Pinning down the cause of a chronic cough

Howard J. Ritz, MPAS, RPA-C

Mr. Ritz practices at Empire State Asthma and Allergy Treatment and Research Center, Plattsburgh, NY. He is on the speakers' bureaus for GlaxoSmithKline and AstraZeneca.

Postnasal drip syndrome, asthma, and gastroesophageal reflux disease can produce a chronic cough. Identifying the exact etiology may be a diagnostic challenge.

 

Earn Category I CME credit by reading this article and the associated article and successfully completing the post-test. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of June 2004.

Learning objectives Identify the differential diagnosis for chronic cough Describe the components of a cost-effective workup Review an empiric algorithm that offers a stepwise approach to the evaluation Explain how to treat the most common causes of chronic cough to successful resolution

Although cough is an important physiologic mechanism that helps maintain the health of the respiratory system, it is not required for normal pulmonary hygiene. It is the major defense against retained secretions and foreign materials, and it also occurs when profuse, dry, or thick mucus is present, when ciliary activity is poor, or when the pulmonary epithelium is diseased.

The two main mechanisms of cough are expiratory reflex and enhancement of mucociliary clearance.¹ The full mechanism of the neural cough pathway is not clearly understood. Cough receptor sites in the respiratory system are concentrated in the trachea and main carina, with distal sites appearing to be most sensitive in eliciting cough.² Outside the respiratory system, cough receptor sites include the esophagus, external ear, and abdominal organs.¹

Determining whether a cough is acute or chronic is the first step in the evaluation; coughs that have persisted for longer than 3 weeks are categorized as chronic, and those that have persisted for less than 3 weeks are considered acute. The duration of the cough is a factor in the differential diagnosis (see Figure 1). Acute cough can be either the presenting or the only symptom of such life-threatening problems as acute bacterial pneumonia, heart failure, pulmonary embolism, and aspiration.³ Although these conditions are usually associated with other symptoms, a chest radiograph should be obtained early in the workup of cough when the history and physical do not suggest a likely cause. This article focuses on evaluating chronic cough in nonsmokers whose radiographic findings are normal and who are not using ACE inhibitor therapy (see Table 1). The most common causes of cough among these patients are postnasal drip syndrome (PNDS), asthma, and gastroesophageal reflux disease (GERD).⁴ Although each entity is discussed separately and in order of prevalence, chronic cough usually cannot be attributed to a single cause.

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TABLE 1 Causes of chronic or persistent cough

Irritants Cigarette smoking Dry air Dust Pollutants Respiratory tract problems Asthma Bronchiectasis Chronic obstructive pulmonary disease Chronic rhinitis Chronic sinusitis Disease of the external auditory canal Foreign body Heart failure Interstitial lung disease Pneumonitis Vocal cord dysfunction or polyps Other ACE inhibitor therapy Adenopathy Aortic aneurysm Malignancy Reflux esophagitis

Data from Goroll AH, May LA, Mulley AG Jr. Primary Care Medicine: Office Evaluation and Management of the Adult Patient. 3rd ed. Philadelphia, Pa: Lippincott Williams & Wilkins;1995.

Postnasal drip syndrome

The most common cause of cough is PNDS associated with chronic bacterial sinusitis or with vasomotor, nonallergic, or allergic rhinitis.⁴ Determining which type of rhinitis is responsible for PNDS is important (see Table 2).

 

TABLE 2 Differentiating VMR, NARES, and allergic rhinitis
Feature	VMR	NARES	Allergic rhinitis
Positive skin test results	No	No	Yes
Elevated serum IgE levels	No	No	Yes
Eosinophils on nasal smear	No	Yes	Possible
Response to nasal corticosteroid	Yes	Yes	Yes
Triggered by odors	Yes	Yes	Possible
Key: NARES, nonallergic rhinitis with eosinophilia syndrome; VMR, vasomotor rhinitis.

Vasomotor rhinitis (VMR) is poorly understood, and the diagnosis is typically made with clues from the history and a negative allergy test result. Symptoms of VMR include nasal obstruction and congestion, and some patients suffer from increased nasal secretions and rhinorrhea. Nasal polyposis is more commonly found in older men who have non-allergic rhinitis than in patients who have VMR. Sneezing, nasal pruritus, and eye irritation are rare in VMR. Asthma is more likely to be associated with allergic rhinitis (AR) than with VMR.

Treatment of VMR may be either targeted or nonspecific. Nonspecific treatment aims at treating all of the symptoms; VMR symptoms can vary, so there may be advantages to using this strategy. A nasal spray such as azelastine (Astelin) and an intranasal corticosteroid are effective and have low systemic absorption; the use of azelastine has been reported to improve symptoms in as many as 85% of patients.⁵ Intranasal corticosteroids are believed to be more effective when the nasal mucosa is inflammed.⁵ Directed treatment of VMR focuses on the presenting symptom; a short course of a topical decongestant and an oral decongestant either with or without dexbrompheniramine can be used for primarily nasal obstruction and congestion. If primary symptoms are secretions and rhinorrhea, an anticholinergic agent, such as ipratropium nasal spray (Atrovent), should be considered as a first step and then perhaps continued for long-term symptom management.

Nonallergic rhinitis with eosinophilia syndrome (NARES) causes symptoms similar to those of VMR, along with sneezing, profuse rhinorrhea, and nasal pruritus. Although nasal smears show marked eosinophiles, allergic disease is not identifiable with skin testing or radioallergosorbent testing (RAST). Nasal smears are easy to obtain, and the findings, together with the clinical history, will establish the diagnosis. Triggers for NARES (and for VAR) include tobacco smoke, perfume, odors from cleaning products, newsprint, paint fumes, windy or cold days, alcoholic beverages, and spicy foods. Although NARES usually responds to intranasal corticosteroids and azelastine, intermittent treatment with prednisone may be necessary to control high levels of nasal eosinophils.^5,6

Allergic rhinitis (AR) is characterized by paroxysms of sneezing, ocular and nasal pruritus, pruritus of the palate or throat, nasal congestion, rhinorrhea, and PNDS. Seasonal allergic rhinitis (SAR) describes the condition when symptoms occur during the same time every year, and perennial allergic rhinitis (PAR) describes year-round symptoms. Skin testing or RAST results will be positive, and patients will report either a seasonal association or exposure to IgE-mediated triggers. Patients who have AR usually develop the condition by age 30 years; incidence peaks between ages 15 and 25 years.⁷ An elderly patient who presents with symptoms suggesting AR for the first time should be evaluated for drug-induced rhinitis.

In AR, the physical exam will reveal pale, bluish, edematous nasal turbinates; thin, clear, watery nasal discharge; a transverse nasal crease; and bleeding of Kiesselbach's area.⁷ Fluid may be seen in the tympanic membranes, along with evidence of conjunctivitis, puffy eyelids, Morgan's lines, or venous dilation of the skin under the eyes that gives the appearance of black eyes (allergic shiner).

Patients who have AR should avoid or at least minimize exposure to triggers. When triggers are not avoidable, a nonsedating antihistamine should be used as needed. These agents work best when they are taken before exposure, so that the histamine receptor is blocked before histamine is released. Addition of a decongestant or combination antihistamine and decongestant will help mitigate congestion. Azelastine nasal spray is effective for nasal symptoms, including congestion, in both AR and NAR.⁷ Intranasal corticosteroids are effective at reducing the four primary symptoms of AR—nasal congestion, rhinorrhea, sneezing, and pruritus.⁷

Chronic bacterial sinusitis can cause persistent nasal obstruction, purulent nasal and posterior pharyngeal discharge, PNDS, cough, halitosis, either hyposmia or anosmia, pharyngitis, malaise, fever, headache, and facial pain. Symptoms of chronic bacterial sinusitis typically last 8 to 12 weeks and may overlap with recurrent sinusitis; in such a case, a patient may report rapid relapse after initially improving on antibiotic therapy (see Table 3).⁸ Sinusitis is the cause of PNDS in as many as 60% of patients who also have a productive cough.²

 

TABLE 3 Antibiotic choices for chronic sinusitis

First-line treatment options Cefuroxime axetil, 250 mg bid Amoxicillin 875 mg-clavulanate 125 mg bid Alternatve first-line treatment options Clarithromycin, 500 mg bid Trimethoprim 160 mg-sulfamethoxazole 800 mg bid Clindamycin, 300 mg tid Treatment-resistant condition Levofloxacin, 500 mg/d Moxifloxacin, 400 mg/d Gatifloxacin, 400 mg/d

Treatment of chronic sinusitis includes 3 to 4 weeks of a broad-spectrum antibiotic, plus an additional 7 days of treatment after symptoms resolve, plus use of a topical intranasal corticosteroid for as long as 6 weeks.⁸ Nasal saline lavage and oral hydration are also important.

A cough that begins with an acute respiratory tract infection that is not complicated by pneumonia and eventually resolves without treatment is termed a postinfectious cough.⁴ Such a cough may be due to postnasal drip or tracheobronchitis. A first-generation antihistamine with a decongestant is the recommended first-line treatment.⁹ These drugs are more effective against postnasal drip because of their anticholinergic effect. Other treatment options include an intranasal corticosteroid and the nasal sprays ipra-tropium and azelastine. A cough that persists for longer than 1 week warrants imaging studies of the sinuses to rule out bacterial sinusitis.

Asthma

The primary symptoms of asthma are cough, wheeze, dyspnea, sputum production, and shortness of breath. Symptoms of asthma do not improve with the use of expectorants, antibiotics, or antitussives.

Inhaled ß₂-agonist and corticosteroid therapy should be initiated following normal chest radiograph findings in a patient who has a cough and a wheeze plus rhonchi or rales.^4,10,11 A short burst of oral prednisone therapy (eg, 30 mg/d for 5 days) may be required to gain control of cough. Improvement with inhaled ß₂-agonist and corticosteroid therapy does not confirm a diagnosis of asthma because these drugs increase mucociliary clearance and decrease the production of mucus in patients who have had a respiratory tract infection.^2,4 Bronchial hyperresponsiveness is also lessened by the use of these inhaled medications. Close follow-up is recommended to guide appropriate therapy.¹²

Note that asthma may be diagnosed in a patient whose only complaint is a persistent, nonproductive cough. This entity, known as cough-variant asthma, is diagnosed by clinical history, positive results on the methacholine inhalation challenge (MIC), response to asthma therapy, or a combination.^2,4,10,11

Spirometry is the mainstay of asthma evaluation; the peak expiratory flow measurement is ineffective in the diagnostic workup of persistent cough.¹³ A forced expiratory volume in one second (FEV₁) of less than 75% of the predicted normal for age and weight or an increase of at least 12% in FEV₁ and 15% in forced vital capacity after inhalation of an inhaled ß₂-agonist suggests asthma.¹² A lack of improvement on spirometry following the inhalation of a ß₂-agonist may be due to significant inflammation and does not indicate irreversible obstruction.

The MIC may help in making the diagnosis of cough-variant asthma in patients who have little or no wheezing or dyspnea, whose physical exam is unremarkable, and whose spirometric results are near normal. The MIC may help the provider to establish the need to use a long-term inhaled corticosteroid (ICS) in an otherwise healthy patient. Because the MIC is inconvenient and a positive result can be nonspecific, a diagnostic and therapeutic trial of prednisone may be tried instead (see Figure 2). Pathophysiologic features of cough-variant asthma are similar to but less severe than those of asthma, and this condition progresses to asthma in 17% to 37% of patients.¹⁴ Patients who have cough-variant asthma must understand that their cough is a symptom of a potentially serious process.

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Eosinophilic bronchitis has characteristics that are similar to cough-variant asthma—relatively normal spirometry results and no wheeze, dyspnea, or signs of airflow obstruction. The cough may be productive, and sputum will contain at least 3% eosinophils. Treatment consists of a mild dosage of an inhaled corticosteroid, and some patients may require use of an oral corticosteroid.^14,15 As many as one third of children who have episodic eosinophilic bronchitis later develop typical asthma.

Gastroesophageal reflux disease

GERD has been shown to be silent in as many as 75% of patients with chronic cough.¹⁶ When heartburn is the presenting symptom, the diagnosis is evident; however, many patients have less specific dyspeptic symptoms.

Why cough occurs in GERD is not well understood. One theory proposes that acid in the distal esophagus stimulates an esophageal-tracheobronchial cough reflex, and another suggests that cough is caused by absorption of esophageal contents into the larynx and tracheobronchial tree.¹⁷

Patients may complain of heartburn, acid regurgitation, chest pain, abdominal bloating, globules, dysphagia, constant throat clearing, food sticking in their throats, halitosis, hoarseness, otalgia, pharyngeal tightness, sore throat, or water brash. Diagnostic modalities include 24-hour pH monitoring, barium swallows, and endoscopy. Some experts recommend a diagnostic trial of a high-dose proton pump inhibitor (eg, omeprazole, 40 mg/bid) for at least 2 weeks, together with dietary and postural adjustments.^4,17,18 These measures will relieve the cough, but improvement may take as long as 3 months.^16,17

Researchers have identified a clinical profile that is 95% accurate in diagnosing chronic cough due to silent GERD:

• The chest radiograph findings are unremarkable

• The patient does not smoke, is not exposed to environmental irritants, and is not using an ACE inhibitor

• The MIC result is negative

• The cough fails to improve with treatment for asthma or PNDS or with inhaled or systemic corticosteroid therapy

• No eosinophils are found in sputum.¹⁶

Conclusion

The clinician must remain alert to the connection between symptoms and disease, particularly in chronic cough. A common diagnostic error is not recognizing that one symptom may be linked to more than one disease.

 

Persistent cough: Is it adult pertussis? Bordetella pertussis is being recognized more and more as a cause of cough lasting more than 14 days in adults. This may be due to a combination of increased awareness on the part of physicians and of waning pertussis immunity in patients. Some experts advise routine booster immunization with acellular vaccine preparations, but no advisory committee has made the recommendation. Unlike pertussis infection in children, pertussis in adults is frequently mild or subclinical. When symptomatic, adults with pertussis typically have prolonged paroxysmal coughing attacks that are worse at night. Dyspnea and a tingling sensation in the throat accompany the cough. The illness can last as long as 3 months, and the classic stages are • Catarrhal, lasting for 1 to 2 weeks and characterized by rhinorrhea, congestion, low-grade fever, and mild cough. • Paroxysmal, lasting for 2 to 4 weeks and characterized by a distressing cough, sputum production, and occasionally emesis, fever, and sore throat. Classic whooping is uncommon in adults. • Convalescent, during which the cough fades away.1 B pertussis can often be identified by culturing nasopharyngeal secretions; serologic tests are under development. Erythromycin is the antibiotic of choice for treatment and prophylaxis. For patients allergic to erythromycin, an alternative is trimethoprim-sulfamethoxazole. Researchers recently assessed the effect of age on the clinical presentation of pertussis in 664 cases.2 Complications were shown to be more frequent in adults than in adolescents: Pneumonia occurred in 2% of patients younger than 30 but in 5% to 9% of older patients, and urinary incontinence occurred in 34% of women older than 50. Smoking and asthma exacerbated the duration of cough, risk of sinusitis, and number of nights with disturbed sleep. In another study, a group of Danish investigators evaluated B pertussis as a cause of persistent cough in adults.3 They examined 365 patients, approximately half of whom had a persistent cough and no pulmonary disease. The researchers obtained a history, chest film, respiratory function measurement, nasopharyngeal aspirate for polymerase chain reaction (PCR), nasopharyngeal swab specimen for culture, and a blood sample. Four patients were B pertussis culture positive; 11 (including the culture-positive patients) were B pertussis PCR positive; and 33, including 10 of the 11 PCR-positive patients, had serologic evidence of recent B pertussis infection. The researchers concluded that B pertussis infection is a common cause of persistent cough in adults and that patients with infection may be B pertussis reservoirs from which transmission may occur to infants, in whom the disease can be devastating. Transmission is by airborne spread of secretions. 1. Wright SW. Pertussis infection in adults. South Med J. 1998;91:702-708. 2. De Serres G, Shadmani R, Duval B, et al. Morbidity of pertussis in adolescents and adults. J Infect Dis. 2000;182:174-179. 3. Birkebaek NH, Kristiansen M, Seefeldt T, et al. Bordetella pertussis and chronic cough in adults. Clin Infect Dis. 1999;29:1239-1242.

 

KEY POINTS in this article The three most common causes of chronic cough in nonsmokers are postnasal drip syndrome, asthma, and gastroesophageal reflux disease. A systematic approach to the evaluation of cough can minimize the invasiveness and cost of the workup. A chest radiograph should be obtained early in the workup of chronic cough when the history and physical exam do not suggest a likely cause.

REFERENCES

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3. Orenstein DM. Cough. In: Kliegman RM, Nieder ML, Super DM, eds. Practical Strategies in Pediatric Diagnosis and Therapy. Philadelphia, Pa: WB Saunders; 1996:64-92.

4. Irwin RS, Madison JM. The diagnosis and treatment of cough. N Engl J Med. 2000;343;1715-1721.

5. Settipane RA, Settipane GA. Nonallergic Rhinitis. In: Kaliner MA, ed. Current Review of Allergic Diseases. Philadelphia, Pa: Blackwell Science; 1999:111-123.

6. Ciprandi G, Pronzato C, Passalacqua G, et al. Topical azelastine reduces eosinophil activation and intercellular adhesion molecule-1 expression on nasal epithelial cells: an antiallergic activity. J Allergy Clin Immunol. 1996;98(6 pt 1):1088-1096.

7. Economides A, Kaliner MA. Allergic rhinitis. In: Kaliner MA, ed. Current Review of Allergic Diseases. Philadelphia, Pa: Blackwell Science; 1999:227-243.

8. Kaliner MA. Medical management of sinusitis. In: Kaliner MA, ed. Current Review of Allergic Diseases. Philadelphia, Pa: Blackwell Science; 1999:139-152.

9. Curley FJ, Irwin RS, Pratter MR, et al. Cough and the common cold. Am Rev Respir Dis. 1988;138:305-311.

10. Lawler WR. An office approach to the diagnosis of chronic cough. Am Fam Phys. 1998;58;2015-2022.

11. Philp EB. Chronic cough. Am Fam Phys. 1997;56:1395-1404.

12. National Institutes of Health. National Heart, Lung, and Blood Institute. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. Washington, DC: NIH; 1997. Publication 97-4051.

13. Thiadens HA, De Bock GH, Van Houwelingen JC, et al. Can peak expiratory flow measurements reliably identify the presence of airway obstruction and bronchodilator response as assessed by FEV₁ in primary care patients presenting with a persistent cough? Thorax. 1999;54:1055-1060.

14. Gibson PG, Fujimura M, Niimi A. Eosinophilic bronchitis: clinical manifestations and implications for treatment. Thorax. February 2002;57:178-182.

15. Brightling CE, Ward R, Goh KL, et al. Eosinophilic bronchitis is an important cause of chronic cough. Am J Respir Crit Care Med. 1999;160:406-410.

16. Irwin RS, Zawacki JK, Wilson MM, et al. Chronic cough due to gastroesophageal reflux disease: failure to resolve despite total/near-total elimination of esophageal acid. Chest. 2002;121:1132-1140.

17. Harding SM, Richter JE. The role of gastroesophageal reflux in chronic cough and asthma. Chest. 1997;111:1389-1402.

18. Ours TM, Kavuru MS, Schilz RJ, Richter JE. A prospective evaluation of esophageal testing and a double-blind, randomized study of omeprazole in diagnostic and therapeutic algorithm for chronic cough. Am J Gastroenterol. 1999;94:3131-3138.

 

Howard Ritz. Pinning down the cause of a chronic cough. JAAPA June 2004;17:27-38.

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