Chronic Cough: Practice Essentials, Mechanism of Cough, Causes of Chronic Cough

Antitussives, such as codeine and dextromethorphan, have been shown to have limited or no efficacy in the treatment of chronic cough and any beneficial effect is largely due to placebo effect. ^{[16, 4, 24]} As such, the clinician should try to elucidate and identify the underlying cause of the cough to effectively manage it.

Every patient with chronic cough needs a thorough history taken and physical examination performed as part of their evaluation. Each patient should also have a chest radiograph taken.

Surprisingly, the medical history (in terms of the patient’s description of the character, timing, and presence or absence of sputum production) has been shown to have little or no diagnostic value. ^{[25, 26]} What is of value from the medical history is whether or not the patient is or has been a smoker; is taking an ACE inhibitor; is living in a geographic area where tuberculosis or certain fungal diseases are endemic; has any systemic symptoms, a history of cancer, tuberculosis, or AIDS; or has a large pulmonary mass visible on chest radiograph.

Management should begin with cessation of smoking or ACE inhibitor use in those patients whose history indicates such action. Most patients have a resolution of their cough within 4 weeks of smoking cessation. ^[10] Cough related to ACE inhibitor use usually subsides within 2 weeks, but the median time has been reported to be 26 days. ^[10]

If the chest radiograph findings are abnormal, further workup depends on the specific finding. Chest CT scan, bronchoscopy, needle biopsy, and sputum studies are all potentially warranted studies if a pulmonary lesion is found.

For the immunocompetent nonsmoker who does not use ACE inhibitors and has normal chest radiograph findings, a systematic approach to the most common causes of chronic cough is warranted, keeping in mind that more than one cause may be present. The body of literature regarding specific treatments and the expected time frame of response is extensive, and the accuracy of the diagnosis is confirmed by the patient’s response to these treatments. From both theoretical and cost effectiveness standpoints, empiric treatment of the 3 most common causes of cough is favored over extensive testing at the outset. ^{[27, 28]} Further, sequential and additive therapy may be needed because more than one cause of cough is often present.

Upper airway cough syndrome

Because upper airway cough syndrome (UACS) is the most common cause of chronic cough, it should be treated first. In patients in whom the cause of the UACS-induced cough is apparent, specific therapy directed at this condition should be instituted. This includes avoiding environmental irritants and offending antigens, treating sinusitis with antibiotics, and weaning patients off nasal decongestants for rhinitis medicamentosa. Further workup may include allergy testing for allergic rhinitis or sinus CT scan for sinusitis, as indicated.

For patients in whom the cause is not apparent, empiric therapy should be instituted with a combination of an antihistamine and decongestant. First-generation antihistamines such as azatadine and dexbrompheniramine plus pseudoephedrine have shown more effectiveness than newer, less-sedating antihistamines. ^{[13, 29]} Patients typically respond within 2 weeks of initiating therapy but may sometimes take several months. ^[11]

Asthma

Asthma should be considered only after the UACS evaluation and empirical treatment trial are complete. Ideally, patients should undergo spirometry and bronchoprovocation challenge with methacholine, which reveals reversible airflow obstruction. The negative predictive value for a negative challenge approaches 100%. ^[26]

The initial treatment of asthma consists of beta-2 agonists and inhaled corticosteroids (ICS), and response is usually seen within 1 week, with complete resolution taking up to 8 weeks. ^[11] Some patients may require a trial of oral corticosteroids before a response is seen. However, because leukotriene inhibitors have been shown to be effective in patients with asthma-induced cough, they should be tried prior to oral corticosteroid therapy. ^[10]

Nonallergic eosinophilic bronchitis

Because its diagnosis is made easily, nonallergic eosinophilic bronchitis (NAEB) is the next etiology to consider, even though GERD is more common. An induced sputum test that reveals increased eosinophils is the diagnostic procedure of choice. ^[10] Treatment includes ICS, with oral corticosteroids reserved for refractory cases. Response is usually seen within 4 weeks.

Gastroesophageal reflux disease

Prospective studies have shown that in a patient who has undergone empiric therapy for UACS, asthma, and NAEB and has had no response or only a partial response, a 92% probability exists that their chronic cough is due to GERD. ^[10] The criterion standard for diagnosis of GERD is dual-channel 24-hour pH probe monitoring. Alternatively, flexible nasopharyngoscopy can reveal glottic changes associated with reflux. These include laryngeal edema and erythema, laryngeal pseudosulcus, and posterior commissure hypertrophy or pachydermia.

Simply because of the percentages, empiric therapy with acid suppression and lifestyle and dietary modification has been advocated as initial management instead of testing, which is reserved for refractory cases. Lifestyle modifications include limiting fat intake; avoiding caffeine, chocolate, mints, citrus products, alcohol, and smoking; and limiting vigorous exercise that increases intra-abdominal pressure. ^[12]

The choice of acid suppressive medication can include histamine 2 (H2) blockers, proton pump inhibitors (PPIs), and prokinetic agents. However, note that maximal medical therapy refers to twice daily PPI in addition to a prokinetic agent with concurrent lifestyle and dietary modifications. ^[12] Although response can be seen in as little as 2 weeks, at least a 6-8 week trial is needed to fully evaluate a response to treatment, with some patients requiring as long as 6 months. ^{[29, 30]}

Further workup and refractory chronic cough

Only when management of the most common causes has failed to yield a resolution of cough should a more extensive workup begin. This can include induced sputum testing for acid-fast bacillus, high-resolution CT scanning of the chest, and bronchoscopy. Often, these tests should be performed by a cough specialist. If further testing does not reveal the cause, then the patient most likely has chronic cough hypersensitivity syndrome. Owing to inflammation and hyperresponsiveness of the airway from some inciting cause, tissue remodeling has occurred, leading to an enhanced cough reflex that maintains the cough even though the inciting cause has resolved. ^[17] In these truly idiopathic cases, therapeutics are limited, but ongoing research is focusing on medicines that either directly or indirectly affect the cough reflex. ^[31]  

Similarities have been demonstrated between neuropathic pain and chronic cough, and centrally acting neuromodulators such as tricyclic antidepressants (amitriptyline, nortriptyline), gabapentin, and pregabalin have shown benefit in improving cough (albeit with risk of side effects). ^{[32, 33, 34]}  A randomized, placebo-controlled trial by Vertigan et al indicated that treatment of refractory chronic cough with a combination of speech pathology therapy and pregabalin (300 mg daily) is more effective than treatment with speech pathology therapy plus placebo. The study involved 40 patients, with improvement measured using the visual analogue scale, the Leicester Cough Monitor, and the Leicester Cough Questionnaire. ^[35]

The P2X3 receptor has been shown to mediate pain responses, with promising results obtained from research into chronic cough treatment with P2X3 receptor antagonists. Studies by Smith et al and Morice and colleagues indicated that the P2X3 receptor antagonist MK-7264 is effective against refractory chronic cough. ^{[36, 37]}

Guidelines

French guidelines on chronic cough published in 2023 include the following for first-line management ^[38] :

• Questioning patients with chronic cough about physical, social, and psychological complications is recommended

• In patients with chronic cough, it is recommended that an objective measurement of cough be used when possible

• It is recommended that the clinician determine whether cough-inducing drugs may be triggering factors and that the cough be reassessed 4 weeks after the drugs have been discontinued

• It is recommended that smoking cessation assistance be offered to chronic cough patients who smoke; at least 4 weeks are required to observe smoking cessation’s benefits on chronic cough

• If the patient does not cease smoking, a decrease in tobacco consumption is also a useful means of reducing cough

• Investigation for respiratory symptoms that may indicate the presence of asthma is recommended in patients with chronic cough

• In patients with chronic cough, spirometry with a bronchodilator reversibility test is recommended, whether or not symptoms suggestive of asthma exist

• If there is no obvious etiology for a patient’s chronic cough, at least 4 weeks of trial treatment with inhaled corticosteroids is recommended

• Background treatment according to the current guidelines is recommended when asthma-like cough (asthma characterized by isolated cough) exists

• Treatment of chronic cough is possible using inhaled β2 mimetics, inhaled anticholinergics, or anti-leukotrienes combined with inhaled corticosteroids, to exercise a small impact on the cough

• Anti-reflux treatment in patients with chronic cough is justified only in the presence of clinical symptoms of reflux (heartburn, regurgitation)

• It is recommended that when symptoms suggestive of UACS exist, trial treatment be initiated combining nasal cavity cleaning with physiologic serum and nasal corticosteroids

• Except in cases of allergic rhinitis, treatment of UACS with an antihistamine is not recommended