Asthma: Diagnosis and Classification 2017

©Timothy Scialla MD /Ambulatory Curriculum

Objectives:

1. Overview of the pathogenesis of asthma

2. Diagnosis of asthma

3. Pulmonary Function Testing and Differential Diagnosis

4. Interpretation of Spirometry

5. Classifying asthma severity

6. Assessing asthma control

Case 1: Pathogenesis and Diagnosis of Asthma

D'Angelo Barksdale decided to leave the family business and moved to the east side of town.

After living there for three months, D'Angelo noted that he had begun to have periodic episodes

of wheezing and cough especially at night. He tried using some of his girlfriend Donette's

albuterol, and it helped. Although the symptoms were quite severe last month, they seem to

be better now without any change to D’s home environment. He comes in to clinic to evaluate

these symptoms. Which of the following statements is correct regarding the diagnosis of

asthma?

A. Wheezing that improves after using an albuterol inhaler is sufficient to diagnose asthma.

B. Periodic episodes of wheezing and cough that resolve spontaneously are not consistent

with the diagnosis of asthma

C. To make the diagnosis of asthma, there needs to be documentation of at least partially

reversible airflow obstruction and alternative diagnoses must be excluded.

D. There are two phases of inflammation in asthma, an acute and subacute phase. After

the trigger is removed, the airways return to normal without evidence of ongoing

inflammation.

Pop Up Answers

A. Incorrect. Although useful in establishing the diagnosis, improvement in symptoms

after inhaler use is not sufficient to diagnose asthma. Other possible diagnoses should

be excluded and objective evidence of at least partially reversible airflow obstruction

should be documented.

B. Incorrect. One of the hallmarks of asthma is that symptoms are episodic and that

airway obstruction can improve either with treatment OR spontaneously.

C. Correct. When making a diagnosis of asthma, the clinician should focus on three key

features: episodic symptoms that can be explained by airflow obstruction and airway

hyperresponsiveness; airflow obstruction that is at least partially reversible; and

exclusion of alternative diagnoses.

D. Incorrect. There are three phases of inflammation: acute, subacute, and chronic.

Chronic inflammation is found in all types of asthma, and predisposes individuals to

bronchial hyperresponsiveness and related symptoms.

Summary Answer

The correct answer is C: To make the diagnosis of asthma, there needs to be documentation of

at least partially reversible airflow obstruction and alternative diagnoses must be excluded.

Introduction

Asthma is a complex lung disorder with the following characteristics:

Variable and recurring symptoms

Reversible airway obstruction, either spontaneously or with treatment

Airway inflammation

Airway hyperresponsiveness to a variety of stimuli.

While asthma was previously thought to be driven by bronchospasm, edema, and mucus

hypersecretion, advances in the last several decades have highlighted inflammation as playing a

critical role in the pathogenesis of asthma. Furthermore, we have come to understand the

importance of individual susceptibility (i.e., genetic predisposition) in the development of

asthma. As such, asthma is no longer believed to be a single disease but rather a heterogeneous

disease with variable inflammatory phenotypes.

Inflammation in Asthma

The traditional “singular hypothesis” for acute inflammation in asthma is referred to as the Th2-

inflammation hypothesis. In this hypothesis, acute inflammation, characterized by mast cell

degranulation and histamine release, is triggered by exposure to viruses, indoor and outdoor

pollutants, or allergen exposure. These alterations ultimately result in vasodilatation, mucus

secretion, and airway smooth muscle contraction. As a result, patients will note that

immediately after being exposed to a trigger (e.g., pollen) they have cough and wheezing,

sometimes with sputum production. In the subacute phase of inflammation, which typically

occurs 6 to 9 hours after an asthma trigger exposure, CD4+ T cells, basophils, neutrophils, and

macrophages are recruited to the lungs, along with eosinophils. Chronic inflammation is found

in all types of asthma, and predisposes individuals to bronchial hyperresponsiveness and related

symptoms. Over time, cyclic chronic inflammation and healing can result in airway remodeling

with subsequent fibrosis and increased mass of both smooth muscle cells and mucus glands.

This type of airflow obstruction can be persistent and unresponsive to therapy.

In recent years, this singular hypothesis for asthma has been challenged. There are many

asthmatics for whom an allergic trigger cannot be identified (nonatopic asthmatics). Moreover,

it has been noted that there is variability in response to standard asthma therapy suggesting

alternative pathways of inflammation. In fact, distinct inflammatory phenotypes have been

described in a cohort of asthmatics based on induced sputum cytology. These inflammatory

subtypes include:

Eosinophilic asthma

Neutrophilic asthma

Paucigranulocytic asthma

Mixed Granulocytic asthma

Endotyping Asthma: The Future of Asthma Diagnosis and Management

The term endotype derives from contracting the word, endophenotyping. It defines an effort to

move beyond simply phenotyping asthma, which traditionally was used to describe only

observable characteristics. An endotype is defined as a disease subtype with the subtype

determined by a distinct molecular mechanism. This mechanism in turn drives the physiology

and pathology of the disease’s presentation. Under this classification, asthma would be

considered a syndrome that encompasses a series of specific endotypes. This concept is already

emerging as a potential path to “personal asthma therapy.” A patient with poorly controlled

asthma will be identified as having a specific endotype for which there are distinct clinical

features and distinct treatment options.

Diagnosis of Asthma

When making a diagnosis of asthma, the clinician should focus on three key features:

Episodic symptoms that can be explained by airflow obstruction and airway

hyperresponsiveness

Airflow obstruction that is at least partially reversible

Exclusion of alternative diagnoses

The recommended steps to establish a diagnosis are shown below:

Figure 1: Diagnostic Steps in Suspected Asthma

The signs and symptoms of asthma vary widely from patient to patient (as well as within the

same patient) over time. Therefore, clinical judgment is very important in conducting the

assessment of asthma.

Medical History

Clinicians should consider the diagnosis of asthma and perform spirometry if any of the

indicators in Table 1 are present. The presence of multiple key indicators increases the

probability of a diagnosis of asthma. Note that spirometry is needed to establish a diagnosis.

Table 1: The Role of the Medical History in Diagnosis of Asthma

Although not considered key indicators of asthma, eczema, hay fever, and family history of

asthma or atopy are often associated with asthma.

Role of Social History

Social history is critical in the evaluation of a patient who may have asthma. Clinicians should

ascertain whether there is an association between the workplace and respiratory symptoms

(e.g., are symptoms worse while the patient is at work, or has the patient noted a difference in

symptom severity in weekdays from weekends). Work activities may suggest potential triggers

of asthma, which are listed in Table 2. For instance, ask if the patient works with chemicals or

powders known to be associated with occupational asthma. Furthermore, the home

environment can present potential triggers of asthma, such as heating and cooling systems,

carpets, pets, cockroaches, and the presence of mold or mildew. Tobacco use by either the

patient or their household contacts should be queried.

Table 2: Typical Asthma Triggers

Physical Examination

The physical examination should focus on the respiratory tract, skin, and chest (Figure 2). The

listed physical findings increase the probability of asthma. It is not unusual, however, for a

patient with asthma, particularly those with intermittent disease, to have a normal physical

examination. Therefore, a normal physical examination does not exclude the diagnosis of

asthma.

Figure 2: The Physical Exam in Asthma

Differential Diagnosis

Episodic wheezing, cough, and dyspnea are most frequently due to asthma in the general adult

population. Nonetheless, the clinician should be aware of other diagnoses that may mimic

asthma (Table 3). Moreover, patients with confirmed asthma can also have other co-morbid

conditions that make their asthma appear worse. For instance, asthma and allergic

bronchopulmonary aspergillosis (ABPA) often go hand and hand in patients with ABPA.

Furthermore, patients with mild asthma may rather abruptly develop severe symptoms with

new infiltrates suggestive of Churg-Strauss syndrome. Recurrent aspiration can certainly worsen

asthma symptoms and vocal cord dysfunction can both mimic asthma or co-exist with it. A

complete review of the diagnosis and management of these conditions (Table 3) is beyond the

scope of this module.

Table 3: Differential Diagnosis of Episodic Wheezing

Case 2: Spirometry Interpretation

Brother Mouzone has recently moved to Baltimore. He had been living in New York City but

relocated because of a new job opportunity. Unfortunately, shortly after arriving, he began to

experience shortness of breath with exertion, along with a non-productive cough that is worse

at night. Work has been stressful lately and he has had little time to relax. Due to his symptoms

you obtain spirometry, with the following results:

Based on the spirometry results, which statement is most accurate?

A. Normal spirometry with no evidence of obstruction.

B. A mild restrictive defect is possible. Further testing is recommended.

C. A mild obstructive defect is present because FEV1 is less than 70% predicted.

D. A mixed obstructive and restrictive defect is present.

Pop Up Answers

A. Incorrect. Although there is no evidence of obstruction, the FVC is low (71% predicted)

making these results abnormal.

B. Correct. The FVC is 71% predicted, which is suggestive of a mild restrictive defect.

However, additional testing is needed to confirm restriction (e.g., helium lung volumes,

body plethysmography).

C. Incorrect. Obstruction is defined by the FEV1/FVC. The American Thoracic Society

suggests an FEV1/FVC of 70% or less as defining obstruction. The severity of obstruction

is defined by the FEV1 % predicted.

D. Incorrect. The spirometry does not show evidence of obstruction.

Summary answer

The correct answer is B. A mild restrictive defect is possible. Further testing is recommended.

This section focuses on spirometry and its application in diagnosing pulmonary disease. For

additional information, the learner is referred to the NEJM or American Family Physician reviews

of this topic.

Spirometry

Spirometry with and without bronchodilators is recommended to evaluate all patients with

ongoing respiratory problems. Spirometry measures total air forcibly expired from the lungs

after maximal inspiration (the forced vital capacity, or FVC) and measures the amount of air

forcibly exhaled in one second after maximal inspiration (the forced exhaled volume in 1 second,

or FEV1). In the presence of airflow limitation, the individual exhales air more slowly, while the

total volume of air exhaled is generally not affected (provided there is not severe air trapping).

Thus airflow obstruction is diagnosed by a reduced FEV1/FVC ratio. The American Thoracic

Society suggests a ratio of <70% as defining obstruction, though individual laboratories may vary

in their diagnostic criteria. Once we have defined obstruction with an FEV1/FVC <70%, we then

classify the severity of obstruction (i.e., mild, moderate, severe, very severe) based on the FEV1

in relation to predicted values (Table 4).

Table 4: Spirometry: Severity of Obstruction

Demonstrating Reversible Airways Obstruction

After identifying obstruction in an individual and classifying its severity, we can then determine

whether it is reversible. Demonstrating reversibility of airways obstruction is useful in

differentiating asthma (in which obstruction is reversible) from COPD (in which obstruction is

not reversible).

Bronchodilators such as albuterol are used to test for reversible obstruction after obtaining

baseline spirometry. An improvement in airflow obstruction due to bronchodilation is reflected

by an increase in the FEV1. Significant reversibility is defined by an increase of ≥12% and 200mL

in FEV1 from baseline measure after inhalation of a short-acting bronchodilator (SABA) (Figure

3). Although lack of reversibility of obstruction typically differentiates asthma from COPD,

patients with poorly-controlled asthma may not demonstrate reversible airways obstruction

when tested. These patients should be treated with a short course of oral corticosteroids for 2-3

weeks and then retested.

Recall that asthma is defined by episodic airway obstruction. Normal PFTs do not exclude

asthma in the asymptomatic patient.

Figure 3: Spirometry and Expiratory Flow Before and After Bronchodilator

Restrictive Lung Disease

Spirometry can also provide important clues to pathology other than obstruction. The first clue

that restrictive lung disease might be present comes from the FVC. An FVC<80% predicted is

consistent with (but not diagnostic of) restrictive lung disease. To diagnose restrictive lung

disease, we need to obtain the total lung capacity (TLC) using static lung volumes. When the

FVC<80% and the TLC<90% predicted, a restrictive ventilatory defect is present. The differential

diagnosis of restrictive lung disease is listed in Table 5.

Table 5: Differential Diagnosis of Common Causes of a Restrictive Ventilatory Defect

In some patients, both a restrictive and obstructive ventilatory defect may be present. PFTs

would show a reduced FVC (<80%) and an FEV1/FVC<70%. This pattern suggests either two

processes are present (i.e., restrictive lung disease and obstructive lung disease), or obstructive

lung disease with air trapping. In this latter scenario, the affected individual is unable to fully

empty the lungs, essentially restricting their FVC. To differentiate restrictive lung disease from

obstructive lung disease with air trapping, look at the TLC. If the TLC is normal or increased,

obstructive lung disease with air trapping is present. If the TLC is reduced (i.e., <90% predicted),

restrictive lung disease is present. This is reviewed in the table and figure below.

Table 6: Obstructive vs. Restrictive Lung Patterns

Figure 4: A Stepwise Approach to Interpreting Spirometry

Flow Volume Loops

Often when spirometry is obtained on a patient suspected of having obstructive lung disease,

flow volume loops will be obtained as well. These loops can be very helpful in differentiating

various causes of shortness of breath and wheezing. In the normal host, inhalation flow rates

are greater than flow rates during exhalation. At times, there may be an obstruction that affects

inhalation, or an obstruction that affects exhalation. This obstruction may be within the chest

cavity (i.e., intrathoracic) or outside of the chest cavity (i.e., extrathoracic). Flow volume loops

are useful to differentiate intrathoracic from extrathoracic variable obstruction. With

intrathoracic obstruction, airflow is limited during exhalation (as we have seen with asthma and

COPD). With extrathoracic obstruction, airflow is limited during inhalation.

On flow volume loops, inspiration is represented below the x-axis and expiration represented

above the x-axis. If there is limitation of flow during inspiration (as seen with an extrathoracic

obstruction), the flow volume loop below the x-axis will be abnormal (an example of this would

be vocal cord dysfunction). When airway flow is limited during both inspiration and expiration,

the pattern is said to be fixed. If flow is limited in only inspiration or expiration, the pattern is

said to be variable.

A full list of flow volume loops patterns are described in Figure 5.

Figure 5: Flow Volume Loops of Different Lung Diseases

Common causes of intrathoracic, extrathoracic, and fixed obstruction are listed in Table 7.

Table 7: Causes of Lung Obstruction

What follows are four practice cases on interpretation of spirometry.

Case 3: Spirometry Practice Case 1

A 71-year-old male undergoes spirometry for shortness of breath with minimal exertion. The

results are as follows:

Additional testing (i.e., lung volumes) is recommended, and shows:

Which interpretation is correct?

A. Mixed obstructive and restrictive defects

B. Obstructive defect alone

C. Restrictive defect alone

D. Normal spirometry

Pop Up Answers

A. Incorrect

B. Correct! This pattern is consistent with very severe COPD.

C. Incorrect

D. Incorrect

Case 4: Spirometry Practice Case 2

A 39-year-old female with a history of asthma with ongoing respiratory symptoms undergoes

spirometry, which is shown below:

Additional testing (i.e., lung volumes) is recommended, and shows:

Which interpretation is correct?

A. Mixed obstructive and restrictive defects

B. Obstructive defect alone

C. Restrictive defect alone

D. Normal spirometry

Pop Up Answers

A. Incorrect

B. Incorrect

C. Correct!

D. Incorrect

Case 5: Spirometry Practice Case 3

A 34-year-old male with exertional dyspnea and nighttime coughing and wheezing undergoes

spirometry, which shows:

Lung volumes are as follows:

Which interpretation is correct?

A. Mixed obstructive and restrictive defects.

B. Obstructive defect alone.

C. Restrictive defect alone.

D. Normal spirometry

Pop Up Answers

A. Correct!

B. Incorrect

C. Incorrect

D. Incorrect

Case 6: Flow Volume Loop Practice Case

32-year-old female comes to your office complaining about shortness of breath on exertion. She

has been diagnosed with asthma, but her asthma medications have not helped in relieving her

symptoms. She has a history of tracheotomy after a motor vehicle accident when she was 14.

Pulmonary function testing reveals:

The flow volume loop is shown below:

Which of the following of upper airway obstructions is suggested by the flow volume loop?

A. A variable extrathoracic obstruction

B. A variable intrathoracic obstruction

C. A fixed upper airway obstruction

D. No evidence of upper airway obstruction.

Pop Up Answers

A. Incorrect

B. Incorrect

C. Correct!

D. Incorrect

Case 7: Airflow Obstruction: Differentiating COPD and Asthma

You are reevaluating your patient Nick Sobatka, who has presented with episodic shortness of

breath. He mentions that his uncle Frank also has shortness of breath, but Uncle Frank never

seems to get better. Upon further questioning, you learn that Uncle Frank has been a heavy

smoker for several decades. Nick brings you results of his pulmonary function tests, and

surprisingly produces a copy of Uncle Frank's pulmonary function tests as well.

Which one of the following is true?

A. Nick's PFTs confirm that he does not have asthma.

B. Uncle Frank's PFTs confirm that he has asthma.

C. Adding a methacholine challenge to Nick's PFT evaluation would demonstrate a 20%

increase in FEV1 with the methacholine challenge if he had asthma.

D. Uncle Frank's PFTs suggest a diagnosis of COPD.

Pop Up Answers

A. Incorrect. Normal PFTs in the asymptomatic patient do not exclude a diagnosis of

asthma.

B. Incorrect. DLCO is either normal or increased in asthma; in Uncle Frank, the DLCO is

decreased.

C. Incorrect. While a methacholine challenge is used to evaluate for asthma, methacholine

would result in at least a 20% reduction in FEV1 in patients with asthma. Unfortunately,

the methacholine challenge is sensitive but not specific for a diagnosis of asthma.

D. Correct. Obstruction, as demonstrated by an FEV1/FVC ratio of <70%, is always present

in COPD, but may or may not be present in asthma.

Summary answer

The correct answer is D: Uncle Frank's PFTs suggest a diagnosis of COPD.

Airflow obstruction (FEV1/FVC < 70%) is present in many diseases, the most common are

asthma and chronic obstructive pulmonary disease (COPD). Others include cystic fibrosis (CF)-

associated bronchiectasis, non-CF bronchiectasis, and diffuse panbronchiolitis. The decline in

FEV1 in asthma is generally reversible, while the pathologic changes in COPD are not associated

with reversible airflow limitations (see figure below); therefore, there is generally not a

significant improvement in FEV1 in response to bronchodilators in persons with pure COPD.

Often, patients with COPD will have a decreased diffusing capacity of carbon monoxide as well.

This is the result of capillary destruction and loss of effective surface area for diffusion. On the

other hand, asthmatics will have normal diffusing capacity and on occasion they can even be

elevated secondary to increased pulmonary blood flow.

Helium lung volumes are often similar in asthma and COPD, demonstrating normal or increased

TLC, especially with less advanced stages of COPD. Therefore, they are not useful in

discriminating between the two diseases. For example, total lung capacity (the maximum

volume of air filling the lungs) can be normal in steady state asthma and early stages of COPD.

In severe asthma and advanced COPD it is often elevated because of hyperinflation. The residual

volume (the volume of air remaining in the lung after a maximal exhalation) can also be normal

or increased (air trapping). A decreased total lung capacity however should prompt an

alternative diagnosis (restrictive lung disease). A comparison of asthma and COPD is provided in

the figure and tables below.

Figure 6: Expiratory Flow Rates Comparing the Response of COPD and Asthma to

Bronchodilators (BD).

In both cases above, there is significant obstruction present, as well as reduction in the peak

expiratory flow rate (PEFR) compared to predicted values. In the patient with severe COPD,

there is no response after BD in the PEFR, FEV1, and FVC. In contrast, the patient with chronic

asthma shows an upward shift in flow curve in response to BD, as well as improvement in all

parameters (PEFR, FEV1, and FVC).

Table 8: Comparison of Clinical Findings in Asthma and COPD

*Hyperpigmented patches on thighs proximal to the knees, from chronic elbow pressure as the

emphysematous patient rests leaning forward to improve breathing.

Table 9: PFTs in Asthma vs. COPD

*In both asthma and COPD, the total lung capacity/residual volume as measured by helium lung

volumes is either normal (steady state asthma/early COPD) or increased (asthma

exacerbation/advanced COPD).

Diurnal Variation of PEF in Asthma

PEF is generally lowest upon awakening in the morning and highest between 2 and 4 pm. In

patients with no airflow limitation on spirometry but symptoms suggestive of asthma, a diurnal

assessment of peak expiratory flow (PEF) rate over 1-2 weeks is recommended. After giving the

patient a peak flow meter and instructing them in the use, the clinician should recommend a

schedule for performing the test, for example upon awaking in the morning, after lunch, and

after dinner. The measurement should be made before the use of a bronchodilator. The early

afternoon value is taken as the maximum value and is then compared to the morning

(minimum) value. A 20% difference (maximum-minimum/ maximum > 20) is consistent with the

diagnosis of airflow limitation from asthma. The accuracy and utility of this assessment has been

called into question, as many values are needed to ensure meaningful results.

The Methacholine Challenge

In cases of suspected asthma with normal spirometry and no significant variation in PEF,

bronchoprovocation with methacholine is indicated. Methacholine is a derivative of

acetylcholine that stimulates muscarinic receptors, causing airway smooth muscle contraction.

The FEV1 is expected to drop by 20% or more in individuals with airway hyperresponsiveness.

Although the mechanics of performing the test are out of the scope of this module, the curious

reader is invited to learn more about the procedure by reading the ATS guidelines. During the

challenge test, increasing concentrations of methacholine are given to the patient and after

each concentration the FEV1 is measured. Like any test, the pre-test probability of having

asthma as well as the total amount of methacholine used to reduce the FEV1 must be

considered when interpreting the results.

The methacholine challenge test is an extremely sensitive test for asthma, though not specific.

Thus individuals without asthma may have a positive methacholine challenge, while a negative

test essentially excludes a diagnosis of asthma. Potential factors other than asthma associated

with a positive test include allergic and non-allergic rhinitis, respiratory infection, COPD, GERD,

obesity, and vocal cord dysfunction. Methacholine administration is not recommended if the

FEV1 is <65%predicted, due to concerns of severe bronchoconstriction and dyspnea. These steps

are reviewed in Figure 7.

Figure 7: Steps in Diagnosing Asthma

*Methacholine is sensitive for diagnosis of asthma, but not specific. Alternate diagnoses remain

possible.

Case 8: Classification of Asthma Severity

Michael Lee presents to your clinic for evaluation of wheezing and nocturnal cough. His

symptoms seem to worsen in cold air and during the spring. In clinic, his spirometry post

bronchodilator shows an 18% improvement in his FEV1. You diagnose him with asthma and

assess his symptoms. In the past 2-4 weeks, he has had symptoms at least once every day. He

borrowed his friend Duquan's albuterol inhaler and used it four days last week. He has

awakened from sleep with cough 3 times in the past month. He has never been treated for an

exacerbation or sought emergency medical attention for his symptoms.

How would you classify and manage Michael’s asthma based on the above?

A. He has mild persistent asthma and should be reevaluated in 2 to 6 months.

B. He has severe persistent asthma and should be sent to the emergency department.

C. He has moderate persistent asthma and should be reevaluated in 2 to 6 weeks.

D. He initially had moderate persistent asthma and should be reevaluated in 2 to 6 months.

Pop Up answers

A. Incorrect. Michael has moderate persistent asthma because he has had symptoms daily.

He should be reevaluated for control in 2 to 6 weeks.

B. Incorrect. Michael has moderate persistent asthma because he has had symptoms daily.

He should be reevaluated for control in 2 to 6 weeks.

C. Correct! Michael has moderate persistent asthma because he has had symptoms daily.

He should be reevaluated for control in 2 to 6 weeks.

D. Incorrect. Michael has moderate persistent asthma because he has had symptoms daily.

He should be reevaluated for control in 2 to 6 weeks.

Summary answer

The correct answer is C: He has moderate persistent asthma and should be reevaluated in 2 to

6 weeks.

Classification of Asthma

Having learned about the diagnosis of asthma, the clinician will need to assess the severity of

disease in order to guide clinical decisions on appropriate medications and interventions

(discussed in detail in the accompanying module on asthma management). Severity describes

the intrinsic intensity of the disease process. This initial assessment of severity should be made

at the time of diagnosis, preferably prior to the patient starting long-term controller therapy.

This assessment is made by combining current spirometry results, the patient's recall of

symptoms over the past 2 to 4 weeks, and history of exacerbations requiring oral systemic

steroids in the past year.

To determine severity, ask the patient the following:

How frequently do you have symptoms of cough, shortness of breath, or wheeze?

How frequently do you have night awakenings?

How frequently are you using SABA to treat your symptoms?

Are you limited in your ability to engage in normal or desired activities?

Next, evaluate the patient's most recent spirometry and assess the FEV1 and the FEV1/FVC.

Compare the patient's best FEV1 value to the percent predicted FEV1. For FEV1/FVC, compare

the patient's value to the normal values based on age.

Finally, ask the patient the number of exacerbations in the past year that required oral systemic

corticosteroids and emergency room visits or hospitalizations.

The NAEPP now recommends that asthma severity be defined in terms of two domains: current

impairment and future risk. The distinction between impairment and risk is emphasized in the

guidelines "to consider separately asthma's effects on quality of life and functional capacity on

an ongoing basis (i.e., at present) and the risks asthma presents for adverse events in the

future” (exacerbations and decline in lung function). Table 8 describes the four classes of

asthma severity in terms of impairment. The level of severity is assigned to the most severe

category in which any feature occurs. In addition to impairment, future risk is taken into

consideration when determining asthma severity by asking each patient the number of asthma

exacerbations in the past year that required oral corticosteroids. If a patient has had more than

one such exacerbation in the past year, they are considered to have at least persistent asthma

even if they have no current impairment. Importantly, the guidelines note that there is no

currently accepted way of correlating the number of exacerbations per year with grade of

severity. Therefore, in the particular case of a patient who has very few symptoms outside of

acute exacerbations, he or she would be classified as having persistent asthma not otherwise

classified.

Table 10: Asthma Classification

Note: SABA = short-acting beta agonist

A few important points:

Normal FEV1/FVC ratios differ by age (for 20-39 year olds, normal is 80%; for 40-59 year

olds, normal is 75%; and for 60-80 year olds, normal is 70%).

Although asthma severity is almost always classified by the most severe symptoms of

impairment, in patients with only intermittent impairment BUT greater than one

exacerbation per year requiring oral corticosteroids, asthma severity would be defined

as mild persistent.

Treatment is discussed in detail in the related module on asthma management, but is

summarized in the figure below. Patients initially diagnosed with moderate or severe persistent

asthma might require a short course of oral corticosteroids at diagnosis. For all patients,

response to therapy should be assessed in 2-6 weeks.

Figure 8: Classification-Based Treatment of Asthma

Case 9: Asthma Diagnosis Practice Case 1

Ms. Sanchez is a 20-year-old woman with no other medical problems. She reports intermittent

wheezing once per month usually in the setting of an exposure to her friend's cat. She has never

had nocturnal symptoms. Her symptoms are easily relieved by one dose of albuterol MDI and

she has normal spirometry. She has never been to the Emergency Department for her

symptoms nor has she had an exacerbation requiring oral corticosteroids. Her asthma is

classified as:

A. Intermittent asthma

B. Mild persistent asthma

C. Moderate persistent asthma

D. Severe persistent asthma

Pop Up Answers

A. Correct!

B. Incorrect

C. Incorrect

D. Incorrect

Summary answer

The correct answer is A: Intermittent asthma

Ms. Sanchez meets criteria for intermittent asthma. Regarding the impairment domain, she has

symptoms fewer than two times per week, never has nocturnal symptoms, uses short-acting

beta-agonists fewer than two days per week and has normal spirometry. Regarding the risk

domain, she has not had exacerbations that require oral steroids in the past year.

Case 10: Asthma Diagnosis Practice Case 2

Mr. Hallowell is a 41-year-old man recently diagnosed with asthma. He reports wheezing

approximately three times per week, often when cleaning his apartment. His symptoms are

relieved with short-acting beta-agonists and he wakes up about three times per month to use

this medication as well. His pulmonary function tests are normal. In the past year, he has

required oral prednisone once for an exacerbation that did not improve with use of his short-

acting beta-agonist (SABA) inhaler. He has never been to the emergency department nor

hospitalized for his asthma. His asthma is classified as:

A. Intermittent asthma

B. Mild persistent asthma

C. Moderate persistent asthma

D. Severe persistent asthma

Pop Up Answers

A. Incorrect

B. Correct

C. Incorrect

D. Incorrect

Summary answer

The correct answer is B: Mild persistent asthma.

Mr. Hallowell has mild persistent asthma characterized by symptoms more than twice a week,

but not daily, and more than twice a month nocturnal awakenings. His use of short-acting beta-

agonists more than twice a week and less than daily as well as normal spirometry is also

consistent with this classification. His use of oral systemic steroids once in the past year does

not alter his classification in this case.

Case 11: Asthma Diagnosis Practice Case 3

Ms. Davison is a 55-year-old woman with a recent diagnosis of asthma. She reports that her

activity is severely limited due to her asthma symptoms and that she uses her albuterol MDI

several times per day. She wakes up every night to use her MDI as well. Her FEV1/FVC ratio is

reduced by 7% on spirometry. She was recently discharged from the hospital, where she was

admitted to the intensive care unit for her asthma. She was not intubated, but did receive

intravenous systemic steroids and was discharged on oral prednisone.

A. Intermittent asthma

B. Mild persistent asthma

C. Moderate persistent asthma

D. Severe persistent asthma

Pop Up Answers

A. Incorrect

B. Incorrect

C. Incorrect

D. Correct

Summary answer

The correct answer is D: Severe persistent asthma

Ms. Simpson has symptoms that are consistent with severe persistent asthma as she has

symptoms throughout the day with severe activity limitation, nightly awakenings and a

reduction in FEV1/FVC ratio of >5%. She also has had a severe asthma exacerbation that raises

concern for future exacerbations and increased risk for morbidity and mortality.

Case 12: The Periodic Assessment of Asthma Control

Avon Barksdale is coming to your clinic for the first time. He is a 37-year-old former Golden

Glove boxer with a long-standing history of asthma. He has been on a fluticasone inhaler for the

past three years and has an albuterol HFA. He reports that he continues to use his albuterol at

least 2 times per week. Despite this, he denies any limitation in his daily activities. He does not

complain of night symptoms. He did have a URI 2 months ago that led to an asthma

exacerbation requiring oral steroid therapy. He also required a course of oral steroids 6 months

ago when he did not refill his steroid inhaler on time. Spirometry obtained in clinic shows

FEV1/FVC that is 85% of predicted.

Which of the following statements about his asthma control is true?

A. His asthma is well controlled because he has had no limitations in his normal activity.

B. His asthma is not well controlled because he has had greater than 2 exacerbations in the

past year requiring oral steroids.

C. His asthma severity has changed from intermittent asthma to mild persistent asthma.

D. His asthma severity has changed from mild persistent asthma to moderate persistent

asthma.

Pop Up Answers

A. Incorrect. Asthma control is equally assessed in the two domains of impairment and risk.

Because of his 2 exacerbations requiring oral steroids, the risk domain places him in the

not well controlled category.

B. Correct. Asthma control is equally assessed in the two domains of impairment and risk.

Under the risk domain he has had 2 exacerbations requiring oral steroids. That classifies

his asthma as not well controlled.

C. Incorrect. Once a patient is on long-term controller therapy, emphasis is placed on

assessing asthma control rather than reclassifying his severity.

D. Incorrect. Once a patient is on long-term controller therapy, emphasis is placed on

assessing asthma control rather than reclassifying his severity.

Summary answer

The correct answer is B: His asthma is not well controlled because he has had greater than 2

exacerbations in the past year requiring oral steroids.

We have thus far reviewed diagnosis and classification of asthma. The next step is to assess how

well asthma is controlled.

Asthma Control

Just as we classify asthma severity, we also classify asthma control. Importantly, once a patient

is placed on controller therapy (see Asthma Management module), only asthma control is

assessed at each visit as it is control (not severity) that is most important in predicting future

morbidity.

Asthma control is categorized as "well controlled", "not well controlled", or "poorly controlled".

The level of control determines whether adjustments to clinical care are made, as shown in

Figure 9. Note the importance of assessment of control, based on the following key points:

Well-controlled patients should maintain their current treatment, and consider step-

down treatment if well-controlled for 3 months.

Not well-controlled patients should step up in treatment, and be re-evaluated in 2-6

weeks.

Poorly-controlled patients should step up two steps in treatment, and be re-evaluated in

2 weeks.

Figure 9: Assessing Control and Adjusting Therapy

As with asthma severity, asthma control is defined in two domains: current impairment and

future risk.

On each subsequent visit, asthma control in the impairment domain is assessed by asking the

asthma patient the following questions:

How frequently do you have symptoms of cough, shortness of breath, or wheeze?

How frequently do you have night awakenings?

How frequently are you using SABA to treat your symptoms

Are you limited in your ability to engage in normal or desired activities?

For the risk domain, the patient is asked about the number of exacerbations requiring oral

corticosteroids in the past year. In addition, adverse effects to medications are assessed in the

risk domain to stress their long-term impact. Serious side effects would likely lead to alternative

treatment options (See Asthma Management module) or review of inhaler technique.

The overall level of control is determined by the most extreme answer to the above questions.

Level of control then dictates the next step in management (e.g., pharmacotherapy).

Remembering to ask all these questions and recalling how the answers affect level of control

can be challenging. Asking how frequently a patient uses a SABA in a given week is a very

useful opening question. If the answer is more than twice a week, the patient’s asthma is not

well controlled and needs adjustments in treatment. In other words, the well-controlled

asthmatic should rarely need to use a SABA!

Case 13: Asthma Diagnosis Practice Case 4

Mr. Dunn is a 36-year-old with a history of intermittent asthma. Up until two weeks ago, when

he went on a haunted hay ride with his children, he never used his SABA, and had no limitations

in his normal activity. However, since the ride, he is coughing and wheezing daily and has been

using his SABA 4 times daily with little benefit. He awakens nightly with his symptoms. He does

not record peak flows at home. His spirometry in clinic showed an FEV1 80% predicted.

Based on this presentation, Mr. Dunn’s asthma is:

A. Well controlled

B. Not well controlled

C. Poorly controlled

Pop Up Answers

A. Incorrect

B. Incorrect

C. Correct

Summary answer

The correct answer is C: Poorly controlled.

Assessment of this patient's control in the impairment domain (current symptoms) reveals his

asthma to be very poorly controlled. The patient is having symptoms through the day, daily

nocturnal symptoms, and is using his SABA several times per day. Recommended therapy

includes consideration of oral systemic steroids and a step up in therapy. The patient should be

reassessed in 2 weeks. The risk domain was not assessed but in this case would not have

changed his level of control.

Case 14: Asthma Diagnosis Practice Case 5

Ms. Keller is a 45-year-old with asthma since childhood. She is on low-dose inhaled

corticosteroids. In the past 2 to 4 weeks, the patient reports needing her albuterol inhaler two

times during exercise. She has no limitations in her normal activity and no nighttime symptoms.

She has one ICU admission for her asthma 5 years ago and has required oral steroids twice in

the past year for worsening symptoms. Both courses were given after the patient had an upper

respiratory infection.

Based on this presentation, Ms. Keller’s asthma is:

A. Well controlled

B. Not well controlled

C. Poorly controlled

Pop Up Answers

A. Incorrect

B. Correct

C. Incorrect

Summary answer

The correct answer is B: Not well controlled.

This patient's asthma is not well controlled. This example stresses the importance of assessing

control in the two domains of impairment and risk. Although the patient does not have any

limitations at the moment (no current impairment), her risk of recurrent exacerbations is

increased because of her need for oral systemic steroids twice in the past year. She should be

followed closely and a 1 level step up would be appropriate.

Case 15 Asthma Diagnosis Practice Case 6

Mr. Kostis is an 82-year-old with a recent diagnosis of asthma. He is a lifetime nonsmoker and

has done well with his asthma symptoms since he was started on fluticasone for mild persistent

asthma. In the past 2 to 4 weeks, he has not needed his SABA, nor has he had any limitations in

his normal activity. His FEV1 is 85% predicted. He has never been hospitalized and has never

needed oral systemic steroids for asthma symptoms. He does complain of sore throat and on

exam has oral thrush.

Based on the above, Mr. Kostis’ asthma is:

A. Well controlled

B. Not well controlled

C. Poorly controlled

Pop Up Answers

A. Correct

B. Incorrect

C. Incorrect

Summary answer

The correct answer is A: Well controlled.

This patient has well-controlled asthma. He has no impairment and does not have any warning

for increased risk of exacerbations and morbidity in the future. However, as is common with

patients on controller therapy, he is experiencing medication adverse effects. The patient

should be assessed for proper medication technique and alternative treatments should be

considered.

References

Pathogenesis and Diagnosis of Asthma

National Heart, Lung, and Blood Institute. Expert panel report 3: guidelines for the

diagnosis and management of asthma: full report 2007. NIH publication 08-4051.

http://www.nhlbi.nih.gov/files/docs/guidelines/asthgdln.pdf

Report, N.W.W., Global Initiative for Asthma Management and Prevention. 1995.

Busse, W.W. and J.E. Gern, Viruses in asthma. J Allergy Clin Immunol, 1997. 100:147-50.

Wardlaw, A.J., The role of air pollution in asthma. Clin Exp Allergy, 1993. 23: 81-96. [link]

Platts-Mills, T.A. and L.M. Wheatley, The role of allergy and atopy in asthma. Curr Opin

Pulm Med, 1996. 2:29-34. [link]

De Monchy, J.G., et al., Bronchoalveolar eosinophilia during allergen-induced late

asthmatic reactions. Am Rev Respir Dis, 1985. 131:373-6. [link]

Robinson, D., et al., Activation of CD4+ T cells, increased TH2-type cytokine mRNA

expression, and eosinophil recruitment in bronchoalveolar lavage after allergen

inhalation challenge in patients with atopic asthma. J Allergy Clin Immunol, 1993.

92:313-24. [link]

Guo, C.B., et al., Identification of IgE-bearing cells in the late-phase response to antigen

in the lung as basophils. Am J Respir Cell Mol Biol, 1994. 10:384-90. [link]

Koh, Y.Y., et al., Neutrophils recruited to the lungs of humans by segmental antigen

challenge display a reduced chemotactic response to leukotriene B4. Am J Respir Cell

Mol Biol, 1993. 8: 493-9. [link]

Montefort, S., et al., Bronchial biopsy evidence for leukocyte infiltration and

upregulation of leukocyte-endothelial cell adhesion molecules 6 hours after local

allergen challenge of sensitized asthmatic airways. J Clin Invest, 1994. 93:1411-21. [link]

Calhoun, W.J., et al., Increased airway inflammation with segmental versus aerosol

antigen challenge. Am Rev Respir Dis, 1993. 147(6 Pt 1):1465-71. [link]

Nasser, S.M., et al., Inflammatory cell populations in bronchial biopsies from aspirin-

sensitive asthmatic subjects. Am J Respir Crit Care Med, 1996. 153: 90-6. [link]

Bradley, B.L., et al., Eosinophils, T-lymphocytes, mast cells, neutrophils, and

macrophages in bronchial biopsy specimens from atopic subjects with asthma:

comparison with biopsy specimens from atopic subjects without asthma and normal

control subjects and relationship to bronchial hyperresponsiveness. J Allergy Clin

Immunol, 1991. 88: 661-74. [link]

Humbert, M., et al., Bronchial mucosal expression of the genes encoding chemokines

RANTES and MCP-3 in symptomatic atopic and nonatopic asthmatics: relationship to the

eosinophil-active cytokines interleukin (IL)-5, granulocyte macrophage-colony-

stimulating factor, and IL-3. Am J Respir Cell Mol Biol, 1997. 16:1-8. [link]

Bentley, A.M., et al., Identification of T lymphocytes, macrophages, and activated

eosinophils in the bronchial mucosa in intrinsic asthma. Relationship to symptoms and

bronchial responsiveness. Am Rev Respir Dis, 1992. 146:500-6. [link]

Sterk, P.J., The place of airway hyperresponsiveness in the asthma phenotype. Clin Exp

Allergy, 1995. 25 Suppl 2:8-11; discussion 17-8.

Boushey, H.A., Bronchial hyperreactivity to sulfur dioxide: physiologic and political

implications. J Allergy Clin Immunol, 1982. 69:335-8.

Rennard, S.I., Repair mechanisms in asthma. J Allergy Clin Immunol, 1996. 98(6 Pt 2):

S278-86. [link]

Bousquet, J., et al., Asthma: a disease remodeling the airways. Allergy, 1992. 47(1): 3-11.

Wenzel, SE. Asthma: defining of the persistent adult phenotypes. Lancet 2006; 368: 804-

13.

Simpson JL et al. Inflammatory subtypes in asthma: assessment and identification using

induced sputum. Respirology 2006; 11: 54-61.

Anderson, G.P., Endotyping asthma: new insights into key pathogenic mechanisms in a

complex, heterogenous disease. Lancet 2008; 372: 1107-19.

Spirometry

Pierce, R., Spirometry: an essential clinical measurement. Australian Family Physician,

2005. 34(7): 535-39. [link]

Barreiro T.J. and Perillo I. An approach to interpreting spirometry. American Family

Physician, 2004. 69(5): 1107-14. [link]

Crapo, R.O., Pulmonary-Function Testing. N Engl J Med, 1994. 331:25-30. [link]

Lung function testing: selection of reference values and interpretative strategies.

American Thoracic Society. Am Rev Respir Dis, 1991. 144: 1202-18. [link]

Weiss TM. Vocal cord dysfunction: Paradoxical vocal cord motion-A thorough review.

Grand Rounds, UTMB, 2001; July 18. [link]

Guideline for Methacholine and Exercise Challenge Testing -1999. Am J Respir Crit Care

Med. 2000. 161: 309-329

COPD vs. Asthma

Enright, P.L., M.D. Lebowitz, and D.W. Cockroft, Physiologic measures: pulmonary

function tests. Asthma outcome. Am J Respir Crit Care Med, 1994. 149(2 Pt 2): S9-18;

discussion S19-20. [link]

Quackenboss, J.J., M.D. Lebowitz, and M. Krzyzanowski, The normal range of diurnal

changes in peak expiratory flow rates. Relationship to symptoms and respiratory

disease. Am Rev Respir Dis, 1991. 143:323-30. [link]

Hewitt D. Interpretation of a Positive Methalcholine Challenge. Journal of Industrial

Medicine. 2008.51: 769-781.