Diagnosing Airway Disease

Jill Ohar, MD


Several presentations at this year's CHEST 2005 meeting addressed the diagnosis of airway disease. Jill Karpel, MD, Director of the Beth Thalheim Asthma Center, North Shore-Long Island Jewish Health System, presented a symposium entitled: "Do patients with asthma experience good symptom control?" The GINA Guidelines define control as:

• Minimal to no chronic symptoms;
• Infrequent exacerbations;
• No emergency visits;
• Minimal to no need for as-needed beta2-agonist;
• No limitations on activities;
• Peak expiratory flow (PEF) circadian variation of <>
• Near-normal PEF; and
• Minimal or no adverse events from medications.[1]

One of the problems with assessing asthma control is what measure should be used? Best practice is to use a composite of asthma measures: quality of life, lung function, symptom scores, exacerbation rates, and indices of inflammation. Fuhlbrigge and coworkers have shown that subjects classified as mild intermittent asthma have 2 times more symptoms than subjects classified as mild persistent asthma.[2] Furthermore, 80% of patients classified as having moderate-to-severe persistent asthma are poorly controlled. The "Asthma is American™" survey showed that 30% of asthma patients don't sleep through the night, more than 30% missed school or work because of asthma symptoms, 48% were limited in their leisure activities, and 23% required unscheduled Medical care.[3] Dolan and coworkers showed that participants in the TENOR study moved among severity categories. Furthermore, control was poor in all categories.[4] Dr. Karpel noted that 90% of asthma deaths (5000 in the United States per year) are preventable. She cited New York State healthcare data that revealed that only 72% of patients receiving inhaled corticosteroids (ICS) prescriptions filled them. More troubling is that only 30% of patients receiving ICS prescriptions used them. A study by Calhoun and coworkers[5] shows that patients characterized by symptoms, peak flow, and albuterol dose all give different estimates of asthma severity. Peak flow correlated with symptoms about 60% of the time. Dr. Karpel reaffirmed the need for use of a composite of asthma severity measures when evaluating control.

Regardless of the control or severity measure used, ICS are effective in achieving control. When ICS are withdrawn, mortality increases 20%.[6] ICS reduce sputum eosinophilia 60% and the reduction in eosinophilia is proportional to frequency of exacerbations.[7] ICS also improve airway hyperresponsiveness[8] and inflammation, as measured with exhaled nitric oxide.[9] Dr. Karpel recommended the use of the Asthma Control Test (ACT) at each visit as an asthma assessment tool. The ACT has content similar to other asthma questionnaires. Clinically meaningful cut points for interpretation of ACT scores have been published.[10] Both the CAMP and the GOAL Studies show that asthma control can be achieved.[11,12] Dr. Karpel concluded with possible reasons why treatment goals are not achieved. These include poor patient perception of control, variability of response to treatment, pharmacogenetic issues, and poor adherence to treatment regimens. Strategies to treat the patient with poorly controlled asthma include revisit their history and asthma control plan; determine specific allergen (skin testing, in vitro testing and history); search for comorbidities (gastroesophageal reflux disease, allergic rhinitis, allergic bronchopulmonary aspergillosis, chronic obstructive pulmonary disease [COPD], and alpha-1 antitrypsin deficiency); exclude conditions such as cystic fibrosis, Ig deficiency, Churg-Strauss syndrome, and chronic obstructive pulmonary disease; assess environmental control issues (asthma triggers, workplace exposures and tobacco smoke); address adherence and inhaler techniques; and assess and monitor drug therapy to optimize benefit.

Chronic Obstructive Pulmonary Disease or Asthma?
Another lecture in the airways disease track was "Is it asthma or COPD -- when to suspect the diagnosis in an adult" presented by Jill Ohar MD, Professor of Medicine, Wake Forest University Medical Center. The Dutch Hypothesis proposes that asthma, chronic bronchitis, and emphysema are different manifestations of the same disease and that the phenotype displayed by a patient is a result of a combination of genetic and environmental factors modulated by age and gender. Bronchial hyperreactivity (BHR), increased rate of decline in forced expiratory volume in 1 second (FEV1), and airway thickness are phenotypic characteristics of both asthma and COPD that have been shown to be associated with genetic sequence alterations in IL-13 and ADAM33.[13-17] BHR, the hallmark of asthma, was seen in 46% of men and 74% of women enrolled in the Lung Health Study.[18] Not only was BHR frequently associated with the presence of COPD, but also the severity of BHR was associated with the annual rate of decline in FEV1[18] and COPD mortality.[19] BHR is associated with airway thickness through Pouseilles Law, and there is a linear relationship between severity of COPD and airway thickness.[20]

Despite similarities between asthma and COPD in regard to BHR, analysis of the dose-response curves to methacholine or histamine is useful in differentiating these 2 distinct disorders. In both asthma and COPD the dose-response curves are shifted to the left, implying enhanced sensitivity to the drugs but the magnitude of this shift is greater for asthma than for COPD. Furthermore, the slope (reactivity) of the dose-response curve is greater with asthma than COPD and in asthma there may be no plateau in the curve. BHR is agent-specific. Generally, patients with asthma, not COPD, respond to eucapnic hyperventilation, and, among children with chronic airway diseases, only those with asthma respond to adenosine 5'-monophosphate.[21]

As clinicians, we tend to rely on other phenotypic characteristics to differentiate between asthma and COPD. These include response to bronchodilators and physiologic differences. Several differences exist between patients with asthma and patients with COPD in their responses to bronchodilators. Patients with asthma develop tolerance to short-acting beta agonists and they therefore should be dosed only on an as-needed basis. In patients with COPD, short-acting beta agonists are not associated with tolerance and should be dosed regularly.[22] In asthma, the use of long-acting beta agonists is associated with increased frequency of exacerbations but their use in COPD is associated with a decrease in the frequency of exacerbations. Anticholinergics have efficacy limited to acute exacerbations in asthma but are a mainstay of therapy in COPD.

Physiologic differences between asthma and COPD include abnormalities in elastic recoil and diffusion in COPD. In asthma these abnormalities do not occur. Hyperinflation that is associated with a volume dominant response to bronchodilators occurs in COPD whereas in asthma the bronchodilator response is flow dominant.[23] The hyperinflation occurs with premature closure of airways during exhalation that results in an increased residual volume that encroaches upon the vital capacity. Often patients with COPD who are not hyperinflated will become so with exertion as minute ventilation increases and time available for exhalation decreases. The diaphragms become flattened and the anterior-to-posterior diameter of the chest is increased, causing a mechanical disadvantage to breathing. The dyspnea experienced by patients with COPD is closely related to the degree of hyperinflation as measured by residual volume/total lung capacity.[24] Bronchodilators relieve this hyperinflation. The volume dominant response to bronchodilators in COPD is seen both with tiotropium[25] and fluticasone-salmeterol combination.[26] COPD subjects treated with tiotropium experienced an increase in vital capacity, and subjects treated with the fluticasone-salmeterol combination experienced an increased inspiratory capacity. Both of these changes are indicative of reduction of hyperinflation. Other differences between asthma and COPD in the response to bronchodilators are the magnitude of response as measured by FEV1 and the reproducibility of response. While both groups of patients respond to bronchodilators, the response of patients with asthma is quantitatively larger than that in COPD.[27] Furthermore, the response to bronchodilators in COPD is erratic as shown by Calverley and coworkers. Patients were evaluated for bronchodilator response on sequential visits. Roughly two thirds of patients responded to albuterol and Atrovent at every visit; however, patients shifted from visit to visit from the responder group to the nonresponder group.[28]

In summary, COPD does differ from asthma by quantity and reproducibility of bronchodilator response, slope of BHR dose-response curve, bronchodilator agent specificity, plateau of dose-response curve, and sensitivity to bronchodilator agent.

Radiologic Screening
Alan Fein, MD, presented "Is radiologic screening ready for prime time?" He noted that the stethoscope was invented in 1819 and the spirometer in 1842. These still remain as useful instruments to help diagnose COPD. Dr. Fein said that much of the morbidity and mortality resultant from COPD stems from its "comorbidities." These include coronary artery disease, lung cancer, and infections. Dr. Fein stated that 50% of patients with COPD have impairment of activities of daily living. The chest radiograph in COPD is often normal and correlates poorly with the magnitude of airways obstruction. Areas of hyperlucency are difficult to evaluate on radiography and computed tomography (CT) because of the inability to determine the normal areas with which apparent hyperlucency may be compared. Dr. Fein noted that although spectacular when present, the finding of low flattened diaphragms is uncommon in mild and moderate COPD. Other classic chest radiograph findings of COPD are an increased anterior-to-posterior diameter, and increased retrosternal airspace and upper lobe enhanced lucency. Because of the relative infrequency of these classic findings, chest radiography is not a sufficient diagnostic tool in COPD.

CT scan technology provides greater accuracy than plain radiographs especially with the use of high-resolution technology. This technology still underestimates the degree of emphysema in panacinar COPD. CT scanning is good in the detection of detect small lung cancers and non-COPD-associated airway obstruction such as proximal airway obstruction, bronchiectasis, and bronchiolitis obliterans. Quantitative CT scanning, which is currently under investigation, uses a density mask to highlight areas below a defined density threshold. It can be used to measure airway thickness and airtrapping. To date, airway thickness as measured by this technique correlates well with histologic specimens. Wall area and lumen area correlate with FEV1. Furthermore, quantitative difference between inspiratory and expiratory CT scans is a measurement of airtrapping. Finally, quantitative CT scanning aids surgical decision making in lung reduction and for excision of tumors.