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InternalMed_Harrison. Although there is considerable variability in the relationships between the FEV1 and other physiologic abnormalities in COPD, certain generalizations may be made. The partial pressure of oxygen in arterial blood Pao2 usually remains near normal until the FEV1 is decreased to ~50% of predicted, and even much lower FEV1 values can be associated with a normal Pao2, at least at rest. An elevation of arterial level of carbon dioxide (Paco2) is not expected until the FEV1 is <25% of predicted and even then may not occur. Pulmonary hypertension severe enough to cause cor pulmonale and right ventricular failure due to COPD typically occurs in individuals who have marked decreases in FEV1 (<25% of predicted) and chronic hypoxemia (Pao2 <55 mmHg); however, recent evidence suggests that some patients will develop significant pulmonary hypertension independent of COPD severity (Chap. 304).


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InternalMed_Harrison. Nonuniform ventilation and ventilation-perfusion mismatching are characteristic of COPD, reflecting the heterogeneous nature of the disease process within the airways and lung parenchyma. Physiologic studies are consistent with multiple parenchymal compartments having different rates of ventilation due to regional differences in compliance and airway resistance. Ventilation-perfusion mismatching accounts for essentially all of the reduction in Pao2 that occurs in COPD; shunting is minimal. This finding explains the effectiveness of modest elevations of inspired oxygen in treating hypoxemia due to COPD and therefore the need to consider problems other than COPD when hypoxemia is difficult to correct with modest levels of supplemental oxygen.


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InternalMed_Harrison. By 1964, the Advisory Committee to the Surgeon General of the United States had concluded that cigarette smoking was a major risk factor for mortality from chronic bronchitis and emphysema. Subsequent longitudinal studies have shown accelerated decline in FEV1 in a dose-response relationship to the intensity of cigarette smoking, which is typically expressed as pack-years (average number of packs of cigarettes smoked per day multiplied by the total number –1 S.D. Mean +1 S.D.


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InternalMed_Harrison. % of Population (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 B Burrows et al: Am Rev Respir Dis 115:95, 1977; with permission.) of years of smoking). This dose-response relationship between reduced pulmonary function and cigarette smoking intensity accounts for the higher prevalence rates of COPD with increasing age. The historically higher rate of smoking among males is the likely explanation for the higher prevalence of COPD among males; however, the prevalence of COPD among females is increasing as the gender gap in smoking rates has diminished in the past 50 years.


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InternalMed_Harrison. 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. 314-2), 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. 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.


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InternalMed_Harrison. 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. 309). 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, whereas COPD results from smoking-related inflammation and damage. Determination of the validity of the Dutch hypothesis versus the British hypothesis awaits


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InternalMed_Harrison. viewed as largely an allergic phenomenon, whereas COPD results from smoking-related inflammation and damage. Determination of the validity of the Dutch hypothesis versus the British hypothesis awaits identification of all of the genetic predisposing factors for asthma and/or COPD, as well as the interactions between these postulated genetic factors and environmental risk factors.


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InternalMed_Harrison. 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. 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 with the development and progression of COPD remains to be proven.


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InternalMed_Harrison. Increased respiratory symptoms and airflow obstruction have been suggested to result from exposure to dust and fumes 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. Although nonsmokers in these occupations can develop some reductions in FEV1, the importance of dust exposure as a risk factor for COPD, independent of cigarette smoking, is not certain for most of these exposures. However, among coal miners, coal mine dust exposure was a significant risk factor for emphysema in both smokers and nonsmokers. In most cases, the magnitude of these occupational exposures on COPD risk is likely substantially less important than the effect of cigarette smoking.


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InternalMed_Harrison. 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 unproved. 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


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InternalMed_Harrison. 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. Although cigarette smoking is the major environmental risk fac tor for the development of COPD, the development of airflow obstruction in smokers is highly variable. Severe α1AT deficiency is a proven genetic risk factor for COPD; there is increasing evidence that other genetic determinants also exist.


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InternalMed_Harrison. α1 Antitrypsin Deficiency Many variants of the protease inhibitor (PI or SERPINA1) locus that encodes α1AT have been described. The common M allele is associated with normal α1AT levels. The S allele, associated with slightly reduced α1AT levels, and the Z allele, associated with markedly reduced α1AT levels, also occur with frequencies of >1% in 1703 most white populations. Rare individuals inherit null alleles, which lead to the absence of any α1AT 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 α1AT deficiency.


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InternalMed_Harrison. Although only approximately 1% of COPD patients are found to have severe α1AT 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 α1AT 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 α1AT deficiency, but only a small minority of these individuals has been identified. The clinical laboratory test used most frequently to screen for α1AT deficiency is measurement of the immunologic level of α1AT in serum (see “Laboratory Findings”).


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InternalMed_Harrison. A significant percentage of the variability in pulmonary function among PiZ individuals is explained by cigarette smoking; cigarette smokers with severe α1AT 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. Asthma and male gender also appear to increase the risk of COPD in PiZ subjects. Other genetic and/or environmental factors likely contribute to this variability. Specific treatment in the form of α1AT augmentation therapy is available for severe α1AT deficiency as a weekly IV infusion (see “Treatment,” below).


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InternalMed_Harrison. Specific treatment in the form of α1AT augmentation therapy is available for severe α1AT deficiency as a weekly IV infusion (see “Treatment,” below). The risk of lung disease in heterozygous PiMZ individuals, who have intermediate serum levels of α1AT (~60% of PiMM levels), is controversial. Several recent large 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.


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InternalMed_Harrison. Association studies have compared the distribution of variants in candidate genes hypothesized to be involved in the development of COPD in COPD patients and control subjects. However, the results have been quite inconsistent, often due to underpowered studies. However, a well-powered association study comprising 8300 patients and 7 separate cohorts found that a minor allele single nucleotide polymorphism (SNP) of MMP12 (rs2276109) associated with decreased MMP12 expression has a positive effect on lung function in children with asthma and in adult smokers. Recent genome-wide association studies have identified several COPD susceptibility loci, including a region near the hedgehog interacting protein (HHIP) gene on chromosome 4, a cluster of genes on chromosome 15 (including components of the nicotinic acetylcholine receptor), and a region within a gene of unknown function (FAM13A). A regulatory SNP upstream from the HHIP gene has been identified as one potential functional variant;


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InternalMed_Harrison. the nicotinic acetylcholine receptor), and a region within a gene of unknown function (FAM13A). A regulatory SNP upstream from the HHIP gene has been identified as one potential functional variant; the specific genetic determinants in the other genomic regions have yet to be definitively identified.


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InternalMed_Harrison. 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. Most individuals follow a steady trajectory of increasing pulmonary function with FEV1, % normal level at age 20 Age, year FIGURE 314-3 Hypothetical tracking curves of forced expiratory volume in 1 s (FEV1) for individuals throughout their life spans.


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InternalMed_Harrison. 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.) growth during childhood and adolescence, followed by a gradual decline with aging. Individuals appear to track in their quantile of pulmonary function based on 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. 314-3. Death or disability from COPD can result from a normal rate of decline after a


InternalMed_Harrison

InternalMed_Harrison. of the natural history of COPD is shown as a function of the influences on tracking curves of FEV1 in Fig. 314-3. 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.


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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 or walking on a treadmill. 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.


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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. Advanced disease may be accompanied by cachexia, 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-α). 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.


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InternalMed_Harrison. The hallmark of COPD is airflow obstruction (discussed above). Pulmonary function testing shows airflow obstruction with a reduction in FEV1 and FEV1/FVC (Chap. 306e). 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 lung parenchymal destruction characteristic of the disease. The degree of airflow obstruction is an important prognostic factor in COPD and is the basis for the Global Initiative for Lung Disease (GOLD) severity classification (Table 314-1). 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 rate than pulmonary function alone. In 2011, the GOLD added an additional classification system incorporating symptoms and exacerbation history; the utility of this


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InternalMed_Harrison. is a better predictor of mortality rate than pulmonary function alone. In 2011, the GOLD added an additional classification system incorporating symptoms and exacerbation history; the utility of this system remains to be defined.


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InternalMed_Harrison. Arterial blood gases and oximetry may demonstrate resting or exertional hypoxemia. Arterial blood gases provide additional information I Mild FEV1/FVC <0.7 and FEV1 ≥80% predicted II Moderate FEV1/FVC <0.7 and FEV1 ≥50% but <80% predicted III Severe FEV1/FVC <0.7 and FEV1 ≥30% but <50% predicted IV Very severe FEV1/FVC <0.7 and FEV1 <30% predicted Abbreviations: COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Lung Disease. Source: From the Global Strategy for Diagnosis, Management and Prevention of COPD 2014, © Global Initiative for Chronic Obstructive Lung Disease (GOLD), all rights reserved. Available from http://www.goldcopd.org.


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InternalMed_Harrison. FIGURE 314-4 Chest computed tomography scan of a patient with chronic obstructive pulmonary disease who underwent a left single-lung transplant. Notethereducedparenchymalmark-ings in the right lung (left side of figure) as compared to the left lung, representing emphysematous destruction of the lung, and mediasti-nal shift to the left, indicative of hyperinflation. 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.


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InternalMed_Harrison. Radiographic studies may assist in the classification of the type of COPD. Obvious bullae, paucity of parenchymal markings, or hyperlucency suggests 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. 314-4). From a practical perspective, the CT scan currently does little to influence therapy of COPD except in individuals considering surgical therapy for their disease (described below) and as screening for lung cancer.


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InternalMed_Harrison. Recent guidelines have suggested testing for α1AT deficiency in all subjects with COPD or asthma with chronic airflow obstruction. Measurement of the serum α1AT level is a reasonable initial test. For subjects with low α1AT levels, the definitive diagnosis of α1AT deficiency requires protease inhibitor (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).


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InternalMed_Harrison. 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 1705 currently suggestive, but not definitive, evidence that the use of inhaled glucocorticoids may alter mortality rate (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.


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InternalMed_Harrison. PHARMACOTHERAPY Smoking Cessation (See also Chap. 470) 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 smoking and educated about the benefits of quitting. An emerging body of evidence demonstrates that combining phar macotherapy with traditional supportive approaches considerably enhances the chances of successful smoking cessation. There are three principal pharmacologic approaches to the problem: bupropion; nicotine replacement therapy available as gum, transdermal patch, lozenge, inhaler, and nasal spray; and varenicline, a nicotinic acid receptor agonist/antagonist. Current recommendations from the U.S. Surgeon General are that all adult, nonpregnant smokers considering quitting be offered pharmacotherapy, in the absence of any


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InternalMed_Harrison. acid receptor agonist/antagonist. 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.


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


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InternalMed_Harrison. Anticholinergic Agents Ipratropium bromide improves symptoms and produces acute improvement in FEV1. Tiotropium, a long-acting anticholinergic, has been shown to improve symptoms and reduce exacerbations. Studies of both ipratropium and tiotropium have failed to demonstrate that either influences the rate of decline in FEV1. In a large randomized clinical trial, there was a trend toward reduced mortality rate in the tiotropium-treated patients that approached, but did not reach, statistical significance. Side effects are minor, and a trial of inhaled anticholinergics is recommended in symptomatic patients with COPD. Recent retrospective analyses raised the possibility that anticholinergic use is associated with increased cardiovascular events in the COPD population. This was not demonstrated in a large, prospective randomized trial of tiotropium.


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InternalMed_Harrison. Beta Agonists These provide symptomatic benefit. The main side effects are tremor and tachycardia. Long-acting inhaled β agonists, such as salmeterol or formoterol, have benefits comparable to ipratropium bromide. Their use is more convenient than short-acting agents. The addition of a β 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 β 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.


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InternalMed_Harrison. Inhaled Glucocorticoids Although a recent trial demonstrated an apparent benefit from the regular use of inhaled glucocorticoids on the rate of decline of lung function, a number of other well-designed randomized trials have not. Patients studied included those with mild to severe airflow obstruction and current and ex-smokers. Patients with significant acute response to inhaled β agonists were excluded from many of these trials, which may impact the generalizability of the findings. Their use has been associated with increased rates of oropharyngeal candidiasis and an increased rate of loss of bone density. Available data suggest that inhaled glucocorticoids reduce exacerbation frequency by ~25%. The impact of 1706 inhaled corticosteroids on mortality rates in COPD is controversial. A meta-analysis and several retrospective studies suggest a mortality benefit, but in a recently published randomized trial, differences in mortality rate approached, but did not reach, conventional


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InternalMed_Harrison. A meta-analysis and several retrospective studies suggest a mortality benefit, but in a recently published randomized trial, differences in mortality rate approached, but did not reach, conventional criteria for statistical significance. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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. Monitoring of blood theophylline levels is typically required to minimize toxicity. The selective phosphodiesterase 4 (PDE4) inhibitor roflumilast has been demonstrated to reduce exacerbation frequency in COPD patients with chronic bronchitis and a prior history of exacerbations; its effects on airflow obstruction and symptoms are modest.


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InternalMed_Harrison. Antibiotics As outlined below, there are strong data implicating bacterial infection as a precipitant of a substantial portion of exacerbations. Early trials of prophylactic or suppressive antibiotics, given either seasonally or year round, failed to show a positive impact on exacerbation occurrence. More recently, a randomized clinical trial of azithromycin, chosen for both its anti-inflammatory and antimicrobial properties, administered daily to subjects with a history of exacerbation in the past 6 months demonstrated a reduced exacerbation frequency and longer time to first exacerbation in the macrolide-treated cohort (hazard ratio, 0.73).


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InternalMed_Harrison. Oxygen Supplemental O2 is the only pharmacologic therapy demonstrated to unequivocally decrease mortality rates 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 rate. Patients meeting these criteria should be on continual oxygen supplementation because the mortality benefit is proportional to the number of hours per 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.


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InternalMed_Harrison. 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 IV α1AT augmentation therapy is available for individuals with severe α1AT 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 α1AT augmentation therapy has been shown, a randomized controlled trial of α1AT augmentation therapy has not definitively established the efficacy of augmentation therapy in reducing decline of pulmonary function. Eligibility for α1AT augmentation therapy requires a serum α1AT level <11 μM (approximately 50 mg/dL). Typically, PiZ individuals will qualify, although other rare types


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InternalMed_Harrison. of pulmonary function. Eligibility for α1AT augmentation therapy requires a serum α1AT level <11 μM (approximately 50 mg/dL). Typically, PiZ individuals will qualify, although other rare types associated with severe deficiency (e.g., null-null) are also eligible. Because only a fraction of individuals with severe α1AT deficiency will develop COPD, α1AT augmentation therapy is not recommended for severely α1AT-deficient persons with normal pulmonary function and a normal chest CT scan.


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InternalMed_Harrison. 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. Similar recommendations and limitations of evidence also exist for vaccination for Bordetella pertussis. 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 6to 12-month period.


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InternalMed_Harrison. 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. 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. Patients with an FEV1 <20% of predicted and either diffusely distributed emphysema on CT scan or diffusing capacity of lung for carbon monoxide (DLCO) <20% of predicted have an increased mortality rate after the procedure and thus are not candidates for LVRS.


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InternalMed_Harrison. 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 post-rehabilitation exercise capacity are important prognostic characteristics. Patients with upper lobe–predominant emphysema and a low post-rehabilitation exercise capacity are most likely to benefit from LVRS. Lung Transplantation (See also Chap. 320e) COPD is currently the second leading indication for lung transplantation (Fig. 314-4). Current recommendations are that candidates for lung transplantation should 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.


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InternalMed_Harrison. Exacerbations are a prominent feature of the natural history of COPD. Exacerbations are 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 stage III or IV; Table 314-1) on average have one to three episodes per year. However, some individuals with very severe airflow obstruction do not have frequent exacerbations; the history of prior exacerbations is a strong


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InternalMed_Harrison. on average have one to three episodes per year. However, some individuals with very severe airflow obstruction do not have frequent exacerbations; the history of prior exacerbations is a strong predictor of future exacerbations. Recently, an elevated ratio of the diameter of the pulmonary artery to aorta on chest CT has been associated with increased risk of COPD exacerbations.


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InternalMed_Harrison. 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. Studies suggest that acquiring a new strain of bacteria is associated with increased near-term risk of exacerbation and that bacterial infection/superinfection is involved in over 50% of exacerbations. 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.


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InternalMed_Harrison. The role of pharmacotherapy in reducing exacerbation frequency is less well studied. Chronic oral glucocorticoids are not recommended for this purpose. Inhaled glucocorticoids reduce the frequency of exacerbations by 25–30% in most 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. Similar magnitudes of reduction have been reported for anticholinergic and long-acting β-agonist therapy. The influenza vaccine has been shown to reduce exacerbation rates in patients with COPD. As outlined above, daily azithromycin administered to subjects with COPD and an exacerbation history reduces exacerbation frequency.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 β 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.


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InternalMed_Harrison. Patients are often treated initially with nebulized therapy, as such 1707 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. Oxygen Supplemental O2 should be supplied to keep arterial saturations ≥90%. Hypoxemic 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.


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InternalMed_Harrison. 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 rate, 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.


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InternalMed_Harrison. Invasive (conventional) mechanical ventilation via an endotracheal tube is indicated for patients with severe respiratory distress despite initial therapy, life-threatening hypoxemia, severe hypercarbia 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 rate 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 rate doubles over the next year


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InternalMed_Harrison. mechanical ventilatory support is 17–30% for that particular hospitalization. For patients age >65 admitted to the intensive care unit for treatment, the mortality rate doubles over the next year to 60%, regardless of whether mechanical ventilation was required.


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InternalMed_Harrison. Talmadge E. King, Jr. taBLe 315-1 Major CategorieS of aLVeoLar anD interStitiaL infLaMMatory Lung DiSeaSe Lung Response: Alveolitis, Interstitial Inflammation, and Fibrosis Known Cause 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 on one of the ILDs.


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InternalMed_Harrison. 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 those structures—as well as the perivascular and lymphatic tissues. The disorders in this heterogeneous group are classified together because of similar clinical, roentgenographic, physiologic, or pathologic manifestations. These disorders often are associated with considerable rates of morbidity and mortality, and there is little consensus regarding the best management of most of them.


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InternalMed_Harrison. 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 315-1). Each of these groups can be subdivided further 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.


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InternalMed_Harrison. Sarcoidosis (Chap. 390), idiopathic pulmonary fibrosis (IPF), and pulmonary fibrosis associated with CTDs (Chaps. 378, 382, 388, and 427) are the most common ILDs of unknown etiology. Among the ILDs of known cause, the largest group includes occupational and environmental exposures, especially the inhalation of inorganic dusts, organic dusts, and various fumes or gases (Chap. 311). A multidisciplinary approach—requiring close communication between clinician, radiologist, and when appropriate, pathologist—is often required to make the diagnosis. High-resolution computed tomography (HRCT) scanning improves the diagnostic accuracy and may eliminate the need for tissue examination in many cases, especially in IPF. For other forms, tissue examination, usually obtained by thoracoscopic lung biopsy, is critical to confirmation of the diagnosis.


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InternalMed_Harrison. 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. 315-1). 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, improve after treatment. The main differential diagnosis is between sarcoidosis (Chap. 390) and hypersensitivity pneumonitis (Chap. 310).


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InternalMed_Harrison. Inflammation and Fibrosis The initial insult is an injury to the epithelial surface that causes inflammation in the air spaces and alveolar walls. 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 Asbestos Residual of acute respiratory distress syndrome Fumes, gases Smoking-related Drugs (antibiotics, amiodarone, Desquamative interstitial pneumonia gold) and chemotherapy drugs Idiopathic pulmonary fibrosis Lymphocytic infiltrative disorders (lympho(usual interstitial pneumonia) cytic interstitial pneumonitis associated with connective tissue disease) Tuberous sclerosis, neurofibromatosis, Idiopathic lymphocytic Niemann-Pick disease, Gaucher disease, interstitial pneumonia Hermansky-Pudlak syndrome Bronchiolocentric patterns of interstitial pneumonia


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InternalMed_Harrison. Bronchiolocentric patterns of interstitial pneumonia Connective tissue diseases Gastrointestinal or liver diseases (Crohn disease, primary biliary cirrhosis, chronic Systemic lupus erythemaactive hepatitis, ulcerative colitis) tosus, rheumatoid arthritis, ankylosing spondylitis, systemic sclerosis, Sjögren syndrome, polymyositisdermatomyositis Goodpasture syndrome, idiopathic pulmonary hemosiderosis, isolated pulmonary capillaritis Lung Response: Granulomatous Hypersensitivity pneumonitis Inorganic dusts: beryllium, silica (organic dusts) Granulomatosis with polyangiitis (Wegener)


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InternalMed_Harrison. Lung Response: Granulomatous Hypersensitivity pneumonitis Inorganic dusts: beryllium, silica (organic dusts) Granulomatosis with polyangiitis (Wegener) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia, respiratory bronchiolitis/desquamative interstitial pneumonia, organizing pneumonia, diffuse alveolar damage (acute or organizing), 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. Dust, fumes, cigarette smoke, autoimmune conditions Drugs, infections, radiation, other diseases


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InternalMed_Harrison. Dust, fumes, cigarette smoke, autoimmune conditions Drugs, infections, radiation, other diseases FIGURE 315-1 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.)


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InternalMed_Harrison. HISTORY Duration of Illness Acute presentation (days to weeks), although 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), pneumoconioses, and CTDs. Episodic presentations are unusual and include eosinophilic pneumonia, hypersensitivity pneumonitis, COP, vasculitides, pulmonary hemorrhage, and Churg-Strauss syndrome.


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InternalMed_Harrison. Age Most patients with sarcoidosis, ILD associated with CTD, lymphangioleiomyomatosis (LAM), PLCH, and inherited forms of ILD (familial IPF, Gaucher disease, Hermansky-Pudlak syndrome) present between the ages of 20 and 40 years. Most patients with IPF are older than 60 years. Gender LAM and pulmonary involvement in tuberous sclerosis occur exclusively in premenopausal women. In addition, 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. IPF is more common in men. Because of occupational exposures, pneumoconioses also occur more frequently in men.


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InternalMed_Harrison. Family History Familial lung fibrosis has been associated with mutations in the surfactant protein C gene, the surfactant protein A2 gene, telomerase reverse transcriptase (TERT), telomerase RNA component (TERC), and the promoter of a mucin gene (MUC5B). Familial lung fibrosis is characterized by several patterns of interstitial pneumonia, including nonspecific interstitial pneumonia, desquamative interstitial pneumonia, and UIP. Older age, male sex, and a history of cigarette smoking have been identified as risk factors for familial lung fibro-1709 sis. Family associations (with an autosomal dominant pattern) have been identified in tuberous sclerosis and neurofibromatosis. Familial clustering has been identified increasingly in sarcoidosis. The genes responsible for several rare ILDs have been identified, i.e., alveolar microlithiasis, Gaucher disease, Hermansky-Pudlak syndrome, and Niemann-Pick disease, along with the genes for surfactant homeostasis in pulmonary alveolar


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InternalMed_Harrison. ILDs have been identified, i.e., alveolar microlithiasis, Gaucher disease, Hermansky-Pudlak syndrome, and Niemann-Pick disease, along with the genes for surfactant homeostasis in pulmonary alveolar proteinosis and for control of cell growth and differentiation in LAM.


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InternalMed_Harrison. Smoking History Two-thirds to 75% of patients with IPF and familial lung fibrosis have a history of smoking. Patients with PLCH, respiratory bronchiolitis/desquamative interstitial pneumonia (DIP), Goodpasture syndrome, respiratory bronchiolitis, and pulmonary alveolar proteinosis are usually current or former smokers. Occupational 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. 310-1), 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. 310). Symptoms may diminish or disappear after the patient leaves the site of exposure for several days; similarly, symptoms may reappear when the patient returns to the exposure site.


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InternalMed_Harrison. 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 because several processes may occur at the time of initial presentation or during the clinical course, e.g., HIV infection, organizing pneumonia, AIP, lymphocytic interstitial pneumonitis, and diffuse alveolar hemorrhage.


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InternalMed_Harrison. 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 those with sarcoidosis, silicosis, PLCH, hypersensitivity pneumonitis, lipoid pneumonia, or lymphangitis carcinomatosis, may have extensive parenchymal lung disease on chest imaging studies 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 middle or late stages of the disease, when findings of pulmonary hypertension and cor pulmonale may become evident (Chap. 304). Cyanosis and clubbing of the digits occur in some patients with advanced disease.


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InternalMed_Harrison. Antinuclear antibodies and anti-immunoglobulin antibodies (rheumatoid factors) are identified in some patients, even in the absence 1710 of a defined CTD. A raised lactate dehydrogenase (LDH) level is a nonspecific finding common to ILDs. Elevation of the serum level of angiotensin-converting enzyme is common in ILDs, especially 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 dilation and/or hypertrophy in the presence of pulmonary hypertension.


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InternalMed_Harrison. CHEST IMAGING STUDIES Chest X-Ray ILD may be first suspected on the basis of an abnormal chest radiograph, which most commonly reveals a bibasilar reticular pattern. A nodular or mixed pattern of alveolar filling and increased reticular markings also may be present. Subgroups 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.


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InternalMed_Harrison. Computed Tomography HRCT is superior to the plain chest x-ray for early detection and confirmation of suspected ILD (Fig. 315-2). In addition, 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.


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InternalMed_Harrison. 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 FIGURE 315-2 Idiopathic pulmonary fibrosis. High-resolution computed tomography image shows bibasal, peripheral predominant reticular abnormality with traction bronchiectasis and honeycombing. The lung biopsy showed the typical features of usual interstitial pneumonia.


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InternalMed_Harrison. (Chap. 306e). Forced expiratory volume in 1 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 but common in tuberous sclerosis and LAM). Pulmonary function studies have been proved to have prognostic value in patients with idiopathic interstitial pneumonias, particularly IPF and nonspecific interstitial pneumonia (NSIP).


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InternalMed_Harrison. 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 important, to mismatching of ventilation and perfusion (V. /Q. ). 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.


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InternalMed_Harrison. 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. Carbon dioxide (CO2) retention is rare and is usually a manifestation of end-stage disease.


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InternalMed_Harrison. 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 [dead space/tidal volume] ratio [Chap. 306e]), 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 and mirror


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InternalMed_Harrison. 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 and mirror the patient’s clinical course.


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InternalMed_Harrison. 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 315-2). The role of 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.


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InternalMed_Harrison. 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 the initiation of treatment. A definitive diagnosis avoids confusion and anxiety later in the clinical course if the patient does not respond to therapy or experiences 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 syndrome, or infection is suspected. If a specific diagnosis is not made by transbronchial biopsy, surgical lung biopsy by video-assisted thoracic surgery or open thoracotomy is


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InternalMed_Harrison. Sarcoidosis Lymphocytosis; CD4:CD8 ratio >3.5 most specific of diagnosis Organizing pneumonia Foamy macrophages; mixed pattern of increased cells characteristic; decreased CD4:CD8 ratio Diffuse alveolar bleeding Hemosiderin-laden macrophages, red blood cells Diffuse alveolar damage, Atypical hyperplastic type II pneumocytes drug toxicity Opportunistic infections Pneumocystis carinii, fungi, cytomegalovirustransformed cells Lymphangitic carcinomatosis, Malignant cells alveolar cell carcinoma, pulmonary lymphoma Alveolar proteinosis Milky effluent, foamy macrophages and lipoproteinaceous intraalveolar material (periodic acid–Schiff stain–positive) Pulmonary Langerhans cell Increased CD1+ Langerhans cells, electron histiocytosis microscopy demonstrating Birbeck granule in lavaged macrophage (expensive and difficult to perform) Asbestos-related pulmonary Dust particles, ferruginous bodies disease Berylliosis Positive lymphocyte transformation test to beryllium


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InternalMed_Harrison. Asbestos-related pulmonary Dust particles, ferruginous bodies disease Berylliosis Positive lymphocyte transformation test to beryllium Lipoidosis Accumulation of specific lipopigment in alveolar macrophages 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, and other major operative risks, especially in the elderly.


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InternalMed_Harrison. Although the course of ILD is variable, progression is common and often insidious. All treatable possibilities should be carefully considered. Because 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 with supplemental oxygen. Management of cor pulmonale may be required as the disease progresses (Chaps. 280 and 304). Pulmonary rehabilitation has been shown to improve the quality of life in patients with ILD.


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InternalMed_Harrison. Glucocorticoids are the mainstay of therapy for suppression of the inflammation present in ILD, but the success rate is low. There have been no placebo-controlled trials of glucocorticoids in ILD, and 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, hypersensitivity pneumonitis, 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.


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InternalMed_Harrison. 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 1711 (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 on glucocorticoids, a second agent (see below) often is added and the prednisone dose is lowered to or maintained at 0.25 mg/kg per day.


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InternalMed_Harrison. Cyclophosphamide, azathioprine (1–2 mg/kg lean body weight per day), and mycophenolate mofetil, with or without glucocorticoids, have been tried with variable success in IPF, vasculitis, progressive systemic sclerosis, 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 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. 320e). 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.


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InternalMed_Harrison. Clinical Manifestations Exertional dyspnea, a nonproductive cough, and inspiratory crackles with or without digital clubbing may be present on physical examination. HRCT lung scans typically show patchy, predominantly basilar, subpleural reticular opacities, often associated with traction bronchiectasis and honeycombing (Fig. 315-2). A definite UIP pattern on HRCT is highly accurate for the presence of a UIP pattern on surgical lung biopsy. Atypical findings that should suggest an alternative diagnosis include extensive ground-glass abnormality, nodular opacities, upper or midzone 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.


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InternalMed_Harrison. 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 usually is 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


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InternalMed_Harrison. 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 frequently are 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 usual interstitial pneumonia is used for patients in whom the


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InternalMed_Harrison. features are present in these situations, thus allowing separation of these lesions from the UIP-like pattern. Consequently, the term usual interstitial pneumonia is used for patients in whom the lesion is idiopathic and not associated with another condition.


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InternalMed_Harrison. Untreated patients with IPF show continued progression of their disease and have a high mortality rate. There is no effective therapy for IPF. Thalidomide appears to improve cough in patients with IPF. Chronic microaspiration secondary to gastroesophageal reflux may play a role in the pathogenesis and natural history of IPF. Gastroesophageal reflux (GER) therapy may be of benefit in IPF. In patients with IPF, treatment with the three-drug regimen of prednisone, azathioprine, and N-acetylcysteine (NAC) or warfarin (in IPF patients who lacked other indications for anticoagulation) has been shown to increase the risks of hospitalization and death. Patients with IPF and coexisting emphysema (combined pulmonary fibrosis and emphysema [CPFE]) are more likely to require longterm oxygen therapy and develop pulmonary hypertension and may have a more dismal outcome than those without emphysema.


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InternalMed_Harrison. Patients with IPF may have acute deterioration secondary to infections, pulmonary embolism, or pneumothorax. Heart failure and ischemic heart disease are common problems in patients with IPF, accounting for nearly one-third of deaths. These patients also commonly experience 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 ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with the UIP pattern; 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. No therapy has been found to


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


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InternalMed_Harrison. Patients should be referred early for lung transplant because of the unpredictability of disease progression (e.g., acute exacerbations) (Chap. 320e). This condition defines a subgroup of the idiopathic interstitial pneumonias that can be distinguished clinically and pathologically from UIP, DIP, AIP, and COP. Importantly, many cases with this histopathologic pattern occur in the context of an underlying disorder, such as a CTD, drug-induced ILD, or chronic hypersensitivity pneumonitis.


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InternalMed_Harrison. Clinical Manifestations Patients with idiopathic NSIP have clinical, serologic, radiographic, and pathologic characteristics highly suggestive of autoimmune disease and meet the criteria for undifferentiated CTD. Idiopathic NSIP is a subacute restrictive process with a presentation similar to that of 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. 315-3). Patchy areas of airspace consolidation and reticular abnormalities may be present, but honeycombing is unusual. Histologic Findings The key histopathologic feature of NSIP is 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.


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InternalMed_Harrison. Treatment 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 or mycophenolate mofetil. FIGURE 315-3 Nonspecific interstitial pneumonia. High-resolution computed tomography through the lower lung shows volume loss with extensive ground-glass abnormality, reticular abnormality, and traction bronchiectasis. There is sparing on the lung immediately adja-cent to the pleura. Histology showed a combination of inflammation and mild fibrosis.


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InternalMed_Harrison. ACUTE INTERSTITIAL PNEUMONIA (HAMMAN-RICH SYNDROME) Clinical Manifestations 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. 322) 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 common manifestations at presentation. Diffuse, bilateral, air-space opacification is present on the chest radiograph. HRCT scans show bilateral, patchy, symmetric areas of ground-glass attenuation. Bilateral areas of air-space consolidation also may be present. A predominantly subpleural distribution may be seen.


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InternalMed_Harrison. Histologic Findings 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. Treatment 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.


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InternalMed_Harrison. CRYPTOGENIC ORGANIZING PNEUMONIA Clinical Manifestations 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.


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InternalMed_Harrison. Histologic Findings Lung biopsy shows granulation tissue within small airways, alveolar ducts, and airspaces, with chronic inflammation in the surrounding alveoli. Foci of organizing pneumonia are a nonspecific reaction to lung injury found adjacent to other pathologic processes or as a component of other primary pulmonary disorders (e.g., cryptococcosis, granulomatosis with polyangiitis [Wegener], 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. Treatment Glucocorticoid therapy induces clinical recovery in two-thirds of patients. A few patients have rapidly progressive courses with fatal outcomes despite glucocorticoids.


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InternalMed_Harrison. Treatment Glucocorticoid therapy induces clinical recovery in two-thirds of patients. A few patients have rapidly progressive courses with fatal outcomes despite glucocorticoids. ILD ASSOCIATED WITH CIGARETTE SMOKING Desquamative Interstitial Pneumonia • CLINICAL MANIFESTATIONS DIP is a rare but distinct clinical and pathologic entity found almost 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.


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InternalMed_Harrison. HISTOLOGIC FINDINGS A diffuse and uniform accumulation of macrophages in the alveolar spaces is the hallmark of DIP. The macrophages contain golden, brown, or black pigment of tobacco smoke. There may be mild thickening of the alveolar walls by fibrosis and scanty inflammatory cell infiltration. TREATMENT Clinical recognition of DIP is important because the process is associated with a better prognosis (10-year survival rate is ~70%) in response to smoking cessation. There are no clear data showing that systemic glucocorticoids are effective in DIP.


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InternalMed_Harrison. 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 that of DIP. Crackles are often heard on chest examination and occur throughout inspiration; sometimes they continue into expiration. The process is best seen on HRCT lung scanning, which shows bronchial wall thickening, centrilobular nodules, ground-glass opacity, and emphysema with air trapping. There is a spectrum of CT features in asymptomatic smokers (and elderly asymptomatic individuals) that may not necessarily represent clinically relevant disease.


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InternalMed_Harrison. HISTOLOGIC FINDINGS The histologic findings in RB-ILD include alveolar macrophage accumulation in respiratory bronchioles, with a variable chronic inflammatory cell infiltrate in bronchiolar and surrounding alveolar walls and occasional peribronchial alveolar septal fibrosis. The pulmonary parenchyma may show presence of smoking-related emphysema. TREATMENT RB-ILD appears to resolve in most patients after smoking cessation alone.


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InternalMed_Harrison. Pulmonary Langerhans Cell Histiocytosis • CLINICAL MANIFESTATIONS 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 common pulmonary function abnormality is a markedly reduced DlCO, although varying degrees of


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InternalMed_Harrison. that reveals a combination of nodules and thin-walled cysts is virtually diagnostic of PLCH. The most common pulmonary function abnormality is a markedly reduced DlCO, although varying degrees of restrictive disease, airflow limita-1713 tion, and diminished exercise capacity may occur.


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InternalMed_Harrison. HISTOLOGIC FINDINGS 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 advances, fibrosis progresses to involve adjacent lung tissue, leading to pericicatricial air space enlargement, which accounts for the concomitant cystic changes. TREATMENT Discontinuance of smoking is the key treatment, resulting in clinical improvement in one-third of patients. Most patients with PLCH experience persistent or progressive disease. Death due to respiratory failure occurs in ~10% of patients.


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InternalMed_Harrison. Clinical findings suggestive of a CTD (musculoskeletal pain, weak ness, fatigue, fever, joint pain 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. For the majority of CTDs, with the exception of progressive system sclerosis, recommended


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InternalMed_Harrison. and secondary infections), complications of therapy (opportunistic infections), and associated malignancies. For the majority of CTDs, with the exception of progressive system sclerosis, recommended initial treatment for ILD includes oral glucocorticoids often in association with an immunosuppressive agent (usually oral or intravenous cyclophosphamide or oral azathioprine) or mycophenolate mofetil.


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InternalMed_Harrison. Progressive Systemic Sclerosis (PSS) • CLINICAL MANIFESTATIONS (See also Chap. 382) 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. The HRCT features of lung disease in PSS range from predominant ground-glass attenuation to a predominant reticular pattern and are mostly similar to idiopathic NSIP. HISTOLOGIC FINDINGS NSIP is the histopathologic pattern in most patients (~75%); the UIP pattern is rare (<10%).


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InternalMed_Harrison. HISTOLOGIC FINDINGS NSIP is the histopathologic pattern in most patients (~75%); the UIP pattern is rare (<10%). TREATMENT Therapy is similar to that in idiopathic NSIP. UIP in PSS has a better outcome than IPF. The most widely used initial treatment regimen is low-dose glucocorticoid therapy and an immunosuppressive agent, usually oral or pulse cyclophosphamide. There are no convincing data showing this regime to be efficacious, and there is concern that the risk of renal crisis rises substantially with corticosteroids. 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 • CLINICAL MANIFESTATIONS (See also Chap. 380)


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InternalMed_Harrison. Rheumatoid Arthritis • CLINICAL MANIFESTATIONS (See also Chap. 380) 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 syndrome (rheumatoid pneumoconiosis), pulmonary hypertension secondary to rheumatoid pulmonary vasculitis, organized pneumonia, and upper airway obstruction due to cricoarytenoid arthritis. HISTOLOGIC FINDINGS There are two primary histopathologic patterns of ILD that are observed in patients with ILD associated with RA: NSIP pattern and UIP pattern.


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InternalMed_Harrison. HISTOLOGIC FINDINGS There are two primary histopathologic patterns of ILD that are observed in patients with ILD associated with RA: NSIP pattern and UIP pattern. 1714 TREATMENT Little data exist to support the management of ILD in RA. Initial treatment of rheumatoid ILD, if required, is typically with oral glucocorticoids, which should be tried for 1–3 months. The potential benefit of anti-tumor necrosis factor α (TNF-α) therapy has been clouded by concerns about the development of a rapid and occasionally fatal lung disease in patients with RA-associated ILD treated with anti-TNF-α therapy.


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InternalMed_Harrison. Systemic Lupus Erythematosus • CLINICAL MANIFESTATIONS (See also Chap. 378) 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 organized pneumonia. Acute lupus pneumonitis characterized by pulmonary capillaritis leading to alveolar hemorrhage is uncommon. Chronic, progressive ILD is uncommon (<10%). 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. HISTOLOGIC FINDINGS The most common pathologic patterns seen include NSIP, UIP, LIP, and, on occasion, organizing pneumonia and amyloidosis.


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InternalMed_Harrison. HISTOLOGIC FINDINGS The most common pathologic patterns seen include NSIP, UIP, LIP, and, on occasion, organizing pneumonia and amyloidosis. TREATMENT There have been no controlled trials of treatment for ILD in SLE. Treatment involves the use of a glucocorticoid, either alone or, more often, in combination with an additional immunomodulating agent. (See also Chap. 388) 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 (NSIP pattern). 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.


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InternalMed_Harrison. HISTOLOGIC FINDINGS NSIP predominates over UIP, organizing pneumonia, or other patterns of interstitial pneumonia. TREATMENT The optimal treatment is unknown. The most widely used initial treatment is oral glucocorticoids. Fulminant disease may require high-dose intravenous methylprednisolone (1.0 g/d) for 3–5 days. Sjögren Syndrome • CliniCal manifestations (See also Chap. 383) General dryness and lack of airway secretion cause the major problems of hoarseness, cough, and bronchitis. HISTOLOGIC FINDINGS Lung biopsy is frequently required to establish a precise pulmonary diagnosis. Fibrotic NSIP is most common. Lymphocytic interstitial pneumonitis, lymphoma, pseudolymphoma, bronchiolitis, and bronchiolitis obliterans are associated with this condition. TREATMENT Glucocorticoids have been used in the management of ILD associated with Sjögren syndrome with some degree of clinical success.


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InternalMed_Harrison. DRUG-INDUCED ILD Clinical Manifestations 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, and 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.


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InternalMed_Harrison. Histologic Findings The patterns of lung injury vary widely and depend on the agent. Treatment Treatment consists of discontinuation of any possible offending drug and supportive care. (See Chap. 310)