6

Techniques for Respiratory Disorders

Respiratory diseases are leading causes of death and disability. About 65 million people suffer from chronic obstructive pulmonary disease (COPD), for example, and 3 million die from it each year, making it the third leading cause of death worldwide (Levine and Marciniuk, 2022). In the United States more than 25 million people have asthma, and approximately 14.8 million adults have been diagnosed with COPD (HHS, 2022). The burden of respiratory diseases affects individuals and their families, schools, and workplaces, and the burden of respiratory diseases also falls on society, through tax dollars, higher health insurance rates, and lost productivity.

Newer methods of diagnosis for respiratory diseases include advances in imaging techniques, less invasive approaches to the biopsy of respiratory structures, the use of serum or exhaled breath inflammation biomarkers in the early detection of airways disease, and the expanded use of genetic analysis in the diagnosis of some lung diseases. In addition, genetic analysis has also revolutionized the diagnosis and treatment of lung cancers.

The chapter provides information about select new and improved diagnostic and evaluative techniques that have appeared since 1990 for diagnosing respiratory diseases. It highlights major advances in testing approaches that have generally resulted in changes leading to better information about impairments that may affect patient functioning. Lastly, it identifies emerging techniques for respiratory disorders that may become more common in practice in the near future.

OVERVIEW OF SELECTED TECHNIQUES

Box 6-1 provides a list of new or improved techniques that exemplify major advances in diagnostic and evaluative techniques in respiratory disease (see inclusion criteria in Chapter 1). The chapter discusses the evidence and information about the selected techniques and responds to the requested items (a)–(j) of the Statement of Task for each technique. A focus is on the respiratory disorders in Social Security Administration (SSA) Listings of Impairments, which include chronic obstructive pulmonary disease (chronic bronchitis and emphysema), pulmonary fibrosis and pneumoconiosis, asthma, cystic fibrosis, bronchiectasis, respiratory failure, chronic pulmonary hypertension, and lung transplant. In addition to techniques that assess anatomical or physiologic function, the committee also presents other new or improved techniques with selective or potential relevance to the assessment of physical function. Following those descriptions, at the end of the chapter the committee emerging respiratory techniques that may become generally available in the next 5–10 years.

SELECTED RESPIRATORY DIAGNOSTICS FOR ASSESSMENT OF ANATOMICAL OR PHYSIOLOGIC FUNCTION

The diagnosis of respiratory disease invariably requires a combination of diagnostic techniques applied in a step-by-step evaluation. Conducting a careful clinical history and physical examination is always the first step. Respiratory symptoms may include dyspnea, abnormal noisy breathing (wheezing or stridor), hoarseness, cough with or without sputum production, snoring, and chest pain. Symptoms may be acute or chronic and vary in severity, can be isolated or combined, and are sometimes accompanied by systemic symptoms such as fatigue, fever, and weight loss. For certain diseases such as those related to environmental or occupational hazards, additional specialized questionnaires can be helpful. A physical examination typically includes focused elements of inspection, palpation, percussion, and auscultation (i.e., listening with a stethoscope) of the thorax in the context of a thorough physical examination. The clinical history and physical examination guide the selection of the appropriate pulmonary function tests, laboratory tests, imaging techniques, and biopsy procedures.

Overview of Pulmonary Function Testing

Pulmonary function testing (PFT) is often the starting point of assessment in the physical examination of respiratory disease. Common elements of PFT are spirometry, lung volumes, and diffusing capacity. Spirometry entails measuring the volume and flow rates of exhaled and inhaled breath. The most frequently used spirometric measures are forced vital capacity (FVC, in liters) which is the largest volume of air that can be exhaled forcefully from a maximal inhalation, and the forced expiratory volume in 1 second (FEV1, in liters), which is the volume exhaled during the first second of a maximal forceful expiratory effort following a maximal inhalation. The ratio of FEV1/FVC is an important indicator of the presence of airflow obstruction typical, e.g., of asthma or chronic obstructive lung disease. Changes in spirometry after bronchodilator administration are another indicator of variable airflow obstruction. Lung volumes include the total lung capacity, the maximal volume of air that can be contained in the lung. This requires, in addition to spirometry, indirect measurements, either by plethysmography or wash-out technique, to estimate air that cannot be exhaled. Reductions in total lung capacity are indicative of a restrictive ventilatory defect which may be due to either intrinsic pulmonary or to extra-pulmonary processes. Diffusing capacity refers to the function of gas transfer between air and blood in the lung and is measured as the diffusing lung capacity for carbon monoxide (DLCO, in ml CO/mmHg/min). Performance of this requires a maximal inhalation of a test gas followed

by breath-hold of 10 or 12 seconds. All of these diagnostic measures were available before 1991, and FEV1, FVC, and DLCO appear in the Listing of Impairments¹ as criteria for disability under SSA for certain respiratory diseases. Over the last three decades there have been incremental changes in technology for making the measurements as well as a refinement of standards for performance, interpretation, and reporting of results, which has been reflected in guidelines published by national and international professional societies (Culver et al., 2017), which increases confidence in test results.

PFT is central to the diagnostic evaluation of any respiratory symptom, including shortness of breath, cough, or wheezing. These symptoms are also indicated to identify pulmonary impairment associated with, or resulting from, another recognized process, such as chest wall deformity, collagen vascular disorder, sickle cell disease, or neuromuscular disorder, or to seek evidence of a lung disease as the cause of another recognized process, such as pulmonary hypertension. PFT is indicated to screen and monitor for pulmonary injury related to exposure to drugs, radiation, or occupational or environmental substances. PFT is also used in the pre-operative risk assessment for high-risk surgeries, and serial pulmonary function testing is used to track the course of pulmonary disease and assess response to therapy.

Pulmonary function testing requires specific equipment and attention to quality control procedures. Most PFT measures involve the performance of maximal maneuvers and so require a patients comprehension, effort, and cooperation with instructions during testing. Sub-optimal efforts (by the patient) or suboptimaly timing will lead to overestimates of impairment. Recent guidelines from the American Thoracic Society (Culver et al., 2017) provide updated criteria for grading the quality of individual maneuvers and recommendations for how to use this in interpretation and reporting. The testing of children requires particular skills for ensuring comfort and cooperation and may include the use of software designed specifically for pediatric use. Interpretation of PFT should be done by a clinician with expertise in the procedures and in standards for reporting.

Changes in PFT over recent years include refinements in the standards for the use of reference values and interpretation. In the past the formulae used to derive reference values for PFTs in the United States were derived primarily from data from healthy Caucasians and commonly adjusted by a fixed percentage for interpreting measures from non-Caucasians. Over recent decades, reference data derived from more diverse populations have become available, including from the NHANES III study (Hankinson et al., 1999) and the Global Lung Function Initiative (see Quanjer et al., 2012)

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¹ For more information about the use of the Listing of Impairments in disability evaluation, see Chapter 1.

which reported separate regression equations for spirometry values based on data from a number of different racial or ethnic sub-populations). Distinguishing between ancestral and environmental factors as the basis for population differences in pulmonary function remains problematic, and recent recommendations variably favor the use of population-specific or multi-racial formulae for calculating normal values (Culver et al., 2017) over the prior practices of adjusting values for Caucasians by a fixed percentage. Historically, fixed percentages of predicted values were also commonly used for distinguishing normal from abnormal; however, because confidence limits for spirometry are found to vary with age, it is now recommended that Z-scores reflect age-specific confidence limits.

These changes in the treatment of normative values may affect the sensitivity of pulmonary function tests for the identification of early or mild impairment, which is important in diagnosis of many respiratory diseases. It should have less effect on the assessment of disability due to advanced disease, however, since the SSA Listing of Impairments used absolute values of spirometric measures stratified by sex, height, and age above or below age 20 to define threshold values for disability and so are independent of reference values.

Notably, in a statement about health equity and pulmonary function testing, the American Thoracic Society reports that efforts are under way to more fully understand the geographical, environmental, genetic, and social determinants of health that play a role in explaining observed differences in lung function between different population groups. Through these efforts, the society anticipates informing future guidance on the interpretation of lung function “with approaches that are free from bias” (ATS, 2022).

Several advances in diagnostic techniques for assessing disabling impairments of the respiratory system are described below.²

High-Resolution Computed Tomography

Computed tomography (CT) of the chest allows more detailed visualisation of thoracic structures than plain radiography. It is often performed with intravenous contrast enhancement (in suspected pulmonary embolism cases, for example). CT is also helpful for guiding needle aspiration of peripheral lung lesions. CT scanning has been an important imaging technique in pulmonary diagnostics for many decades, and specific imaging techniques, protocols, and applications are continuously evolving. Low-dose CT is used in lung

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² While many of the diagnostic tests that are discussed are used predominantly, but not exclusively, in cancer diagnosis, the committee does not elaborate on lung cancer screening and assessment in this chapter. See Diagnosing and Treating Adult Cancers (NASEM, 2021) for detailed information about lung cancer.

cancer screening in high-risk individuals. This application is not specifically addressed here as it falls under the heading of cancer rather than respiratory disease. CT can be used for virtual bronchoscopy or angiography, but this has not become routine. CT is applied in combination with positron emission tomography mainly for staging lung cancer and other malignancies and in the differential diagnosis between benign and malignant lung lesions.

Improvements in imaging resolution have included what is termed high-resolution CT (HRCT), which has improved the diagnostic utility and accuracy of CT. In the evaluation of a number of conditions, the benefits of HRCT are so substantial as to represent a qualitative, rather than simply incremental, improvement over convential CT. In the case of diffuse interstitial lung diseases (ILDs), HRCT images, along with clinical history and findings, are sometimes sufficient for diagnosis of a specific ILD, which would otherwise require surgical biopsy for histologic diagnosis.

The responses to the items in the statement of task are as follows:

1. The accepted uses of HRCT involve characterizing diffuse ILD, including occupational or environmental pneumonconioses, and identifying bronchiectasis of the airways in individuals with or without cystic fibrosis. It may also be used to evaluate lung structure in individuals with respiratory symptoms but normal findings on plain X-ray or conventional CT scan. Comparison of images obtained during different phases of the respiratory cycle is used to identify regional differences in density due to air trapping resulting from disease of small airways or to distinguish between pulmonary vascular versus airways disease as the cause of regional inhomogeneities in tissue density.
2. HRCT scanning represents an advance in that it uses imaging protocols that average smaller volumes of lung tissue within each image slice, increasing the spacial resolution of the images and therefore allowing for the identification of smaller structures and a more precise characterization of patterns of structural change which are useful in diagnosis of both airway and interstitial processes.
3. Bronchiectasis and interstitial lung disease are specific impairments that are more accurately assessed by HRCT. In bronchiectasis, CT/HRCT has almost wholly replaced contrast bronchography for the diagnosis of bronchiectasis, which requires a demonstration of structural distortion of the airways. Contrast bronchography, now a rarely used procedure, requires passage of a catheter into the airway to deliver a small amount of contrast material as well as control of breathing to avoid cough during the procedure. HRCT requires less cooperation, does not require entering the airway, and avoids irritation of airways by contrast material, so it is better

tolerated. In cystic fibrosis, HRCT can identify early airways disease prior to changes in routine pulmonary function tests. Pertaining to interstitial lung disease, compared with conventional CT imaging, HRCT is more sensitive and specific in the evaluation of diffuse interstitial lung diseases For example, HRCT may provide sufficient characterization of findings to support a diagnosis of idiopathic pulmonary fibrosis (IPF) without the need for surgical biopsy and histopathologic evaluation. In ILD, HRCT findings, such as a pattern of “ground glass attenuation” characteristic of inflammation without distortion of the lung archeticture, or “honeycombing,” indicative of advanced fibrosis, are useful in both predicting and tracking response to therapy.

4. The first published report reflecting the clinical use of HRCT for characterizing diffuse interstital lung disease was in 1982 in the Japanese Journal of Clinical Imaging (Todo). Based on detailed reviews of the technique (Kazerooni, 2001), HRCT became widely appreciated and adopted in radiologic practices in the early 1990s.
5. High-resolution CT scanning is widely available in the United States; however, disparities in the use of low-dose CT scanning for lung cancer screening have been identified based on race, ethnicity and geography. Whether there are similar disparities in other applications of HRCT is not clear.
6. Limitations of routine CT imaging include failure to identify small nodules in the sub-centimeter size range or subtle infiltrates. In imaging diffuse ILD, the volume averaging of images often results in insufficient resolution to distinguish between patterns of lung involvement, e.g., nodular, reticular, or ground glass opacities, which are characteristic of different clinical conditions.
7. Regarding outcomes, HRCT interpretation includes characterization of the pattern and distribution of abnormalities affecting lung parenchyma, airways and airspaces. This may suggest or confirm specific diagnostic entities or narrow the range of potential diagnoses to be pursued. Some findings are helpful in predicting the likelihood of response to therapies.
8. HRCT is performed in a radiology suite equipped with a multidetector CT scanner and staffed with licensed radiology technologists trained in CT protocols. Tests should be interpreted by radiologists with expertise in lung imaging.
9. Impediments to the widespread use of HRCT are not clearly identified. Capabilities for this imaging are present in most radiology facilities that perform regular CT scanning.
10. A drawback of CT imaging is that it involves exposure to ionizing radiation, so the imaging should be carried out only at necessary

points in time and should be avoided in pregnancy. Some uses of HRCT benefit from the use of intravenous contrast material; sensitivity to contrast limits its use in some individuals, which can reduce the information gained regarding mediastinal and vascular structures. Although HRCT can characterize patterns of radio-graphic abnormalities, e.g., in ILD, not all patterns are unique to specific clinical diagnoses. The integration of clinical history, imaging, and lung function tests is generally needed to establish specific diagnoses of lung diseases.

Cardiopulmonary Exercise Test

Chapter 3 provides an overview of cardiopulmonary exercise testing (CPET), and this section reviews the use of CPET in respiratory medicine. The responses to the items in the statement of task are as follows:

1. In respiratory medicine the accepted use of CPET is as part of the diagnostic assessment of the cause of exercise dyspnea or exercise limitation. Some examples of specific diagnoses that can be established with CPET include exercise-induced arrhythmias, chronotropic incompetence, myocardial ischemia, and hyperventilation syndromes. In other cases, CPET may distinguish broadly among limitations due to pulmonary, cardiovascular, and other categories of disease as the likely cause of symptoms (Balady et al., 2010; Palange et al., 2007). CPET is also used diagnostically for evaluating individuals with more than one known condition affecting exercise function to both identify the aggregate effect on functional capacity and to assess the roles of individual conditions on overall impairment. CPET is also an evaluative test for individuals with known diagnoses. Peak V^∙O₂ is an objective and standardized measure of cardiorespiratory capacity, so it can be used to grade the degree of impairment in individuals with respiratory disease. Peak V^∙O₂ is predictive of survival in many clinical populations, including respiratory conditions such as pulmonary hypertension, cystic fibrosis, COPD, and IPF. Prognostic assessment in these conditions can be helpful in decisions regarding advanced therapies such as lung transplant. Peak V^∙O₂ is also predictive of surgical risk associated with lung resection surgery in individuals with potentially resectable lung cancer (Brunelli et al., 2013). Peak V^∙O₂ and other variables (e.g., ΔV^∙E/ΔV^∙CO₂, i.e., change in ventilation divided by change in carbon dioxide output) are useful in tracking response to therapy for conditions such as pulmonary hypertension.

2. CPET represents an advance in that it allows the measurement of multiple aspects of heart and lung function under the conditions that cause symptoms. In contrast, measures of resting pulmonary function alone may not identify impairments that underlie symtpoms occurring with activity. Similarly, tests of exercise performance alone, without simultaneous assessment of breathing mechanics or gas exchange efficiency, do not allow identification of pulmonary processes as the cause of a measured limitation.
3. Impairments that are more accurately assessed include:
   • Ventilation as the cause of exercise limitation. In any chronic lung disease, breathing capacity may be reduced; chronic lung disease additionally may increase breathing requirements for a given level of activity, the extent of which is difficult to predict from resting tests alone. The result of either or both of these processes can be limitation of exercise by the mechanical capacity to breath. This is identified on CPET by comparison of exercise ventilation with breathing capacity determined by pulmonary function testing.
   • Dynamic hyperinflation. Among individuals with chronic obstructive lung disease, exercise limitation can result from the development of dynamic hyperinflation (a progressive rise in lung volumes due to incomplete exhalation as respiratory rate increases), a mechanical consequence of airflow obstruction, during exercise, which reduces exercise breathing capacity compared to rest. This can be identified by serial measurement of inspiratory capacity during CPET. Dynamic hyperinflation increases the work of breathing, increases the degree of dyspnea associated with a given level of ventilation, and may worsen gas exchange efficiency due to changes in the distribution of ventilation (O’Donnell et al., 2020). Identification of dynamic hyperinflation can therefore explain discrepancies between the degree of impairment of resting lung function and the degree of actual activity limitation.
   • Co-morbid conditions. CPET is useful in identifying additional conditions, such as cardiac disease or obesity, that may coexist with lung disease and contribute to or account for the individual’s exercise impairment.
   • Cardiopulmonary interactions. Exercise can also be impaired by secondary cardiovascular constraints imposed by the pulmonary vascular effects of lung disease or from dynamic cardiopulmonary interactions during exercise (Harms and Dempsey, 1999). These effects may not be amenable to direct measurement but can often be inferred from CPET results, which could then

support additional diagnostic testing. For example, exercise-induced hypoxemia is variable in individuals with lung disease and not necessarily predicted from resting lung function. This can be identified and estimated by non-invasive pulse oximetry or more precisely measured from arterial blood gas analysis on blood obtained during exercise testing. The mechanism for exercise-induced hypoxemia can often be identified from the pattern of changes measured during CPET, particularly if it is due to exercise-induced right-to-left shunt via a patent foramen ovale in individuals with pulmonary arterial hypertension.

7. Table 6-1 shows some typical findings from CPET when respiratory diseases, such as COPD, are the primary limitation to exercise.
8. CPET is best performed in pulmonary function laboratories or cardiac stress testing laboratories in community or academic hospitals and clinics. The testing should be carried out by technicians with appropriate training and the results should be interpreted by pulmonologists, cardiologists, or other physicians with appropriate expertise; failure to do so will limit the usefulness of the findings.
9. The main impediments to greater use of the technique are the limited availability of the necessary facilities, equipment, and personnel in medically underserved areas of the country.
10. Concerning the limitations of diagnostic CPET, many abnormalities identified from testing could be common to several different pathologic conditions. The test is often most useful for making broad distinctions, e.g., between pulmonary and cardiac etiologies, rather than establishing a highly specific diagnosis (Palange et al., 2007). Its diagnostic utility is dependent on an interpretation

TABLE 6-1 Typical CPET Findings in Uncomplicated Respiratory Disease

NOTE: V^∙O₂ = rate of oxygen uptake; ΔV^∙O₂/ΔWR = change in V^∙O₂ relative to changing work rate during incremental test protocols; HR = heart rate; VE = ventilation in l/min; VCO₂ = rate of output of carbon dioxide; MVV = maximal voluntary ventilation in l/min or percent; IC = inspiratory capacity; TV = tidal volume, SpO₂ = arterial oxygen saturation estimated by pulse oximeter; FEV1 = forced expiratory volume measured during the first second.

of the test results in light of other clinical history and findings. In some circumstances, other established diagnostic procedures may be combined with CPET to increase diagnostic specificity. An example of this is invasive CPET, which uses a right heart catheter to measure hemodynamics during exercise.

Bronchoprovocation Test

Bronchoprovocation testing involves the administration by inhalation of materials or maneuvers with the potential to cause broncho constriction with repeated measurement of spirometry (Borak and Lefkowitz, 2016). It is used to identify or quantify bronchial hyper-reactivity, which is characteristic of asthma, when a diagnosis of asthma is suspected but has not been demonstrated by standard pulmonary function testing. A variety of exogenous broncho constrictor agents, as well as exercise and voluntary hyperventilation, have been used for testing. Over the past 20 years standardized protocols have been developed (Crapo et al., 2000) and updated to reflect changes in technology (Coates et al., 2017). Testing with the direct broncho constrictor methacholine has emerged as the most common procedure, is widely available, and is highly sensitive for identifying airway hyper-reactivity. A negative methacholine challenge test is useful for excluding a diagnosis of asthma. The responses to the items in the statement of task are as follows:

1. Bronchoprovocation testing is most commonly used to identify bronchial hyperreactivity in cases in which asthma is suspected but routine pulmonary function tests have not demonstrated airflow obstruction, which is intermittent. The test identifies bronchial hyperreactivity, which is typical of, but not unique to, asthma. A positive methacholine test can therefore support the diagnosis of asthma, especially if typical symptoms are reproduced by the test, although it is not entirely specific. Conversely, a negative methacholine test makes the diagnosis of asthma extremely unlikely. Bronchoprovocation is sometimes performed with specific antigens as the challenge agent, e.g., when an occupational asthma is suspected; this is generally limited to highly specialized centers. It is sometimes used in clinical trials to quantify changes in bronchial hyperreactivity in response to therapeutic interventions. Exercise or eucapnic hyperventilation (voluntary hyperventilation with supplemental carbon dioxide breathing to maintain the arterial PCO₂ (partial pressure of CO2) value in a safe range) are sometimes used as indirect agents of broncho provocation, especially when exercise-induced asthma is suspected. These indirect

bronchoprovocation tests have fairly wide ranges of reported sensitivity and specificity for exercise induced asthma, however (Hull et al., 2016). Negative broncho provocation tests may be sought to exclude reactive airways disease in selected occupational fitness evaluations. A demonstration of bronchial hyperreactivity is sometimes required of athletes with exercise-induced asthma in order for them to be allowed to use bronchodilator drugs in competition.

2. Asthma is intermittent by nature, and pulmonary function tests may be normal if they are performed when the disease is quiescent. Bronchoprovocation identifies whether an individual has hyper-reactive airways, which could support or exclude a clinical diagnosis of asthma when routine pulmonary function is normal. Although differences have been recognized in the prevalence and severity of asthma based on racial identity, there do not appear to be clear differences in the test performance characteristics of methacholine challenge among population subgroups.
3. An example of a specific impairment that is more accurately assessed is an incorrect asthma diagnosis. If impairment due to asthma was diagnosed on the basis of history and symptoms without documentation of typical airflow obstruction, a negative methacholine test would make the diagnosis of asthma highly unlikely and suggest a search for an alternative diagnosis such as upper airway dysfunction.
4. Bronchoprovocation testing has been carried out for over 50 years using a wide variety of provocative agents. In the last 30 years standardized protocols have been developed for a number of agents, and in 1999 the American Thoracic Society developed guidelines for the use of methacholine bronchoprovocation (Crapo et al., 2000).
5. Access to bronchoprovocation testing may vary by medical facilities, and it is not performed in all pulmonary function laboratories. Disparities in access related to racial, ethnic, socioeconomic, or geographic lines are not specifically identified.
6. Drawbacks of previous techniques: Bronchoprovocation testing has been performed using a variety of agents, delivery devices, and dosing strategies, which can make the interpretation of tests performed in different settings or using different protocols difficult. The development of a standardized protocol has improved confidence in the interpretation of results.
7. In terms of outcomes, methacholine bronchoprovocation testing involves the inhalation of escalating concentrations of drug at 5-minute intervals, with measurement of spirometry following each dose. The test is continued until the highest scheduled dose is

completed or the FEV1 declines by at least 20 percent. Test results may be reported as the PC20, i.e., the provocative concentration resulting in 20 percent fall in FEV1, by interpolation of data. Generally a PC20 of over 16 mg/ml is reported as negative or normal, a PC20 of less than 4 as positive, and values of 4–16 as borderline. Differences in specific protocols and equipment can result in different cutoff values in reporting, so results should be reported in comparison with appropriately referenced cutoffs.

8. A pulmonary function laboratory equiped for the measurement of spirometry, with suitable ventilation, and a device for dose delivery are needed. Dosimetry varies with nebulizing devices, so the equipment should be matched to the protocols used. Bronchodilating medications are needed for the reversal of bronchoconstriction following a positive test. Personnel with expertise in pulmonary function testing and appropriate training and liscensure for administration of the drugs are needed to administer the test. Tests should be performed under the supervision of a physician who may or may not be present at the time of testing.
9. Bronchoprovocation testing can be time-consuming and requires specific protocols and training of personnel. It may not be cost-effective to perform this testing, especially in settings with limited laboratory time and space. As a result, it is not universally provided in all pulmonary function laboratories.
10. In term of limitation, as noted above, bronchial hyperresponsiveness is not unique to asthma and may be demonstrated, for example, in individuals with atopy or upper airway disease, so positive tests are non-specific. As a result, bronchoprovocation is used to support a diagnosis that is suspected on the basis of other clinical findings but not to establish a diagnosis in itself. Bronchial hyperreactivity may be masked by the use of some asthma medications prior to testing, so appropriate withholding of medications needs to be conveyed and documented. Bronchoprovocation testing is time-consuming with respect to laboratory and personnel resources. Adequate ventilation is needed to avoid exposure of staff or bystanders to the test materials. These factors may limit the test’s availability in pulmonary function laboratories. Despite standardized protocols, there remains variability in the results of bronchoprovocation testing. Some reasons for this include nebulizer characteristics, inhalation technique, and prior use of asthma medications by the test subject. The results of the testing need to be interpreted in light of the clinical history and alternative diagnoses that may account for symptoms.

6-Minute Walk Test

The responses to the items in the statement of task are as follows:

1. The strongest indication for the 6-minute walk test (6MWT) in respiratory medicine is for measuring response to medical interventions in patients with moderate to severe lung or heart disease. It is also used as a measure of functional status in patients with known diagnoses and in a number of conditions as a predictor of morbidity and mortality. It is often used in conjunction with pulse oximetry to assess the need or adequacy of supplemental oxygen therapy (Crapo et al., 2002).
2. Pulmonary function tests alone provide only moderate correlations with overall functional status and quality of life in patients with respiratory disease (Agarwala and Salzman, 2020). Compared with pulmonary function tests, functional performance tests such as the 6MWT capture the effects of secondary and coexisting conditions such as cardiovascular disease, frailty, obesity, deconditioning, and sarcopenia on the physical performance of individuals with primary respiratory disease. While other exercise tests such as CPET incorporate a broader range of measurements than 6MWT, the 6MWT provides information on functional status and relates to quality of life in chronic lung disease populations, but requires minimal equipment and technical expertise (Agarwala and Salzman, 2020).
3. Specific impairments that have been shown to be more accurately assessed with the 6MWT than with resting pulmonary function tests include those related to pulmonary arterial hypertension (PAH), COPD, and IPF; the 6MWT has also been used in the evaluation of lung transplant candidates.
   • PAH is a hemodynamic diagnosis, established by measurement of pulmonary artery pressures via right heart catheterization or presumptively diagnosed by estimates of pulmonary artery pressure made from echocardiography. In either case, however, the correlation between hemodyamic indices and disease severity is imperfect, especially once right ventricular failure develops. Pulmonary function tests are even less useful in quantifying severity or tracking the progression of PAH. Functional performance tests are a better reflection of the overall degree of cardiorespiratory impairment due to pulmonary vascular disease. Low 6-minute walk distances or decreases in distances over time have been associated with an increased risk of mortality compared with stability or improvement. The 6MWT has been used effectively in the evaluation of therapeutic interventions in PAH.

• In COPD, the 6-minute walk distance (6MWD) may be a more accurate assessment of disease severity than pulmonary function tests alone, in part because it captures both pulmonary and extrapulmonary manifestations of the disease, the latter accounting for more than 50 percent of deaths in patients with COPD. Therefore, 6MWD coupled with FEV1 is a better predictor of mortality and morbidity than FEV1 alone (Agarwala and Salzman, 2020). A study of longitudinal changes in patients with severe COPD found that over a 2-year period, the rate of decline in 6MWD between survivors and nonsurvivors was significantly different (22-meter decline versus 40-meter decline), whereas the difference in FEV1 was not (Pinto-Plata et al., 2004).
• IPF is characterized by a variable clinical course, which has led to interest in independent and reliable predictors of disease progression such as the 6MWT. In patients with IPF, the 6MWT has been reported to be more reproducible than CPET and simpler to perform, and yet it correlates strongly with the V^∙O₂ max (Eaton et al., 2005). The 6MWT is a significant independent predictor of near-term mortality in patients with IPF.
• Lung transplant assessment. For advanced respiratory diseases including PAH, COPD, IPF, and cystic fibrosis (CF), consideration may be given to lung transplantation. Rates of disease progression and mortality risk vary among those with these conditions and are not readily summarized in any single evaluative measure. In order to improve the equitable distribution of donor lungs, an allocation system was put in place in 2005 which prioritized mortality risk rather than waitlist time. The 6MWT (dichotomized at a walk distance above or below 150 feet, or 45.7 meters) is a component of the post-2005 lung allocation score because it contributes significantly to mortality risk assessment. (Agarwala and Salzman, 2020).

others (Singh et al., 2014). In the United States the 6MWT has been used more widely than most and in a wide variety of clinical populations. There are both normative data related to 6MWT distance in healthy individuals selected in various ways and data on the prognostic significance of 6MWD in a number of chronic lung disease populations. So while the 6MWT is not necessarily superior to other functional tests, the volume of comparative data make it among the most useful. Acceptance of standard protocols for performance of the test makes results more generalizable than tests without such standardization. And unlike some other functional assessments, the physical and technical requirements for tests performance are minimal.

7. Chapter 3 describes the range of outcomes, but in addition to distance walked, a secondary outcome of the 6MWT in individuals with lung disease is SpO₂.
8. The technician performing the test should be certified in cardiopulmonary resuscitation and trained in the use of the standard protocol and supervised for several tests before performing them alone; physician attendance is usually not required (ATS, 2002). The test should be performed on a level-grade corridor with a track 30 m in length, although reference equations exist for 20-m and 10-m tracks in the event that a 30-m track is unavailable; repeat testing should always use an identical track.
9. There are few impediments to more widespread use, with the main one being access to an appropriate indoor 30-m track.
10. Concerning limitations of its diagnostic or evaluative efficiency, the 6MWT has a ceiling effect related to the effective upper limit of walking speed and therefore is likely to be insensitive to the presence of, or changes in, mild disease.

Modified Medical Research Council Dyspnea Scale

There are many instruments available for characterizing and rating symptoms of individuals with respiratory disease. The Medical Research Council (MRC) dyspnea scale has been widely used in respiratory diseases since first developed in the 1940s (Fletcher et al., 1959). A modified form (mMRC) has been more frequently used in recent years. Either version is a simple single-item index in which individuals choose one of five descriptions that best characterizes the level of activity that causes them shortness of breath. The responses to the items in the statement of task are as follows:

1. mMRC does not quantify dyspnea itself, but characterizes its severity based on its effect on physical function (Williams, 2017).

Originally intended for use in epidemiology, the scale has been widely used both in clinical research and practice and has been incorporated into a number of composite scales of disease severity (Williams, 2017). It corrolates with assessments of lung function impairment and of exercise impairment, and it is complementary to lung function in predicting disability due to lung disease (Bestall et al., 1999). With only five possible scores, it is not sensitive to small changes, making it relatively stable over short durations of time.

2. mMRC is evaluative and not diagnostic and represents an advance as it characterizes dyspnea severity based on its effect on physical function. Unlike a pure dyspnea score such as the Borg scale, the questions on the MCR scale relate occurrence of symptoms to broad categories of physical activity that are common to daily life. Biases in test characteristics related to demographic subpopulations do not appear to have been identified.
3. Examples of specific impairments includes dyspnea, which is commonly the proximal cause of exercise or activity limitation in individuals with respiratory diseases. It is not measured in pulmonary function tests and usually not explicitly quantified in functional performance measures.
4. The MRC breathlessness scale first came into use in the 1940s and 1950s for assessment of occupational lung diseases, and it was first published in 1959 (Fletcher et al., 1959). The most recent version was published by the MRC in 1986 as part of a respiratory questionnaire for use in epidemiology studies. A modified version of the dyspnea or breathlessness scale has been widely adopted over the last three decades, (see table below), but an exact date for these modifications could not be identified.
5. The mMCR is widely available, and there is no evidence of disparities in access related to demographic or geographic factors.
6. Assessment techniques reflecting diagnostic findings, resting lung function, or exercise performance are incomplete reflections of disease impact without a metric reflecting the role of symptoms on an individual’s activity. The mMCR grade is supplementary to other evaluative measures in characterizing symptom occurrence across a range spanning basic, instrumental, and normal activities of daily living.
7. Outcomes: The modified MRC breathlessness scale is reported as a single number from 0 to 4 as shown in Table 6-2.
8. The mMRC can be self-administered or administered by an interviewer. No specialized training or permissions are required for its use. The original scale was intended specifically for epidemiologic use and not for evaluation of individuals. However the mMRC has

TABLE 6-2 Modified Medical Research Council Breathlessness Scale

SOURCE: Williams, 2017.

been demonstrated in numerous studies to be a meaningful adjunct to other clinical data in the evaluation of patients with chronic lung diseases (Williams, 2017).

9. The mMRC is widely available at no cost and is simple to administer. Impediments to its use are likely limited to lack of awareness of the scale.
10. A limitation of the mMCR is that it is not diagnostic and does not characterize the specific nature of impairment related to respiratory disease. It is a broad grading system and not highly sensitive to modest changes in disease severity. It should be viewed as an adjunct to other diagnostic and evaluative measures in characterizing impact of disease.

BODE Index

The overall burden of respiratory disease includes aggregate effects not only of impaired lung function, but also of symptoms, periodic exacerbations, and treatments. A number of multidimensional instruments have been developed for use in respiratory diseases, particularly in COPD (van Dijk et al., 2011; Oga et al., 2011). One of the more widely studied and used in the United States is the BODE index, calculated from body mass index, airflow obstruction as reflected in FEV1, dyspnea as reflected in the modified MRC dyspnea scale, and walking exercise performance as reflected in 6MWT distance (Celli et al., 2004). There is general correlation among different multi-dimensional instruments developed for use in COPD which vary in emphasis and specific components. Their validity as reflections of disease severity is generally demonstrated by their ability to predict mortality or other adverse outcomes. The BODE index is not necessarily better than others, but it has been widely used in the United States and uses

components that are readily measured. Similar multidimensional instruments for asthma are less well developed, such as ASSESS (Fitzpatrick et al., 2020), which is discussed in the section on emerging techniques, below.

The responses to the items in the statement of task are as follows:

1. The BODE index has been used in clinical research to characterize severity of COPD. It has been demonstrated to predict mortality in this population and also to predict exacerbations and health care resource usage and costs (Li et al., 2020). In 2014 it was incorporated into guidelines for the selection of patients with COPD for lung transplant based on its prognostic value (Weill et al., 2015). Recalibrated recommendations for the use of BODE index in this context were adapted in the 2021 transplantation guidelines. (Leard et al., 2021), based on observations of better survival among lung transplant candidates with COPD than in less selected cohorts (Reed et al., 2018).
2. As an advance, the BODE index is a stronger predictor of mortality than FEV1 alone in individuals with COPD (Celli et al., 2004). Although FEV1 is the most widely used single measure of impairment in lung mechanics in COPD, the BODE index also incorporates elements of the consequences of impairment in the form of self-reported symptoms during common activities, observed performance on a walking test, and low body mass index (BMI), which is a poor prognostic marker in this population). As such it is a broader reflection of the primary and secondary effects of disease on physical functioning.
3. The BODE index more accurately predicts mortality, disease exacerbation, hospitalizations, and health care usage than single variables such as FEV1. The BODE index combines measures reflecting lung function, exercise capacity, symptoms, and a systemic risk factor, so it is multi-dimensional.
4. The BODE index was first reported in 2004 and is widely available (Celli et al., 2004).
5. The components of the BODE index are all widely available without evident dispairities across demographic or geographic lines.
6. In terms of limitations, the calculation of BODE index uses the percent of predicted value for FEV1, which makes it subject to effects of the choice of reference values. Historically, predicted values for FEV1 for non-Caucasian individuals were based on data from Caucasian populations that were adjusted downward to account for observed differences in the distributions of measured values. This could affect the index values calculated for non-Caucasian individuals who are near stratification points for this variable.

7. Outcomes: The BODE index is a score ranging from 0 to 10 with more severe disease reflected in higher score. It is the sum of scores for body mass index (1 point if less than 21), airflow obstruction (0–3 points based on FEV1as a percent of predicted value, dyspnea (0–3 points based on modified Medical Research Council dyspnea index), and 0–3 points for exercise (based on distance in the 6-min-ute walking test).

NOTE: The BODE score is the sum of points as shown in the top row assigned for results of measures for each of the four measures shown in the variable rows.

SOURCE: Celli et al. (2004).

8. There are no specified requirements for calculating the BODE index, but some elements, such as the FEV1 and the 6-minute walk distance, require expertise and training to measure. As described in a preceding section, the mMRC dyspnea scale is a simple instrument, requiring minimal training to collect or administer.
9. The individual components of the BODE index are widely available, so there should be little impediment to its use other than lack of familiarity with it on the part of providers.
10. A limitation of the BODE index is that it is evaluative and not diagnostic. It requires separate performance of its component parts, which can limit its availability. Evidence that the BODE index is a significant reflection of disease severity is its ability to predict mortality and other significant endpoints. A consideration of additional factors, including diffusing capacity, age, and co-morbidities, adds to the prognostic value of the BODE index. Importantly, analyses of survival in individuals with COPD who are under age 65, while less than that for all ages, is still significantly related to the BODE quintile (Pirard and Marchand, 2018) Of the components of the BODE index, BMI is the only measure that is not dependent on the individual’s cooperation and candor. FEV1 and 6-minute walk distances are effort-dependent, and the MRC dyspnea index is self-reported. Its validity among individuals seeking disability is not reported. However, limited data do demonstrate a relationship

between the BODE index and employment. Among 608 individuals of working age with COPD, those with scores in the highest quintile were significantly less likely to be employed than those in the lowest quintile (Rai et al., 2017). In that study, the dyspnea score was the only individual component of the BODE index independently associated with employment status.

A number of modifications of the BODE index have been reported, most of which are modifications to the exercise component. An updated BODE index increases the weight given tp the 6-minute walk distance. Other modifications substitute the 6-minute walk test with another field test such as incremental shuttle walk test or with peak oxygen uptake from CPET, either of which are likely more rigorous measures of exercise capacity, or else with the 1-minute sit-to-stand test, which may be easier to perform in limited space.

INDIRECT OR POTENTIAL RELEVANCE TO PHYSICAL FUNCTION

A number of diagnostic procedures in respiratory medicine meet the first two inclusion criteria identified in Chapter 1 for this report—that is, they are new or improved or have become generally available in the last 30 years—but they do not meet the third criteria as they would generally not have a direct impact on re-assessment of disability. Some examples of these diagnostic advances are acknowledged briefly below by way of general background.

Endobronchial Bronchoscopy

There have been major advances in diagnostic bronchoscopy over the last 30 years. Chief among these is the use of endobronchial ultrasound (EBUS), which has greatly increased the capacity for identifying lymph nodes and pulmonary masses and providing visual guidance to needle biopsy of these structures for diagnostic purposes. This technique has greatly reduced the need for surgical mediastinoscopy for the thoracic staging of primary lung cancer. EBUS allows the endoscopist to visualize airway walls and the location and size of structures immediately adjacent to airways. This also allows more precisely targeted sampling of tissue by needle aspiration biospies performed through the airway and therefore increases the diagnostic yield for these procedures, which had previously been guided by pre-procedure imaging and endobronchial landmarks. There is no indication of disparity in these benefits based on demographic or other population characteristics.

The impairments that EBUS more accurately assesses include the following:

• Staging of lung cancer requires identification of spread to intrathoracic lymph nodes. Spread to mediastinal lymph nodes in most cases identifies disease that is not resectable and therefore not curable. Radiographic techniques alone are not as sensitive or specific for staging as tissue biopsy. Before EBUS became available, trans-bronchial biopsies were performed “blind” based on prior imaging and anatomic landmarks, or biopsies were obtained surgically by mediastinoscopy or open thoracotomy. EBUS has greater diagnostic yield than the former and is less invasive than the latter.
• Nonmalignant processes affecting mediastinal lymph nodes, such as sarcoidosis or infection, are also more reliably diagnosed with EBUS-guided biopsy than without.
• Concerning the diagnostic evaluation of peripheral lung lesions of unknown cause, with the evolution of smaller ultrasound probes, EBUS can also guide bronchsopic biopsy of peripheral masses or infiltrates in the lung which would otherwise require an open thoracotomy to sample. Tissue sampling is often essential to establishing diagnosis, treatment recommendations, and prognosis.

The basic procedures of EBUS have become a standard component of training in the field of pulmonary medicine, but not all specialists in the field are proficient in it, and not all medical centers have the specialized equipment required. Access to more advanced procedures and techniques (such as visualization of peripheral lesions) may vary based on geographic or practice patterns. Racial and ethnic disparities have been reported in the diagnosis and treatment of lung cancer, including the use of staging procedures (Lathan et al., 2006).

Video-Assisted Thoracic Surgery/Pleuroscopy

Video-assisted thoracic surgery (VATS) uses small incisions in the chest wall to introduce instruments to visualize and perform minimally invasive surgery of the lung and other thoracic structures. The diagnostic procedures possible through VATS include lung biopsy for diagnosis of diffuse parenchymal disease, biopsy of peripheral mass lesions or lymph nodes, and even resection of an entire lobe of a lung. The smaller incisions required are generally associated with shorter recovery times and less extensive postoperative wound healing than traditional thoracotomy. Medical pleuroscopy or thoracoscopy is similar to VATS for visualization of the pleural surfaces through small incisions using a pleuroscope. It is

distinguished from VATS in that although the parietal pleura (on the inner lining of chest wall) may be biopsied, lung tissue and visceral pleura (adherent to the lung) are not. Its advantage over older pleural biopsy techniques using a specialized biopsy needle, which it has largely replaced, is the direct visualization of the biopsy site with greater diagnostic yield for the identification of primary or metastatic pleural malignancy or of pleural infections such as tuberculosis.

Compared with a blind closed needle biopsy of the parietal pleura, pleuroscopy or VATS has improved diagnostic sensitivity because the targeted biopsy site can be visualized, avoiding sampling bias. The use of VATS for biopsy or resection of intrathoracic lesions is less invasive, requires smaller incisions, and has a shorter recovery time than formal thoracotomy. These advantages appear to be similar for different subpopulations of individuals.

VATS leads to more accurate assessments in the following areas:

• The diagnosis of pleural tuberculosis or other infection, if not established by culture of fluid aspirated by simple thoracentesis, is more accurately made by thorascopic biopsy than blind biopsy.
• The biospy of peripheral lung tissue for diagnosis of interstitial lung disease is accomplished with a less extensive surgery with VATS than with thoracotomy.
• The diagnosis of primary (mesothelioma) or metastatic malignant pleural disease is made reliably by biopsy via either pleuroscopy or VATS. In some cases the diagnostic yield may not be very much higher than simple thoracentesis, but VATS or pleuroscopy allow simultaneous performance of therapeutic pleurodesis, a procedure promoting scarring of the pleural surfaces together to prevent re accumulation of malignant effusion, which is often an important palliative procedure.

VATS and medical thoracoscopy are both widely used in clincal practice. Racial and socioeconomic biases have been identified in the treatment of lung cancer with differences in therapeutic interventions and outcomes (Allen et al., 2021) and also in use of diagnostic procedures such as imaging (Morgan et al., 2020). Specific information on bias in the use of VATS and pleuroscopy could not be identified in a review of the published literature.

VATS and medical pleuroscopy have already become well established as less invasive alternatives to open surgical procedures both for diagnostic and therapeutic purposes. There are anatomic limitations to structures that can be visualized and procedures that can be performed by these approaches, and in some cases formal thoracotomy is required instead. Diagnoses based on tissue sampling through these techniques require

appropriate histopathology, culture, or genetic analyses performed by qualified laboratories and personnel.

Positron Emission Tomography

Positron emission tomography (PET) uses a radiopharmaceutical, typically 18F-labelled fluorodeoxyglucose (FDG), in conjunction with CT imaging. Because metabolically active tissues predominantly metabolize glucose and increase the expression of glucose transporters when activated, FDG-PET/CT can detect tissues with increased metabolic activity. It is predominantly used in the staging and monitoring of cancers, as it identifies sites of tumor or metastases that may not be visible on plain imaging. Less commonly, PET/CT may be used for nonmalignant lung diseases, such as chronic infection or inflammatory conditions, to identify the distribution of disease activity or responses to treatment. It may also be useful in distinguishing between infection and rejection as a cause of signs and symptoms in individuals with a lung transplant. The addition of PET scanning to routine CT scanning has increased sensitivity in the identification of some small lesions and makes it possible to better distinguish metabolically active from inert lesions. There is no literature to suggest that the capabilities of PET Imaging differ across demographic or other subpopulations. PET is widely used to evaluate the significance of a solitary pulmonary nodule identified with an X-ray or CT scan. In addition, PET is reported to be useful in identifying the extent and activity of sarcoidoisis, a systemic inflammatory condition that most commonly affects lungs and intrathoracic lymph nodes.

A number of analyses have been reported on the relationship of race and ethnicity to imaging procedures specifically in the evaluation of lung cancer. At least two report less use of guideline-recommended imaging, including PET or PET-CT, in non-Caucasian groups (Gould et al., 2011; Morgan et al., 2020), whereas one contemporaneous report (Suga et al., 2010) found no such disparity. Disparities in other uses of this imaging have not been identified.

Genetic Testing

Genetic testing for mutations in tissue from non-small-cell lung cancers has become a routine part of diagnosis and has transformed the approach to treatment. Currently close to half of all non-small-cell lung cancers can be identified as having a genetic basis that can be targeted by specific therapeutic agents. The identification of genes associated with specific nonmalignant respiratory diseases is also expanding. Testing for mutations in the cystic fibrosis trans-membrane conductance regulator gene associated with CF, along with the measurement of sweat chloride, is already included

in the SSA Listing of Impairments for CF diagnosis. In recent years the specific genotype in this condition has become integral to selection of therapeutic interventions. There is a growing number of other respiratory diseases for which specific mutations are known. For most of these, clinical diagnosis is still based first on findings related to the gene product or function, or phenotype, followed by targeted genetic testing to identify the specific mutations. The associated degree of impairment is assessed with pulmonary function testing or other techniques, although the diagnosis may provide important information related to treatment or prognosis. Examples include mutations in the SERPINA1 gene which codes for alpha-1 anti-trypsin; deficiency or dysfunction of this protein can lead to emphysema and chronic liver disease. Identification of this defect as the cause of emphysema is of value because of the potential for enzyme replacement therapy. Another example is mutations of PHOX 2B which have been found in neonates or older individuals with sleep-related alveolar hypoventilation (also known as congenital hypoventilation syndrome) and other abnormalities of autonomic function.

The addition of genetic analysis to the characterization of lung cancer allows for directed therapy in a significant proportion of cases, which leads to better treatment outcomes than conventional chemotherapy. In nonmalignant diseases genetic testing may confirm a diagnosis that was suspected on the basis of screening tests (e.g., of newborns for cystic fibrosis) or clinical findings (e.g., emphysema) known to be associated with specific gene modifications. The genetic analyses in these applications are performed in specialized laboratories with expertise in the procedures.

EMERGING DIAGNOSTIC AND EVALUATIVE TECHNIQUES

This section reviews the major emerging breakthroughs in the field that will likely influence how repiratory disorders are diagnosed and evaluated in the future.

Forced Oscillation Technique

Forced oscillometry was first developed as a means of assessing the mechanics of the respiratory system in 1956 (duBois) so is not new. It is based on the application of small amplitude pressure oscillations to the airway while the tested subject breathes quietly at normal tidal volumes. The resulting spectral relationship between measured pressures and airflow reflects the respiratory system impedance, from which the values of the variables resistance and reactance are derived. These outcome values cannot be translated into the volumes and flows measured during spirometry, but they do provide complementary information about respiratory system mechanics.

Oscillometry has the potential to fill important gaps in conventional pulmonary function testing. First, because it is performed during tidal breathing (i.e., inhalation and exhalation during restful breathing), it requires little cooperation or effort on the part of the patient. This makes it particularly valuable in assessment of young children or others who may not be able to adequately cooperate with PFT maneuvers. Another potential role for this technique is the identification of small airways disease, such as bronchiolitis, which is often difficult to identify or quantify on spirometry or imaging but is an important cause of morbidity. The feasibility of oscillometry use in clinical practice has increased considerably in recent decades with the development of computers for signal processing and production of instruments by commercial vendors either as standalone products or integrated into suites of pulmonary function testing equipment. Normative values for oscillometry have been reported and continue to be studied. Preliminary data suggest the utility of oscillometry in a number of clinical settings, including the monitoring of airway resistance in asthma, bronchoprovocation and broncho-reactivity testing, and identifying acute rejection in lung transplant recipients. However, no one has yet quantified these effects or defined what role these measures can best play in clinical diagnostics and decision making; as a result, while the technology for oscillometry is readily available, expertise in its use is less widespread, and hasnot yet been integrated into routine clinical practice.

Multidimensional Instruments for Composite Scoring of Asthma Severity

Asthma is a common disease characterized by airway inflammation and hyperreactivity. Asthma is by nature intermittent or variable, and it is also heterogenous with different phenotypes identified in which different manifestations of disease dominate. Grading the severity of asthma is not a simple construct. Multiple instruments have been developed to characterize aspects of asthma in clinical research and in clinical practice. The majority of these focus on “control” and relatively fewer on “severity,” with control refering to the extent of symptoms and other clinical features of asthma and “severity” reflecting the level of treatment required to achieve control symptoms and exacerbations. Because of the dynamic nature of asthma, neither of these characteristics is static. Capturing the global effect of asthma on functionality is therefore challenging and likely to require a multi-dimentional tool.

The Asthma Severity Scoring System (ASSESS) is an instrument developed by members of the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program for use in adolescents and adults with asthma (Fitzpatrick et al., 2020). It scores four domains of asthma: asthma control, which is assessed using a previously developed tool, the Asthma Control

Test; lung function, as reflected in FEV1 as a percent of the predicted value; current medications; and the occurrence and severity of exacerbations over the preceding 6 months. It is scored from 0 to 20, with higher scores reflecting more severe disease. Preliminary reports about this instrument indicate that it correlates with other accepted measures of its component parts and has acceptable test–retest reliability and responsiveness to changes in asthma-related quality of life in heterogeneous asthmatic populations. It is recommended by its developers as a tool in epidemiologic and research studies. Evidence of its utility in clinical assessments and management awaits additional study.

Cell Free DNA (cfDNA) and Related Measures

The measurement of fragments of genetic material in circulating blood (Szilágyi et al., 2020) has gained enormous interest in recent years. It is currently used in clinical practice for the prenatal testing of maternal blood for fetal genetic disorders. There are many forms of circulating genetic material, including free, protein bound, and vescicular forms of nucleic acids from nuclear or mitochondrial DNA or RNA. The term “liquid biopsy” is often used to highlight the potential diagnostic utility of identifying these entities. The analysis of methylation patterns may further identify their tissue sources. In the field of oncology, there is great interest in the potential of liquid biopsy to diagnose cancer at an early stage, identify mutations to target in treatment, and detect sites of metastases or recurrence. Non-oncology conditions for which circulating genetic material has been proposed as biomarkers include rejection in solid organ transplant and the presence of microbial infections. In the area of respiratory disease, a preliminary report by Brusca and colleagues (2022) has found cfDNA analysis to be predictive of prognosis among individuals with pulmonary arterial hypertension. Other potential applications in the area of respiratory medicine include the diagnosis or tracking of chronic infections, including tuberculosis, and of endemic mycoses, which can be difficult to culture, as well as the identification of lung involvement by inflammatory and autoimmune conditions.

REFERENCES