-defined or stellate nodules (2–10 mm in diameter), reticular or nodular opacities, bizarre-shaped upper zone cysts, preservation of lung volume, and sparing of the costophrenic angles are characteristics of PLCH. HRCT that reveals a combination of nodules and thin-walled cysts is virtually diagnostic of PLCH. The most frequent pulmonary function abnormality is a markedly reduced DLCO, although varying degrees of restrictive disease, airflow limitation, and diminished exercise capacity may occur. The characteristic histopathologic finding in PLCH is the presence of nodular sclerosing lesions that contain Langerhans' cells accompanied by mixed cellular infiltrates. The nodular lesions are poorly defined and are distributed in a bronchiolocentric fashion with intervening normal lung parenchyma. As the disease progresses, fibrosis progresses to involve adjacent lung tissue leading to pericicatricial airspace enlargement, which accounts for the concomitant cystic changes. Discontinuance of smoking is the key treatment, resulting in clinical improvement in one-third of patients. Most patients with PLCH suffer persistent or progressive disease. Death due to respiratory failure occurs in ~10% of patients.

ILD Associated with Connective Tissue Disorders

Clinical findings suggestive of a CTD (musculoskeletal pain, weakness, fatigue, fever, joint pains or swelling, photosensitivity, Raynaud's phenomenon, pleuritis, dry eyes, dry mouth) should be sought in any patient with ILD. The CTDs may be difficult to rule out since the pulmonary manifestations occasionally precede the more typical systemic manifestations by months or years. The most common form of pulmonary involvement is the nonspecific interstitial pneumonia histopathologic pattern. However, determining the precise nature of lung involvement in most of the CTDs is difficult due to the high incidence of lung involvement caused by disease-associated complications of esophageal dysfunction (predisposing to aspiration and secondary infections), respiratory muscle weakness (atelectasis and secondary infections), complications of therapy (opportunistic infections), and associated malignancies.

Progressive Systemic Sclerosis (PSS)

(See also Chap. 316) Clinical evidence of ILD is present in about one-half of patients with PSS, and pathologic evidence in three-quarters. Pulmonary function tests show a restrictive pattern and impaired diffusing capacity, often before any clinical or radiographic evidence of lung disease appears. Pulmonary vascular disease alone or in association with pulmonary fibrosis, pleuritis, or recurrent aspiration pneumonitis is strikingly resistant to current modes of therapy.

Rheumatoid Arthritis (RA)

(See also Chap. 314) ILD associated with RA is more common in men. Pulmonary manifestations of RA include pleurisy with or without effusion, ILD in up to 20% of cases, necrobiotic nodules (nonpneumoconiotic intrapulmonary rheumatoid nodules) with or without cavities, Caplan's syndrome (rheumatoid pneumoconiosis), pulmonary hypertension secondary to rheumatoid pulmonary vasculitis, BOOP, and upper airway obstruction due to crico-arytenoid arthritis.

Systemic Lupus Erythematosus (SLE)

(See also Chap. 313) Lung disease is a common complication in SLE. Pleuritis with or without effusion is the most common pulmonary manifestation. Other lung manifestations include the following: atelectasis, diaphragmatic dysfunction with loss of lung volumes, pulmonary vascular disease, pulmonary hemorrhage, uremic pulmonary edema, infectious pneumonia, and BOOP. Acute lupus pneumonitis characterized by pulmonary capillaritis leading to alveolar hemorrhage is uncommon. Chronic, progressive ILD is uncommon. It is important to exclude pulmonary infection. Although pleuropulmonary involvement may not be evident clinically, pulmonary function testing, particularly DLCO, reveals abnormalities in many patients with SLE.

Polymyositis and Dermatomyositis (PM/DM)

(See also Chap. 383) ILD occurs in ~10% of patients with PM/DM. Diffuse reticular or nodular opacities with or without an alveolar component occur radiographically, with a predilection for the lung bases. ILD occurs more commonly in the subgroup of patients with an anti-Jo-1 antibody that is directed to histidyl tRNA synthetase. Weakness of respiratory muscles contributing to aspiration pneumonia may be present. A rapidly progressive illness characterized by diffuse alveolar damage may cause respiratory failure.

Sjögren's Syndrome

(See also Chap. 317) General dryness and lack of airways secretion cause the major problems of hoarseness, cough, and bronchitis. Lymphocytic interstitial pneumonitis, lymphoma, pseudolymphoma, bronchiolitis, and bronchiolitis obliterans are associated with this condition. Lung biopsy is frequently required to establish a precise pulmonary diagnosis. Glucocorticoids have been used in the management of ILD associated with Sjögren's syndrome with some degree of clinical success.

Drug-Induced ILD

Many classes of drugs have the potential to induce diffuse ILD, which is manifest most commonly as exertional dyspnea and nonproductive cough. A detailed history of the medications taken by the patient is needed to identify drug-induced disease, including over-the-counter medications, oily nose drops, or petroleum products (mineral oil). In most cases, the pathogenesis is unknown, although a combination of direct toxic effects of the drug (or its metabolite) and indirect inflammatory and immunologic events are likely. The onset of the illness may be abrupt and fulminant, or it may be insidious, extending over weeks to months. The drug may have been taken for several years before a reaction develops (e.g., amiodarone), or the lung disease may occur weeks to years after the drug has been discontinued (e.g., carmustine). The extent and severity of disease are usually dose-related. Treatment consists of discontinuation of any possible offending drug and supportive care.

Eosinophilic Pneumonia

(See Chap. 249)

Pulmonary Alveolar Proteinosis (PAP)

Although not strictly an ILD, PAP resembles and is therefore considered with these conditions. It has been proposed that a defect in macrophage function, more specifically an impaired ability to process surfactant, may play a role in the pathogenesis of PAP. This diffuse disease is characterized by the accumulation of an amorphous, periodic acid–Schiff-positive lipoproteinaceous material in the distal air spaces. There is little or no lung inflammation, and the underlying lung architecture is preserved. Mutant mice lacking the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) have a similar accumulation of surfactant and surfactant apoprotein in the alveolar spaces. Moreover, reconstitution of the respiratory epithelium of GM-CSF knockout mice with the GM-CSF gene completely corrects the alveolar proteinosis. Data from BAL studies in patients suggest that PAP is an autoimmune disease with neutralizing antibody of immunoglobulin G isotype against GM-CSF. These findings suggest that neutralization of GM-CSF bioactivity by the antibody causes dysfunction of alveolar macrophages, which results in reduced surfactant clearance. There are three distinct classes of PAP: acquired (>90% of all cases), congenital, and secondary. Congenital PAP is transmitted in an autosomal recessive manner and is caused by homozygosity for a frame shift mutation (121ins2) in the SP-B gene, which leads to an unstable SP-B mRNA, reduced protein levels, and secondary disturbances of SP-C processing. Secondary PAP is rare among adults and is caused by lysinuric protein intolerance, acute silicosis and other inhalational syndromes, immunodeficiency disorders, and malignancies (almost exclusively of hematopoietic origin) and hematopoietic disorders.

The typical age of presentation is 30–50 years, and males predominate. The clinical presentation is usually insidious and manifested by progressive exertional dyspnea, fatigue, weight loss, and low-grade fever. A nonproductive cough is common, but occasionally expectoration of "chunky" gelatinous material may occur. Polycythemia, hypergammaglobulinemia, and increased LDH levels are frequent. Markedly elevated serum levels of lung surfactant proteins A and D have been found in PAP. Radiographically, bilateral symmetric alveolar opacities located centrally in mid and lower lung zones result in a "bat-wing" distribution. HRCT shows a ground-glass opacification and thickened intralobular structures and interlobular septa. Whole-lung lavage(s) through a double-lumen endotracheal tube provides relief to many patients with dyspnea or progressive hypoxemia and also may provide long-term benefit.

Pulmonary Lymphangioleiomyomatosis

Pulmonary LAM is a rare condition that afflicts premenopausal women and should be suspected in young women with "emphysema," recurrent pneumothorax, or chylous pleural effusion. It is often misdiagnosed as asthma or chronic obstructive pulmonary disease. Pathologically, LAM is characterized by the proliferation of atypical pulmonary interstitial smooth muscle and cyst formation. The immature-appearing smooth-muscle cells react with monoclonal antibody HMB45, which recognizes a 100-kDa glycoprotein (gp100) originally found in human melanoma cells. Caucasians are affected much more commonly than members of other racial groups. The disease accelerates during pregnancy and abates after oophorectomy. Common complaints at presentation are dyspnea, cough, and chest pain. Hemoptysis may be life threatening. Spontaneous pneumothorax occurs in 50% of patients; it may be bilateral and necessitate pleurodesis. Meningioma and renal angiomyolipomas (hamartomas), characteristic findings in the genetic disorder tuberous sclerosis, are also common in patients with LAM. Chylothorax, chyloperitoneum (chylous ascites), chyluria, and chylopericardium are other complications. Pulmonary function testing usually reveals an obstructive or mixed obstructive-restrictive pattern, and gas exchange is often abnormal. HRCT shows thin-walled cysts surrounded by normal lung without zonal predominance. Progression is common, with a median survival of 8–10 years from diagnosis. Progesterone (10 mg/d) and luteinizing hormone–releasing hormone analogues have been used. Oophorectomy is no longer recommended and estrogen-containing drugs should be discontinued. Lung transplantation offers the only hope for cure despite reports of recurrent disease in the transplanted lung.

Syndromes of ILD with Diffuse Alveolar Hemorrhage

Injury to arterioles, venules, and the alveolar septal (alveolar wall or interstitial) capillaries can result in hemoptysis secondary to disruption of the alveolar-capillary basement membrane. This results in bleeding into the alveolar spaces, which characterizes DAH. Pulmonary capillaritis, characterized by a neutrophilic infiltration of the alveolar septae, may lead to necrosis of these structures, loss of capillary structural integrity, and the pouring of red blood cells into the alveolar space. Fibrinoid necrosis of the interstitium and red blood cells within the interstitial space are sometimes seen. Bland pulmonary hemorrhage (i.e., DAH without inflammation of the alveolar structures) may also occur.

The clinical onset is often abrupt, with cough, fever, and dyspnea. Severe respiratory distress requiring ventilatory support may be evident at initial presentation. Although hemoptysis is expected, it can be absent at the time of presentation in one-third of the cases. For patients without hemoptysis, new alveolar opacities, a falling hemoglobin level, and hemorrhagic BAL fluid point to the diagnosis. The chest radiograph is nonspecific and most commonly shows new patchy or diffuse alveolar opacities. Recurrent episodes of DAH may lead to pulmonary fibrosis, resulting in interstitial opacities on the chest radiograph. An elevated white blood cell count and falling hematocrit are frequent. Evidence for impaired renal function caused by focal segmental necrotizing glomerulonephritis, usually with crescent formation, may also be present.

Varying degrees of hypoxemia may occur and are often severe enough to require ventilatory support. The DLCO may be increased, resulting from the increased hemoglobin within the alveoli compartment. Evaluation of either lung or renal tissue by immunofluorescent techniques indicates an absence of immune complexes (pauci-immune) in Wegener's granulomatosis, microscopic polyangiitis pauci-immune glomerulonephritis, and isolated pulmonary capillaritis. A granular pattern is found in the CTDs, particularly SLE, and a characteristic linear deposition is found in Goodpasture's syndrome. Granular deposition of IgA-containing immune complexes is present in Henoch-Schönlein purpura.

The mainstay of therapy for the DAH associated with systemic vasculitis, CTD, Goodpasture's syndrome, and isolated pulmonary capillaritis is IV methylprednisolone, 0.5–2.0 g daily in divided doses for up to 5 days, followed by a gradual tapering, and then maintenance on an oral preparation. Prompt initiation of therapy is important, particularly in the face of renal insufficiency, since early initiation of therapy has the best chance of preserving renal function. The decision to start other immunosuppressive therapy (cyclophosphamide or azathioprine) acutely depends on the severity of illness.

Goodpasture's Syndrome

Pulmonary hemorrhage and glomerulonephritis are features in most patients with this disease. Autoantibodies to renal glomerular and lung alveolar basement membranes are present. This syndrome can present and recur as DAH without an associated glomerulonephritis. In such case, circulating anti-basement membrane antibody is often absent, and the only way to establish the diagnosis is by demonstrating linear immunofluorescence in lung tissue. The underlying histology may be bland hemorrhage or DAH associated with capillaritis. Plasmapheresis has been recommended as adjunctive treatment.

Inherited Disorders Associated with ILD

Pulmonary opacities and respiratory symptoms typical of ILD can develop in related family members and in several inherited diseases. These include the phakomatoses, tuberous sclerosis and neurofibromatosis (Chap. 374), and the lysosomal storage diseases, Niemann-Pick disease and Gaucher's disease (Chap. 355). The Hermansky-Pudlak syndrome is an autosomal recessive disorder in which granulomatous colitis and ILD may occur. It is characterized by oculocutaneous albinism, bleeding diathesis secondary to platelet dysfunction, and the accumulation of a chromolipid, lipofuscin material in cells of the reticuloendothelial system. A fibrotic pattern is found on lung biopsy, but the alveolar macrophages may contain cytoplasmic ceroid-like inclusions.

ILD with a Granulomatous Response in Lung Tissue or Vascular Structures

Inhalation of organic dusts, which cause hypersensitivity pneumonitis, or of inorganic dust, such as silica, which elicits a granulomatous inflammatory reaction leading to ILD, produces diseases of known etiology (Table 255-1) that are discussed in Chaps. 249 and 250. Sarcoidosis (Chap. 322) is prominent among granulomatous diseases of unknown cause in which ILD is an important feature.

Granulomatous Vasculitides

(See also Chap. 319) The granulomatous vasculitides are characterized by pulmonary angiitis (i.e., inflammation and necrosis of blood vessels) with associated granuloma formation (i.e., infiltrates of lymphocytes, plasma cells, epithelioid cells, or histiocytes, with or without the presence of multinucleated giant cells, sometimes with tissue necrosis). The lungs are almost always involved, although any organ system may be affected. Wegener's granulomatosis and allergic angiitis and granulomatosis (Churg-Strauss syndrome) primarily affect the lung but are associated with a systemic vasculitis as well. The granulomatous vasculitides generally limited to the lung include necrotizing sarcoid granulomatosis and benign lymphocytic angiitis and granulomatosis. Granulomatous infection and pulmonary angiitis due to irritating embolic material (e.g., talc) are important known causes of pulmonary vasculitis.

Lymphocytic Infiltrative Disorders

This group of disorders features lymphocyte and plasma cell infiltration of the lung parenchyma. The disorders either are benign or can behave as low-grade lymphomas. Included are angioimmunoblastic lymphadenopathy with dysproteinemia, a rare lymphoproliferative disorder characterized by diffuse lymphadenopathy, fever, hepatosplenomegaly, and hemolytic anemia, with ILD in some cases.

Lymphocytic Interstitial Pneumonitis

This rare form of ILD occurs in adults, some of whom have an autoimmune disease or dysproteinemia. It has been reported in patients with Sjögren's syndrome and HIV infection.

Lymphomatoid Granulomatosis

This multisystem disorder of unknown etiology is an angiocentric malignant (T cell) lymphoma characterized by a polymorphic lymphoid infiltrate, an angiitis, and granulomatosis. Although it may affect virtually any organ, it is most frequently characterized by pulmonary, skin, and central nervous system involvement.

Bronchocentric Granulomatosis

Rather than a specific clinical entity, bronchocentric granulomatosis (BG) is a descriptive histologic term that describes an uncommon and nonspecific pathologic response to a variety of airway injuries. There is evidence that BG is caused by a hypersensitivity reaction to Aspergillus or other fungi in patients with asthma. About half of the patients described have chronic asthma with severe wheezing and peripheral blood eosinophilia. In patients with asthma, BG probably represents one pathologic manifestation of allergic bronchopulmonary aspergillosis or another allergic mycosis. In patients without asthma, BG has been associated with RA and a variety of infections, including tuberculosis, echinococcosis, histoplasmosis, coccidioidomycosis, and nocardiosis. The chest roentgenogram reveals irregularly shaped nodular or mass lesions with ill-defined margins, which are usually unilateral and solitary, with upper-lobe predominance. Glucocorticoids are the treatment of choice, often with excellent outcome, although recurrences may occur as therapy is tapered or stopped.

Global Considerations

Limited epidemiologic data exists describing the prevalence or incidence of ILD in the general population. With a few exceptions, e.g., sarcoidosis, certain occupational and environmental exposures, there appear to be no significant differences in the prevalence or incidence of ILD among various populations. For sarcoidosis, there are important environmental, racial, and genetic differences