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In recent years our understanding of asthma has changed. We no longer think of asthma as a collection of intermittent symptoms, but as a chronic syndrome. This shift in our point of reference has changed not only the way we treat the disease but also in how we approach the diagnosis of a patient with intermittent shortness of breath (SOB) and cough.

OUR CASE:

A 42 year old African-American female presents for evaluation of chronic cough. For the last year, she has been experiencing intermittent shortness of breath and a cough which has persisted following an upper respiratory tract infection. The cough occurs throughout the day and is nonproductive with no episodes of hemoptysis. At night, she awakes coughing with occasional wheezing.

Chronic cough (defined as >8 weeks duration) is a common presenting symptom to physicians. The first step in identifying the cause of cough is a good medical history about the onset of cough (acute versus chronic), the nature of the cough (productive versus nonproductive), frequency, seasonal and diurnal variation and possible triggers of cough (allergies, angiotensin-converting enzyme (ACE) inhibitor, smoking). In patients with an acute cough (<3 weeks duration), physicians should first rule out catastrophic causes such as pulmonary embolism, foreign body aspiration or malignancy, a respiratory tract infection (upper respiratory tract infection, bronchitis or pneumonia) or exposure to some noxious or irritating agent (allergic or irritant-induced rhinitis). With chronic cough, upper airway cough syndrome (UACS, formerly known as postnasal drip), asthma, nonasthmatic eosinophilic bronchitis (NAEB), chronic obstructive lung disease (COPD), vocal cord dysfunction (VCD), gastroesophageal reflux disease (GERD) are frequently the end diagnosis. Other causes of chronic cough are congestive heart failure (CHF) and interstitial lung disease (ILD).

Case Continued:

 

The patient’s medical history includes hypertension, dyslipidemia and depression. She denies a history of heartburn. Her medications are lisinopril 40mg/d, hydrochorothiazide 25mg/d, atorvastatin 40mg/d and citalopram 20mg/d. There have been no recent medication changes. She is allergic to sulfa, ASA and ibuprofen. She has a family history of asthma and hypertension. She is a lifelong nonsmoker, married, works as a secretary, denies seasonal allergies or occupational/environmental exposures and has no pets.

Symptoms suggestive of asthma include episodic wheezing, dypsnea, chest tightness and cough with nocturnal, seasonal, or exertional characteristics. Cough is the only presentation of asthma in about 20% of asthmatics. Atopy and positive family history for asthma increase the likelihood of a diagnosis of asthma. A negative smoking history makes COPD unlikely.

Case Continued:

 

The patient’s physical examination was normal.

The physical exam is helpful in narrowing or suggesting other diagnoses. For example, wet crackles would be consistent with diagnosis of CHF. Velcro rales may be auscultated in patients with ILD. Although wheezing may be present is asthma, it is not soley specific to asthma and may be present in COPD, CHF, VCD and others disorders such as foreign body aspiration and endobronchial carcinoid tumors.

What is the next most appropriate step test?

a) Start albuterol as needed
b) Start oral first-generation antihistamine/decongestant
c) Start proton pump inhibitor (PPI)
d) Stop ACE inhibitor
 

ACE inhibitors cause a nonproductive cough in approximately 20% or more of patients. The proposed mechanism for cough is accumulation of bradykinin or tachykinins and substance P. Resolution of cough after discontinuation typically occurs within days but may be weeks in some patients. Stopping lisinopril is the most appropriate next step. Starting albuterol is not appropriate at this time as a diagnosis of asthma or airway hyperreactivity has not been made. While starting an oral first-generation antihistamine/decongestant may seem like a good choice to improve the patient’s symptoms as empiric treatment for UACS, stopping lisinopril is the first line of action. If cough persists after discontinuation, an empiric trial of an oral, first-generation antihistamine/decongestant should be considered. Even though she denies a history of reflux, GERD may be clinically unapparent to the patient yet may produce symptoms of cough in 75% of patients.

Case Continued:

 

The patient’s lisinopril was stopped and patient was reevaluated two months later. No improvement in cough and intermittent shortness of breath (SOB) was seen.

What is the next most appropriate diagnostic test?

a) Chest radiograph
b) Sinus radiographs
c) Spirometry with flow volume loops
d) 24-hour esophageal pH probe
e) Transthoracic echocardiography (TTE)
 

A chest radiograph is usually performed to look for a cause of cough, but most commonly is normal in the evaluation for chronic cough (unless ILD or malignancy is present). Yet it should be considered in the initial evaluation.

Case Continued:

 

The patient had PA and lateral chest radiographs performed which where normal.

What is the next most appropriate diagnostic test?

a) Computed Tomography (CT) of chest
b) Sinus radiographs
c) Spirometry with flow volume loops
d) 24 hour esophageal pH probe
e) Transthoracic echocardiography (TTE)
 

Since the patient’s chest radiographs were normal, CT of the chest would not provide any more information. Sinus radiographs to evaluate for chronic sinusitis leading to UACS would be appropriate if the clinical history suggested sinusitis, but patient denied rhinitis. Esophageal probes used to diagnose GERD have a sensitivity of 96% and a specificity of 95% but does not necessarily correlate with the timing or severity of cough. Also, a short empiric trial of acid suppression prior to invasive studies such as esophageal probes is usually performed, therefore the probe is not the next best step. A TTE would be appropriate if a history of CHF was present or evidence of heart failure on clinical examination (jugular venous distention, crackles, lower extremity edema) was present, however, the was not seen with this patient. Assessment of lung function with spirometry is the next best step to assess for asthma. Airflow obstruction is demonstrated by a reduced Forced Expiratory Volume in 1 second (FEV1)1 and FEV1/ Forced Vital Capacity (FVC) relative to reference or predicted values. Reversibility of airflow obstruction is defined by an increase in the FEV1 and/or FVC by > 12 percent and > 200 mL after inhaling a short-acting β-agonist. A mimicker of asthma, VCD, can simultaneously be evaluated with flow volume loops obtained with spirometry. VCD is paradoxical adduction of the vocal cords during inspiration that produces airflow obstruction. Truncation of the inspiration limb of the flow volume loop is characteristic of VCD.

Case Continued:

 

The patient underwent spirometry with flow volume loops without difficulty. Flow volume loops and spirometry were normal. The FEV1, FVC and FEV1/FVC are 2.8L, 3.2L, and 88%, respectively.

What diagnosis is suggestive of her spirometry and flow volume loops?

a) Asthma
b) ILD
c) COPD
d) VCD
 
Figure One

Figure 1. Examples of flow volume loops.

Case Continued:

 

The patient’s spirometry and flow volume loops are normal.

Because the flow volume loops are normal, VCD is unlikely. A normal FVC also makes ILD unlikely as the FVC would have been reduced. Without obstructive physiology (FEV1/FVC < 70), COPD cannot be present; however, a normal spirometry does not rule out a diagnosis of asthma since the obstruction is intermittent. Therefore provocative pulmonary testing is indicated. Typically, this is performed with a methacholine challenge test (MCT). Other agents used for bronchial provocation testing are mannitol, exercise and hypertonic saline. Absolute contraindications to MCT include an FEV1 of less than 1.5 L in adults, less than 1 L in children, recent severe acute asthma, myocardial infarction or cerebral vascular accident within 3 months, uncontrolled hypertension (systolic BP >200 or diastolic BP > 100) and known aortic aneurysm. Since MCT has high sensitivity for the diagnosis of bronchial hyperreactivity, a negative test excludes asthma in most patients.

Case continued: The patient underwent MCT which resulted in a 20% decrease in the FEVI after inhaling 4 mg/ml methacholine (PC20) indicating bronchial hyperreactivity. She was diagnosed with asthma and started on albuterol as needed. The next week, she was seen for follow-up. She states that she has improved but continues to cough daily and wakes up two times a week with SOB. She is using her inhaler several times a day. She demonstrates her inhaler technique, which is good.

Reviewing her spirometry values and her symptoms, how is this patient’s asthma classified?

Answer: Her asthma is moderate persistent.
NOML Article Graphic 1

National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma Full Report 2007.
http://www.nhlbi.nih.gov/guidelines/asthma/asthsumm.pdf. Accessed August 19, 2011.

Case Continued:

 

What is best therapy for this patient?

Since patient has moderate persistent asthma, a low dose inhaled corticosteroid (ICS) needs to be added to her albuterol. If she does not respond to the low dose of, a medium dose ICS or adding a long acting beta2-agonist (LABA) may be tried.

NOML Article Graphic 2

National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma Full Report 2007.
http://www.nhlbi.nih.gov/guidelines/asthma/asthsumm.pdf. Accessed August 19, 2011.

Case Continued:

 

A LABA and low dose ICS are prescribed. Patient is reevaluated one month later with complete resolution of her cough.

The Diagnosis of Cough-Variant Asthma

Discussion

 

Cough is the most common complaint in the outpatient setting therefore, a working knowledge of the most common causes of cough and their evaluation is imperative. There are four main causes of chronic cough in nonsmokers with a normal chest radiograph and who are not on an ACE inhibitor: asthma, UACS, NAEB and GERD. Obviously, the patient that presents with chronic cough on an ACE inhibitor should have the ACE inhibitor discontinued if no compelling reason to continue it. Likewise, the smoking patient should undergo cessation counseling. Up to 25% of patients with chronic cough have multiple causes. Evaluation and treatment should be sequential and additive. The typical algorithm (if no clear etiology is elicited by history and physical) starts with empiric treatment for UACS.

Upper Airway Cough Syndrome (UACS)

 

Formerly known as postnasal drip, UACS encompasses postinfectious, rhinitis (allergic, perennial nonallergic, nonallergic rhinitis with eosinophilia (NARES), due to anatomic abnormalities, due to physical or chemical irritants, occupational, and rhinitis medicamentosa) and sinusitis (bacterial and allergic fungal sinusitis). Inflammatory mediators within mucus that deposit on the pharynx and larynx are the proposed mechanism for cough. There is no patho-pneumonic history or physical findings but a history of rhinnorhea, frequent throat clearing and presence of cobblestoning of the oropharyngeal mucosa hint towards the diagnosis. The diagnosis is made based on the patient’s response to therapy.

For patients with clear causes of UACS such as allergies, infection or structural abnormalities, treatment includes avoidance of the allergen, antibiotics and surgical correction, respectively. For patients with less clear cut etiologies, first-generation oral antihistaminic compounds and decongestants are cost-effective and should be the initial treatment. Some of the side effects are dry mouth, dizziness, insomnia or sedation, hypertension and increased intraocular pressures in patients with glaucoma. If contraindicated because of the potential for or as a result of side effects, intranasal preparations (antihistamines, anticholinergics, decongestant, and corticosteroids) or oral leukotriene inhibitors are possible alternatives. Allergy treatments with allergen desensitization and anti-IgE preparations and short-term oral corticosteroids can be used in select cases.

Sinus imaging is performed if a patient is strongly suspected of having UACS but does not respond to empiric therapy with an oral first-generation antihistamine/decongestant. If no sinus abnormality is demonstrated, consider asthma as an alternate diagnosis.

Asthma

 

Accounting for 25-30% of chronic cough, asthma is a complex disorder involving variable airflow obstruction, airway inflammation and airway hyper-responsiveness. The main clinical features of asthma are wheezing, shortness of breath, chest tightness and cough but it has been recognized that cough (productive or nonproductive) may be the sole presentation in some patients, termed cough variant asthma (CVA). The features of CVA are isolated chronic cough without wheezing or dyspnea, airway hyper-responsiveness to methacholine and symptomatic improvement of coughing with the use of inhaled beta2-agonists, sustained-release theophylline and corticosteriods. Bronchospasm is not a prominent feature. A medical history of atopy and wheezing, and cough as well as wheezing on lung auscultation are suggestive, but are not reliable in either ruling in or ruling out asthma. Spirometry should be performed. If spirometry does not reveal reversible airflow obstruction, a bronchial provocation challenge should be performed with methacholine. The methacholine challenge test is positive with a negative predictive value approaching 100% when a decrease of > 20% in the FEV1 is seen after inhalation of methacholine at < 8mg/ml (provocation concentration resulting in a > 20% decline in the FEV1, PC20). The treatment for CVA is analogous to the treatment for classic asthma.

If airway obstruction is present, therapy with beta2-agonists and inhaled corticosteroids (ICS) should be initiated. Response is typically seen within 1 week, with complete resolution taking up to 8 weeks. For refractory cough after treatment with ICS and bronchodilators, leukotriene receptor antagonists (LTRA) may be added to the therapeutic regimen before oral steriods. If there is no response, a short course (1 to 2 weeks) of oral corticosteroids followed by inhaled corticosteroids is the next step in management.

Nonasthmatic Eosinophilic Bronchitis (NAEB)

 

Even though GERD is more common than NAEB, evaluation for NAEB is the next step for patients after the diagnoses of UACS and asthma have been eliminated or treated without avail. NAEB is estimated to cause chronic cough in 13-33% of patients. It is characterized by eosinophilic infiltration of the bronchial tree without airflow obstruction and airway hyperresponsiveness. Cough is the only manifestation. Since airflow obstruction is not present, the methacholine challenge test is negative. Diagnosis is made by the presence of >3% non-squamous, sputum eosinophils in induced sputum or bronchial alveolar lavage. If an allergen or occupational irritant is the culprit, the best treatment is avoidance. Otherwise, ICS are the mainstay of treatment. If refractory, oral corticosteroids are prescribed. Most patients note improvement within 4 weeks.

Gastroesophageal Reflux Disease (GERD)

 

Chronic cough from GERD is postulated to be caused by distal esophageal acid exposure causing an esophageal-tracheobronchial cough reflex via the vagus nerve and/or microaspiration into the laryngopharynx and tracheobronchial tree of esophageal contents. For patients with a clinical history highly (heartburn, regurgitation) suggestive of cough due to GERD, empiric treatment is initiated. For other patients, treatment for GERD should be begun if partial or no response at all to treatments for UACS, asthma or NAEB. The 24-hour esophageal pH-monitoring test is the most sensitive and specific test to link chronic cough to GERD caused by acid reflux. Flexible nasopharyngoscopy be used to identify glottic changes caused by reflux. Non-acid reflux can cause chronic cough, thus barium esophagography is needed to demonstrate gastroesophageal reflux but normal esophagoscopy does not rule out GERD as the cause of cough. The diagnosis of GERD-related cough is made by response to anti-reflux therapy.

The treatment of GERD involves lifestyle modification (i.e. reduction in alcohol, smoking cessation, weight loss) and medical management, which involves acid suppression with H2-blockers and/or proton-pump inhibitors (PPI) and/or prokinetic agents. Response to treatment is usually seen in 6-8 weeks but 6 months may be needed for optimal control. Anti-reflux therapy is considered only after definitive diagnosis of GERD and alternative treatments have not met with satisfactory results.

Referral to a cough specialist is indicated there is no response to interventions.

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