on 16-Dec-2023 (Sat)

If we see that knowing is not the act of an outside spectator but of apartici- pator inside the natural and social scene, then the true object of knowledge resides in the consequences of directed action. When we take this point of view, if only by way of ahy- pothesis, the perplexities and difficulties of which we have been speaking vanish. For on this basis there will be as many kinds of known objects as there are kinds of effectively con-

The severity and characteristics of hepatic injury depend upon the blood vessels that are involved and the degree to which injury is related to passive congestion or diminished perfusion [1-3].

There are several well-recognized forms of vascular injury to the liver, including Budd-Chiari syndrome, hepatic sinusoidal obstruction syndrome, passive congestion due to heart failure, hepatic infarction, and ischemic hepatitis

Congestive hepatopathy refers to hepatic manifestations attributable to passive hepatic congestion, as occurs in patients with right-sided heart failure. Passive congestion often coexists with reduced cardiac output, making their relative contributions to hepatic injury intertwined. (See "Pathogenesis of liver injury in circulatory failure".)

Any cause of right-sided heart failure can result in hepatic congestion, including constrictive pericarditis, mitral stenosis, tricuspid regurgitation, cor pulmonale, and cardiomyopathy. Tricuspid regurgitation in particular can be associated with severe hepatic congestion because of the transmission of right ventricular pressure directly into the hepatic veins.

Liver dysfunction and passive congestion are common in patients with congenital heart disease and single-ventricle physiology who have undergone the Fontan procedure, which directs systemic venous return to the pulmonary artery with bypass of the right ventricle [5,6].

Patients with hepatic congestion are usually asymptomatic. In such patients, hepatic congestion may be suggested only by abnormal liver biochemical tests during routine evaluation.

Symptomatic patients may present with jaundice, which may be mistaken for biliary obstruction [7]. Patients with acute cardiac decompensation may have jaundice and a significant increase in serum aminotransferases, simulating acute viral hepatitis [8,9]. Right upper quadrant discomfort (due to stretching of the liver capsule) and ascites may also be present.

The term "acute cardiogenic liver injury" has been used when ischemic hepatitis occurs in the setting of congestive hepatopathy [13].

In addition to jaundice, patients may have hepatomegaly, which can be massive (normal liver span on physical examination as measured by the liver dullness is 10 to 12 cm for men and 8 to 11 cm for women; by ultrasound, a normal liver is typically less than 16 cm in the midclavicular line).

The liver edge in congestive hepatopathy is typically firm, smooth, and somewhat tender. Ascites may be detected. Splenomegaly is uncommon, but like cardiac ascites, is attributable to transmitted central venous hypertension rather than liver disease.

Hepatojugular reflux is generally present and is useful in differentiating hepatic congestion from either primary intrahepatic liver disease or Budd-Chiari syndrome. In patients with significant tricuspid regurgitation, the liver may be pulsatile, with palpable presystolic pulsations corresponding to prominent "v waves" on a right atrial pressure tracing. A loss of hepatic pulsatility in a patient with long-standing congestive hepatopathy suggests progression to cardiac cirrhosis.

The most common liver biochemical abnormality is a mild elevation in the serum bilirubin level, which occurs in up to 70 percent of patients [14]. The total serum bilirubin is usually less than 3 mg/dL, most of which is unconjugated [14,15].

The precise cause of the hyperbilirubinemia is uncertain. Contributing factors may include hepatocellular dysfunction, hemolysis, pulmonary infarction, canalicular obstruction due to distended hepatic veins, medications, and superimposed sepsis [16].

Serum bilirubin levels correlate with right atrial pressures but not with the cardiac output [ 16].

The serum alkaline phosphatase level is usually normal or only minimally elevated in acute heart failure even in the presence of jaundice, helping distinguish jaundice due to congestion from biliary obstruction. However, the serum alkaline phosphatase level may be elevated in chronic severe heart failure [17-19].

The serum gamma-glutamyl transpeptidase (GGT) may also be increased in patients with an acute exacerbation of heart failure [ 20].

Serum aminotransferase levels are elevated in about one-third of patients, but typically no more than two to three times the upper limit of normal.

Striking elevations in aminotransferases (exceeding 1000 international units/L or 50 times the upper limit of normal) may be seen in patients with hypotension due to heart failure and may cause diagnostic confusion with viral hepatitis [22].

Hypoalbuminemia is more likely to be caused by malnutrition and protein-losing gastroenteropathy due to increased intestinal lymphatic pressure.

Limited data suggested that hyperammonemic encephalopathy due to heart failure improved with lactulose therapy [26].

Other causes of liver dysfunction should also be considered, including biliary obstruction, acute or chronic viral hepatitis, hepatic infiltrative disorders, and drug or herbal medication toxicity, depending upon the clinical setting.

Serologic testing for viral hepatitis, hemochromatosis, Wilson disease (especially in a young person), autoimmune hepatitis, alpha-1 antitrypsin deficiency, celiac disease, and thyroid dysfunction can be obtained.

Imaging studies include right upper quadrant ultrasonography with Doppler studies of the portal and hepatic veins and hepatic artery, electrocardiogram, and echocardiography.

Patients with ascites should undergo a diagnostic paracentesis, which typically reveals a high ascitic protein content, usually greater than 2.5 g/dL, reflecting the relatively well-preserved serum albumin levels and the contribution of "hepatic lymph" to the ascites. The increased protein is presumed to be due to the rupture of hepatic lymphatics, which are rich in protein. The serum-to-ascites albumin gradient is ≥1.1, reflecting portal hypertension [36].

Before considering a percutaneous liver biopsy, careful attention should be given to coagulation parameters, and a percutaneous biopsy should not be performed in patients with ascites.

Care should be given to avoid excess diuresis, which could impair hepatic perfusion and precipitate zone 3 necrosis [12]. Of paramount importance is maintenance of cardiac output.

As noted above, patients may have an underlying coagulopathy, making them particularly sensitive to warfarin anticoagulation. Therefore, coagulation status should be monitored closely if warfarin anticoagulation is being considered. Similar concerns relate to other drugs that require hepatic metabolism.

However, increasing serum aminotransferases on day 3 and decreasing serum albumin on day 4 of a hospital admission for acute heart failure have been associated with adverse outcomes at six-month follow up [42].

Early histologic changes associated with passive congestion may resolve with medical therapy to treat the underlying cardiac condition. By contrast, prolonged hepatic congestion over months to years can lead to cirrhosis. Most of these patients have either constrictive pericarditis or mitral valve disease and secondary tricuspid regurgitation.

The Model for End-Stage Liver Disease (MELD) score excluding the international normalized ratio predicts outcomes in patients with congestive hepatopathy, who are frequently taking an anticoagulant [34,48].

Hepatocellular carcinoma may occur in patients with cardiac cirrhosis, particularly those who have had a Fontan procedure in childhood [49-51]

Constrictive pericarditis is associated with clinical and pathologic changes in the liver similar to those seen in the Budd-Chiari syndrome [52].

Patients with pericardial constriction may present with two types of complaints: those related to fluid overload, ranging from peripheral edema to anasarca; and those related to diminished cardiac output in response to exertion, such as fatigability and dyspnea on exertion. Constriction should be considered in any patient with an unexplained elevation in jugular venous pressure, particularly if there is a history of a predisposing condition. (See "Constrictive pericarditis: Diagnostic evaluation".)

Hepatomegaly, a pulsatile liver, massive ascites, and peripheral edema are common. By contrast, jaundice is characteristically absent, for unclear reasons [53].

Thus, a high index of suspicion for the diagnosis must be maintained. Important clues include elevated jugular venous pressure, Kussmaul's sign (a rise in the jugular venous pressure on inspiration), a pericardial knock, and pericardial calcification on chest radiograph. A correct diagnosis is critical since pericardiectomy is curative if performed early.

Chronic obstructive pulmonary disease (COPD) is a common respiratory condition characterized by cough, dyspnea, and airflow limitation [1].

Approximately 10 percent of individuals aged 40 years or older have COPD, although the prevalence varies between countries and increases with age [ 1-4].

Establishing a correct diagnosis of COPD is important because appropriate management can decrease symptoms (especially dyspnea), reduce the frequency and severity of exacerbations, improve health status, improve exercise capacity, and prolong survival [9].

COPD should be understood in the context of other closely related common respiratory conditions (emphysema, chronic bronchitis, and chronic obstructive asthma) that represent an overlapping spectrum of airway diseases.

Key indicators for considering a diagnosis of COPD

Symptoms

Dyspnea

Cough

Sputum

Risk factors

Smoking

Biomass fuel exposure

Asthma

Childhood infections

Prematurity

Family history

Comorbidities

Heart disease

Metabolic syndrome

Osteoporosis

Sleep apnea

Depression

Lung cancer

Skin wrinkling

Consider the diagnosis of COPD and perform spirometry if any of these indicators are present. These indicators are not diagnostic by themselves, but the presence of multiple key indicators increases the probability of a diagnosis of COPD. Spirometry is needed to establish a diagnosis of COPD.

In practice, the diagnosis of COPD requires all of the following (see 'Diagnosis' below):

● The presence of pulmonary symptoms (dyspnea, cough, or sputum production)

● The appropriate clinical context (most notably but not exclusively tobacco exposure) (table 1)

● Evidence of airflow limitation

Chronic bronchitis — Chronic bronchitis is defined as a chronic productive cough over a defined period, classically for at least three months in each of two successive years, in a patient in whom other causes of chronic cough (eg, bronchiectasis) have been excluded [1]. It may precede or follow development of airflow limitation [1,11,12]. This definition has been used in many studies, despite the arbitrarily selected symptom duration. By age 35 to 40 years, cigarette smokers may develop chronic bronchitis and start to have intermittent exacerbations of their symptoms even in the absence of airflow obstruction [13].

Emphysema — Emphysema describes enlargement of the airspaces distal to the terminal bronchioles that is accompanied by destruction of the airspace walls, a pathologic finding frequently seen in patients with COPD [14]. This finding manifests clinically with decreased breath sounds and evidence of hyperinflation of the lungs on examination or imaging; it is frequently associated with dyspnea. Emphysema is classically not accompanied by macroscopic fibrosis. While emphysema can exist in individuals who do not have airflow limitation, it is more common among patients who have moderate or severe airflow obstruction [1,15-17].

Airflow limitation — Airflow limitation is physiologically defined as an abnormally reduced ability to exhale efficiently. The severity and presence of airflow limitation are determined by evaluating the forced expiratory volume in one second (FEV₁) and the ratio of the FEV₁ to the total forced expiratory volume (aka, forced vital capacity [FVC]).

Airflow limitation may be fixed or may change in response to exogenous factors (eg, environmental exposure, temperature, and medications). Asthma is defined by significant variability in airflow obstruction, whereas COPD is characterized by obstruction that is not fully reversible with medication.

Asthma — The Global Initiative for Asthma (GINA) gives the following definition of asthma: "Asthma is a chronic inflammatory disorder of the airways that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. These episodes are associated with widespread, but variable, airflow obstruction that is often reversible either spontaneously or with treatment" [1].

The episodic nature of the symptoms and reversibility of airflow obstruction are clinical features that help distinguish asthma from COPD. However, adults with longstanding asthma may develop persistent airflow limitation. Distinguishing these patients from those with COPD is difficult, particularly in the context of additional COPD risk factors ( table 1).

COPD – Patients with emphysema or chronic bronchitis and persistent postbronchodilator airflow limitation meet the definition of COPD. Chronic bronchitis, emphysema, and postbronchodilator airflow limitation commonly occur together [20]

Asthma and COPD – Patients with asthma whose airflow limitation does not remit completely and who have other appropriate clinical risk factors (eg, older age, exposure history) are considered to have both asthma and COPD. The etiology and pathogenesis of COPD in such patients may be different from that of other COPD patients (table 2).

While descriptors "asthma and COPD overlap (ACO)" and "COPD-A" have been proposed to identify patients with airway disease who have features of both asthma and COPD, the topic remains controversial. No single, universally accepted definition has emerged. Central to most of the proposed definitions are age >40 years, history of asthma at a younger age, persistent postbronchodilator airflow obstruction, and evidence of partial bronchodilator reversibility.

Peripheral eosinophilia is recommended by GOLD and our authors for use clinically to guide pharmacotherapy in all patients with COPD. (See "Stable COPD: Follow-up pharmacologic management", section on 'Blood eosinophils, inhaled corticosteroids, and exacerbations'.)

Subgroups of COPD patients with eosinophilia may experience clinical improvement with biologic medications shown to have benefit in asthma.

Pre-COPD – Patients with chronic bronchitis or emphysema without irreversible airway obstruction do not have COPD but are at high risk for developing the disease [25,26]. The term "pre-COPD" is used to identify such individuals who have either respiratory symptoms, radiographic abnormalities consistent with COPD, or early lung function changes in the context of COPD risk factors but do not have airway obstruction as defined by FEV₁/FVC <0.7. There is not full consensus on the defining features of pre-COPD, but diagnostic criteria have been proposed (table 3) [1,27,28].

Epidemiologic studies suggest that nearly 50 percent of current and former smokers without airway obstruction have respiratory symptoms, which correlate with reduced exercise capacity, radiographic emphysema and wall thickening, and lung function at the lower end of the normal range [16,17]. Those with borderline airway obstruction (FEV₁/FVC <0.75), greater smoking history, and chronic bronchitis have an increased likelihood of subsequent COPD diagnosis [29]

While many of these "pre-COPD" patients are treated off-label with bronchodilators or inhaled glucocorticoids, one large trial failed to show improvement in respiratory symptoms or quality of life with dual long-acting bronchodilator therapy (indacaterol-glycopyrrolate) versus placebo in this population [30].

Other airway diseases – Patients with airflow limitation due to diseases that have a known etiology or a specific pathology (eg, cystic fibrosis, bronchiectasis, obliterative bronchiolitis) are not considered to have COPD. However, these exclusions are loosely defined [31].

In a given individual, the pattern of pathologic changes depends on features of the underlying disease (eg, chronic bronchitis, emphysema, alpha-1 antitrypsin deficiency), genetic susceptibility, and disease severity [1].

Airways – In the airways, COPD results in chronic inflammation, increased numbers of goblet cells, mucus gland hyperplasia, fibrosis, as well as narrowing in and loss of small airways. In addition, airway collapse frequently occurs due to the loss of tethering caused by emphysematous destruction of alveolar walls [15]. Among patients with chronic bronchitis who have mucus hypersecretion, an increased number of goblet cells and enlarged submucosal glands are typically seen.

Lung parenchyma – Emphysema affects the structures distal to the terminal bronchiole, consisting of the respiratory bronchiole, alveolar ducts, alveolar sacs, and alveoli, known collectively as the acinus. These structures in combination with their associated capillaries and interstitium form the lung parenchyma. The part of the acinus that is affected by permanent dilation or destruction determines the subtype of emphysema.

• Proximal acinar (also known as centrilobular) emphysema refers to abnormal dilation or destruction of the respiratory bronchiole, the central portion of the acinus. It is commonly associated with cigarette smoking and is the most common emphysema subtype seen in patients with COPD. Centrilobular emphysema is also seen in coal workers’ pneumoconiosis.

• Panacinar emphysema refers to enlargement or destruction of all parts of the acinus. Diffuse panacinar emphysema is a characteristic of alpha-1 antitrypsin deficiency, although it can be seen in combination with proximal acinar emphysema in other patients with COPD. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency".)

• In distal acinar (also known as paraseptal) emphysema, the alveolar ducts are predominantly affected. Distal acinar emphysema may occur alone or in combination with proximal acinar and panacinar emphysema. When it occurs alone, extensive subpleural paraseptal emphysema may be associated with spontaneous pneumothorax, but it is otherwise of little clinical significance.

Pulmonary vasculature – Changes in the pulmonary vasculature in COPD include intimal hyperplasia and smooth muscle hypertrophy/hyperplasia, which are thought to be due to chronic hypoxic vasoconstriction of the small pulmonary arteries [43].

Diagnosis of chronic obstructive pulmonary disease: Clinical features

History

Risk factors Family history Smoking history Age at initiation Average amount smoked per day since initiation Date when stopped smoking or a current smoker Environmental history The chronologically taken environmental history may disclose important risk factors for COPD History of childhood pulmonary infections, HIV, or tuberculosis Asthma

Symptoms Dyspnea Ask about the amount of effort required to induce uncomfortable breathing. Many individuals will deny symptoms of dyspnea, but will have reduced their activity levels substantially. Cough Cough with or without sputum production should be an indication for spirometric testing. The presence of chronic cough and sputum has been used to define chronic bronchitis. Wheezing Wheezing or squeaky noises occurring during breathing indicate the presence of airflow obstruction Acute chest illnesses Inquire about occurrence and frequency of episodes of increased cough and sputum with wheezing, dyspnea, or fever

Physical examination

Physical findings are generally present only with severe disease

Chest The presence of emphysema (only when severe) is indicated by: overdistention of the lungs in the stable state (chest held near full inspiratory position at end of normal expiration, low diaphragmatic position), decreased intensity of breath and heart sounds, and prolonged expiratory phase Evidence of airflow obstruction: wheezes during auscultation on slow or forced breathing and prolongation of forced expiratory time Frequently observed with severe disease (characteristic, but not diagnostic): pursed-lip breathing, use of accessory respiratory muscles, retraction of lower interspaces

Other Unusual positions to relieve dyspnea at rest Digital clubbing is NOT typical in COPD (even with associated hypoxemia) and suggests other diagnoses (eg, lung cancer, bronchiectasis, pulmonary fibrosis) Mild dependent edema may be seen in the absence of right heart failure

Symptoms and pattern of onset — The three cardinal symptoms of COPD are dyspnea, chronic cough, and sputum production; the most common early symptom is exertional dyspnea. Less common symptoms include wheezing and chest tightness (table 4A). However, any of these symptoms may develop independently and with variable intensity.

Patients who have an extremely sedentary lifestyle but few complaints – These patients require careful questioning to elicit a history that is suggestive of COPD. Some patients unknowingly avoid exertional dyspnea by shifting their expectations and limiting their activity. They may be unaware of the extent of their limitations or that their limitations are due to respiratory symptoms, although they may complain of fatigue

Patients who present with progressive dyspnea and chronic cough – For these patients, dyspnea may initially be noticed only during exertion. However, it eventually becomes noticeable with progressively less exertion or even at rest. The chronic cough is characterized by the insidious onset of sputum production, which occurs in the morning initially but may progress to occur throughout the day. The daily sputum volume rarely exceeds 60 milliliters. The sputum is usually mucoid but becomes more purulent during exacerbations

Patients who present with intermittent pulmonary symptoms and signs – These patients have minimal symptoms at baseline but episodically develop some of the following: cough, purulent sputum, wheezing, fatigue, and dyspnea. Typically, the interval between exacerbations decreases as the severity of the COPD increases. This symptom complex can be a diagnostic challenge due to overlap with other common chronic diseases. For example, the combination of intermittent wheezing and dyspnea may lead to an incorrect diagnosis of asthma. Conversely, other illnesses with similar episodic manifestations (eg, heart failure, bronchiectasis, bronchiolitis) are often incorrectly diagnosed as a COPD exacerbation (table 5). (See "COPD exacerbations: Management".)

Approximately 62 percent of patients with moderate to severe COPD report variability in symptoms (eg, dyspnea, cough, sputum, wheezing, or chest tightness) over the course of the day or week to week; morning is typically the worst time of day [45].

Patients with COPD may experience weight gain (due to activity limitations), weight loss (possibly due to dyspnea while eating or increased metabolic work of breathing), limitation of activity (including sexual), cough, syncope, or feelings of depression or anxiety. Weight loss generally reflects more advanced disease and is associated with a worse prognosis.

Comorbid diseases that may accompany COPD include lung cancer, bronchiectasis, cardiovascular disease, osteoporosis, metabolic syndrome, skeletal muscle weakness, anxiety, depression, and cognitive dysfunction.

For patients presenting with respiratory symptoms, it is critical to assess for the genetic, developmental, and environmental risk factors that can predispose to the development of COPD (table 4A) [1,27,52].

With enough smoking, almost all smokers will develop measurably reduced lung function [9]. While studies have shown an overall "dose-response curve" for smoking and lung function, some individuals develop severe disease with fewer pack-years and others have minimal to no symptoms despite many pack-years [9].

The amount and duration of smoking contribute to disease severity [1,55-57]. Thus, a key step in the evaluation of patients with suspected COPD is to ascertain the number of pack-years smoked (packs of cigarettes per day multiplied by the number of years). A smoking history should include the age of starting and the age of quitting, as patients may underestimate the number of years they smoked.

The exact threshold for the duration/intensity of cigarette smoking that will result in COPD varies from one individual to another. In the absence of an additional genetic/environmental/occupational predisposition, smoking less than 10 to 15 pack-years of cigarettes is unlikely to result in COPD.

History of fume and dust exposure – The environmental/occupational history may disclose other important risk factors for COPD, such as exposure to fumes or organic or inorganic dusts, including household biomass smoke. These exposures help to explain the significant minority of patients with COPD who never smoked [55,58,59].

Certain pulmonary and systemic infections are known to cause permanent structural changes in the lung that predispose to COPD. In particular, childhood pneumonias, tuberculosis infection, and human immunodeficiency virus (HIV) are associated with high risk for later development of COPD [52].

Similarly, premature birth and early-life asthma may affect the development of the lung and increase the risk of COPD. A history of asthma is also important to elicit because poorly controlled asthma in adulthood may progress to fixed airflow limitation and COPD [ 58,60].

Mild disease – In mild disease, the physical examination may be normal. Subtle clues include prolonged expiratory time and faint end-expiratory wheezes on forced exhalation.

Moderate to severe disease – As the severity of the airway obstruction increases, physical examination may reveal hyperinflation (eg, increased resonance to percussion), decreased breath sounds, wheezes, crackles at the lung bases, and/or distant heart sounds [61]. Features of severe disease include an increased anteroposterior diameter of the chest ("barrel-shaped" chest) and a depressed diaphragm with limited movement based on chest percussion.

End-stage disease and chronic respiratory failure – Patients with end-stage COPD may adopt positions that relieve dyspnea, such as leaning forward with arms outstretched and weight supported on the palms or elbows. This posture may be evident during the examination or may be suggested by the presence of callouses or swollen bursae on the extensor surfaces of forearms. Other physical examination findings include use of the accessory respiratory muscles of the neck and shoulder girdle, expiration through pursed lips, paradoxical retraction of the lower interspaces during inspiration (ie, Hoover sign) [62,63], cyanosis, asterixis due to severe hypercapnia, and an enlarged, tender liver due to right heart failure. Neck vein distention may also be observed because of increased intrathoracic pressure, especially during expiration.

Adjunctive signs – Yellow stains on the fingers due to nicotine and tar from burning tobacco are a clue to ongoing and heavy cigarette smoking [64]. Clubbing of the digits is not typical in COPD (even with associated hypoxemia). Its presence suggests comorbidities such as lung cancer, interstitial lung disease, or bronchiectasis.

Whom to evaluate — Further diagnostic evaluation for COPD is appropriate in adults who report dyspnea, chronic cough, or chronic sputum production, or who have had a gradual decline in activity level, particularly if they have risk factors for COPD (eg, cigarette smoking, indoor biomass smoke) (table 4A) [1,56].

The CAPTURE questionnaire (Chronic obstructive pulmonary disease Assessment in Primary care To identify Undiagnosed Respiratory disease and Exacerbation risk) is a well-validated tool that can help identify occultly symptomatic patients who would likely benefit from therapy for COPD and would therefore be candidates for diagnostic evaluation using spirometry (table 6) [65,66].

Based both on the post hoc analysis of results from the CAPTURE screening trial [67] and the increased emphasis on symptoms rather than airflow limitation as a driver of therapeutic strategies [1], use of CAPTURE without peak flow measurements may identify patients appropriate for further evaluation and therapy. Patients with a questionnaire score of 0 to 2 are at lower risk, whereas those with scores 3 to 6 should undergo spirometric evaluation.

Asymptomatic and nonsmoking individuals with mild airflow obstruction but no history of asthma do not have the same progressive decline in lung function that is observed among individuals who have a similar degree of airflow obstruction and are symptomatic or continue to smoke [70].

How to evaluate — Patients at risk for COPD should be evaluated with spirometry; we also typically obtain laboratory testing for dyspnea (eg, complete blood count, thyroid-stimulating hormone, N-terminal pro hormone brain natriuretic peptide [BNP]) and a chest radiograph to assess for other cardiac and pulmonary conditions.

The most important values measured during spirometry are the forced expiratory volume in one second (FEV₁) and the forced vital capacity (FVC). The postbronchodilator ratio of FEV₁/FVC determines whether nonreversible airflow limitation is present [1]; the postbronchodilator percent predicted value for FEV₁ determines the severity of airflow limitation (algorithm 1).

The ratio of FEV ₁/FVC is not used to determine severity of airflow limitation because FVC often decreases with increasing obstruction due to air trapping or premature termination of exhalation.

Patients with significant smoking exposure and abnormal prebronchodilator FEV₁/FVC, but normal postbronchodilator FEV₁/FVC, do not meet diagnostic criteria for COPD; however, they are at high risk for developing COPD. Such patients comprised 6 percent of former or current heavy smokers in one cohort [73]. Compared with smokers without prebronchodilator obstruction, these patients had a higher likelihood of progression to COPD (hazard ratio [HR] 6.2, 95% CI 4.6-8.3), with 61 percent (versus 14 percent) progressing to COPD within five years [73]. We reassess this group of patients with repeat spirometry after one year, or earlier if they have worsening symptoms.

Threshold for airflow limitation – The ideal threshold for establishing airflow limitation in the diagnosis of COPD has not been empirically determined. We agree with the GOLD recommendations, which support the simple and well-established use of postbronchodilator FEV₁/FVC <0.7 as the threshold for nonreversible airflow limitation [1].

However, the FEV₁/FVC ratio decreases with age, so use of the fifth percentile lower limit of normal (LLN) of the FEV₁/FVC ratio (or, equivalently, a z-score of -1.645) rather than the absolute value of <0.7 has been advocated by some as a dividing point for the diagnosis of COPD and other obstructive lung diseases [74-79].

In practice, the adverse consequences of overdiagnosis of COPD in the elderly by use of a fixed ratio are somewhat mitigated by checking spirometry only in patients with symptoms and risk factors for COPD, but underdiagnosis of younger persons with abnormal airflow for age remains a concern.

Alternatives to FEV₁/FVC – The forced expiratory volume in six seconds (FEV₆), obtained by stopping the expiratory effort after six seconds rather than at cessation of airflow, is an acceptable surrogate for the FVC [83-87]. The advantages of the FEV₁/FEV₆ include less frustration by the patient and technician trying to achieve an end-of-test plateau, less chance of syncope, shorter testing time, and better repeatability, without loss of sensitivity or specificity.

Plain chest radiographs have a poor sensitivity for detecting COPD. As an example, only about half of patients with COPD of moderate severity are identified as having COPD by a plain chest radiograph (ie, sensitivity of 50 percent).

Radiographic features suggestive of COPD (usually seen in advanced disease) include:

• Rapidly tapering vascular shadows, increased radiolucency of the lung, a flat diaphragm, and a long, narrow heart shadow on a frontal radiograph (image 1).

• A flat diaphragmatic contour and an increased retrosternal airspace on a lateral radiograph (image 2). These findings are due to hyperinflation.

• Bullae, defined as radiolucent areas larger than one centimeter in diameter and surrounded by arcuate hairline shadows. They are due to locally severe disease and may or may not be accompanied by widespread emphysema (image 3).

• When advanced COPD leads to pulmonary hypertension and cor pulmonale, prominent hilar vascular shadows and encroachment of the heart shadow on the retrosternal space may be seen [88,89]. The cardiac enlargement may become evident only by comparison with previous chest radiographs.

Expiratory scans, particularly when used in conjunction with the inspiratory scans, can help to assess nonemphysematous air trapping as a surrogate measure for small airway abnormalities [95]

In the absence of other findings, CT-detected emphysema, air trapping, and airway remodelling involving a significant portion of the lungs is highly suggestive of COPD, and some have advocated for these findings as an alternative diagnostic pathway [52]. Because spirometry has a larger role in disease staging, is more cost-effective, and avoids unnecessary radiation exposure, we do not favor this approach unless spirometry cannot be obtained.

Centriacinar emphysema occurs preferentially in the upper lobes and produces holes in the center of secondary pulmonary lobules. The walls of emphysematous spaces are usually imperceptible, but central vessels may be visible (image 4). In contrast, the walls of cysts in pulmonary Langerhans histiocytosis, another cystic lung disease of cigarette smokers, are thicker (image 5)

Panacinar emphysema more commonly involves the lung bases and involves the entire secondary pulmonary lobule (image 6). Panacinar emphysema can cause a generalized paucity of vascular structures. Among patients with alpha-1 antitrypsin deficiency, panacinar emphysema is the more common pattern.

Paraseptal (distal acinar) emphysema produces small, subpleural collections of gas located in the periphery of the secondary pulmonary lobule (image 7). It is considered to be the precursor of bullae (image 8).

The diagnosis of COPD is confirmed by the following [1,100]:

● Spirometry demonstrating airflow limitation (ie, a forced expiratory volume in one second/forced vital capacity [FEV₁/FVC] ratio less than 0.7 or below the lower limit of normal [LLN]) that is incompletely reversible after the administration of an inhaled bronchodilator (table 4A-B). (See 'Spirometry' above.)

● Absence of an alternative explanation for the symptoms and airflow limitation (table 5) [1].

Typically, persistent airflow limitation on pulmonary function testing and absence of radiographic features of heart failure or interstitial lung disease direct the clinician to a narrower differential, which includes COPD, chronic obstructive asthma, bronchiectasis, tuberculosis, constrictive bronchiolitis, and diffuse panbronchiolitis [1]. Importantly, these conditions are not mutually exclusive and commonly occur together. For example, patients with asthma may develop COPD, and patients with COPD may have concurrent bronchiectasis.

As an example, a patient who has suffered from atopic asthma since childhood and smoked cigarettes for 15 years in their twenties and thirties could present in their fifties with a combination of asthma and COPD. Recognizing the coexistence of these diseases is essential in devising a treatment plan that reflects both underlying disease processes.

Chronic bronchitis with normal spirometry – A small portion of cigarette smokers have a chronic productive cough for three months in each of two successive years but do not have airflow limitation on pulmonary function tests. They are not considered to have COPD, although they may develop COPD if they continue to smoke.

Conditions associated with central airway obstruction

Malignant

Nonmalignant

Primary endoluminal malignancy Bronchogenic Adenoid cystic Mucoepidermoid Carcinoid Plasmacytoma Metastatic carcinoma to the airway Bronchogenic Renal cell Breast Thyroid Colon Sarcoma Melanoma Laryngeal and nasopharyngeal carcinoma Esophageal carcinoma Mediastinal tumors Thymic carcinoma Thyroid carcinoma Germ cell tumors (eg, teratoma) Lymphadenopathy Associated with any of the above malignancies Lymphoma

Benign airway tumors Squamous cell papilloma Hamartoma Lymphadenopathy Sarcoidosis Infectious (ie, tuberculosis) Vascular Vascular ring Vascular aneurysm Cartilage Relapsing polychondritis Granulation tissue Endotracheal tubes Tracheostomy tubes Airway stents Foreign bodies Surgical anastomosis (eg, post resection or transplant) Granulomatosis with polyangiitis (Wegener) Rhinoscleroma (klebsiella infection) Pseudotumor Endobronchial pseudotumor Hyperdynamic Tracheomalacia Bronchomalacia Webs Idiopathic progressive subglottic stenosis Tuberculosis Sarcoidosis Other Goiter Mucus plug Vocal cord paralysis Airway hematoma Burn/smoke injury Epiglottitis Blood clot Amyloid

Central airway obstruction – Central airway obstruction can be caused by numerous benign and malignant processes and can mimic COPD with a slowly progressive dyspnea on exertion followed by dyspnea with minimal activity (table 7). Monophonic wheezing or stridor may be present. Symptoms are minimally improved by inhaled bronchodilator, if at all. A high index of suspicion is needed as conventional chest radiographs are rarely diagnostic. Though insensitive, flow-volume loops can show the characteristic changes of central airway obstruction, frequently before abnormalities in the spirometric volumes are noted (figure 1 and figure 2) [101]. A high-resolution computed tomography (HRCT) scan with three-dimensional reconstruction can be helpful. The gold standard for diagnosis is direct visualization.

Bronchiectasis – Bronchiectasis, a condition of abnormal widening of the bronchi that is associated with chronic or recurrent infection, shares many clinical features with COPD, including inflamed and easily collapsible airways, obstruction to airflow, and exacerbations characterized by increased dyspnea and sputum production. Bronchiectasis is suspected on the basis of prominent symptoms of cough and daily mucopurulent sputum production. The diagnosis is usually established clinically based on the characteristic cough and sputum production and the presence of bronchial wall thickening and luminal dilatation on chest CT scans.

Heart failure – Heart failure is a common cause of dyspnea among middle-aged and older patients and some patients experience chest tightness and wheezing with fluid overload due to heart failure. Occasionally, airflow limitation is noted, although a restrictive pattern is more common. Heart failure is usually differentiated by the presence of fine basilar crackles, radiographic evidence of an increased heart size, and pulmonary edema. The brain natriuretic peptide (BNP) is typically increased in heart failure but can also be increased during right heart strain from cor pulmonale.

Tuberculosis – In an area endemic for tuberculosis, the overall prevalence of airflow obstruction was 31 percent among those with a past history of tuberculosis compared with 14 percent among those without [102,103]. This association was unchanged after adjustment for respiratory disease in childhood, smoking, and exposure to dust and smoke. Thus, tuberculosis is both a risk factor for COPD and a potential comorbidity [1].

Constrictive bronchiolitis – Constrictive bronchiolitis, also known as bronchiolitis obliterans, is characterized by submucosal and peribronchiolar fibrosis that causes concentric narrowing of the bronchiolar lumen. Constrictive bronchiolitis is most commonly seen following inhalation injury, transplantation (eg, bone marrow, lung), or in the context of rheumatoid lung or inflammatory bowel disease (table 8). Symptoms include progressive onset of cough and dyspnea associated with hypoxemia at rest or with exercise. Crackles may be present. Pulmonary function tests show a progressive and irreversible airflow limitation. Findings on inspiratory CT scan include centrilobular bronchial wall thickening, bronchiolar dilation, tree-in-bud pattern, and a mosaic ground-glass attenuation pattern.

Lymphangioleiomyomatosis – Lymphangioleiomyomatosis (LAM) is seen primarily in young females of childbearing age. Pulmonary function testing frequently reveals mild airflow obstruction, although a mixed obstructive-restrictive pattern may be seen. CT scans typically demonstrate small, thin-walled cysts that can at times be confused with emphysema. However, the airspaces in emphysema are not actually cysts but are caused by the destruction of alveolar walls and permanent enlargement of distal airspaces, so the "walls" are typically inapparent.

Etiologic evaluation, including alpha-1 antitrypsin testing — If not performed prior to establishing the diagnosis, a new diagnosis of COPD should prompt a search for underlying etiologic factors. For many patients, the etiology is long-term cigarette smoking. However, it is important to review with the patient whether underlying asthma, workplace exposures, indoor use of biomass fuel, a prior history of tuberculosis, or familial predisposition is contributory because mitigation of ongoing exposures may reduce disease progression (table 2). (See 'Risk factors, including smoking and inhalational exposures' above and "Chronic obstructive pulmonary disease: Risk factors and risk reduction".)

It is appropriate to test all patients with COPD for alpha-1 antitrypsin (AAT) deficiency by obtaining an AAT serum level and AAT genotyping (algorithm 2) [1,104,105].

Exercise capacity — Objectively measured exercise impairment is a strong signal of overall health status and a predictor of prognosis in COPD [106,107]. For patients with COPD, we perform a formal six-minute walk test with ambulatory oximetry measurement. This allows for assessment of exercise capacity as well as a determination of gas exchange during exercise. Patients with exertional hypoxemia should have further assessment of their gas exchange.

Lung volumes, for those with impaired vital capacity — When a reduced forced vital capacity (FVC) is present on postbronchodilator spirometry, we perform lung volume measurement by body plethysmography to determine whether the reduction in FVC is due to air trapping, hyperinflation, or a concomitant restrictive ventilatory defect. Body plethysmography is strongly preferred for lung volume measurement when available because gas dilution methods may be insensitive for the detection of air trapping.

An increased FRC or RV with a normal TLC is indicative of air trapping without hyperinflation.

Assessing gas exchange, in select patients — We perform additional assessment of gas exchange in patients with COPD with moderate to severe airflow limitation (forced expiratory volume in one second [FEV₁] ≤50 percent predicted or z-score ≤-2.5), marginal resting oxygen saturation [O₂Sat] (O₂Sat ≤92 percent), exertional hypoxemia (O₂Sat <90 percent), or severe dyspnea (modified Medical Research Council [mMRC] score ≥2) (calculator 1).

Arterial blood gas – A resting arterial blood gas demonstrating arterial oxygen tension (PaO₂) ≤55 mmHg (7.33 kPa) is an indication for continuous supplemental oxygen. Similarly, the presence of chronic respiratory acidosis (figure 3 and figure 4) should lead to evaluation for sleep-disordered breathing and possible nocturnal noninvasive ventilation. (See "Long-term supplemental oxygen therapy" and "Nocturnal ventilatory support in COPD".)

CT imaging – While chest CT imaging is not recommended for all patients, we agree with the global initiative for obstructive lung disease recommendations, which suggest CT imaging in the following circumstances: patients with persistent exacerbations; symptoms out of proportion to disease severity on lung function testing; FEV₁ less than 45 percent predicted with significant hyperinflation (as consideration for endobronchial valve placement); those meeting criteria for lung volume reduction surgery; and patients meeting criteria for lung cancer screening [1].

While historical approaches generally weighed spirometric values more strongly, it has been increasingly recognized that other aspects of disease, such as the severity of symptoms, risk of exacerbations, and the presence of comorbidities, are important to the patient's experience and to disease prognosis [1,111].

● GOLD 1 (mild disease): FEV₁ ≥80 percent predicted

● GOLD 2 (moderate disease): FEV₁ between 50 and 80 percent predicted

● GOLD 3 (severe disease): FEV₁ between 30 and 50 percent predicted

● GOLD 4 (very severe disease): FEV₁ <30 percent predicted

This spirometric severity grading system is important due to its simplicity and subsequent use in many clinical trials and observational studies; however, its prognostic capacity for mortality is modest [112].

Other groups have suggested potential spirometry-derived alternatives to the GOLD Grade system. For example, the STaging of Airflow obstruction by Ratio (STAR) severity classification scheme was derived using approximately the 25^th, 50^th, and 75^th percentile of the FEV₁/FVC ratios from the COPDGene cohort study and validated using COPDGene and a second independent cohort [113]. Like GOLD, this classification divides patients with COPD into 4 stages: STAR stage 1 is defined by an FEV₁/FVC ratio between 0.6 and 0.7; STAR stage 2 by an FEV₁/FVC ratio between 0.5 and 0.6; STAR stage 3 by an FEV₁/FVC ratio between 0.4 and 0.5; and STAR stage 4 by an FEV₁/FVC ratio <0.4.

STAR requires further validation in population-based cohorts before it can be widely adopted.

While GOLD grade relates to spirometric severity of disease, GOLD recommends a different system, the ABE assessment tool, for use in determining initial therapy. The GOLD ABE assessment tool uses an individual’s symptoms (ie, modified Medical Research Council [mMRC] dyspnea scale (calculator 1) or COPD Assessment Test (calculator 2)) and exacerbation history to guide pharmacotherapy (algorithm 3) [1]. The multidimensional GOLD "ABE" evaluation is discussed in more detail separately in the context of initial management of COPD. (See "Stable COPD: Initial pharmacologic management".)

We agree with the GOLD strategy to monitor postbronchodilator spirometry yearly to track decline in FEV₁, which may identify patients whose disease is progressing more quickly than usual.

BODE index — The BODE index is another system for assessment of COPD severity and prognosis. It is calculated based on weight (body mass index [BMI]), airflow limitation (FEV₁), dyspnea (mMRC dyspnea score) (calculator 1), and exercise capacity (six-minute walk distance) (calculator 3), and it has been used to assess an individual’s risk of death.

While FEV₁ is used to gauge severity, the FEV₁/FVC ratio is not used for this purpose because measurement of FVC becomes less reliable as the disease progresses (the long exhalations are difficult for the patients), thus making the ratio less accurate unless high-quality spirometry is ensured (algorithm 1).