Lactology Foundation

Assessment of chronic cough

Cough is the most common presenting symptom in primary practice. Sub-acute cough is defined as cough persisting for 3 to 8 weeks, and chronic cough as that persisting for more than 8 weeks.
Sub-acute cough is most often self-limiting, but chronic cough may provide significant challenges for effective evaluation and management.

Aetiology
All chronic cough begins as sub-acute, and differential diagnosis includes all causes of sub-acute cough. Post-infectious cough is the most common aetiology of sub-acute cough. Most cases will be self-limiting. Once cough duration has exceeded 8 weeks, a systematic approach to elucidating cause and best treatment is needed.
Common aetiologies
In most non-smoking adults with a normal chest x-ray who do not take ACE inhibitors, chronic cough is caused by one or more of 4 conditions:
• Upper airway cough syndrome (formerly postnasal drip syndrome): 34%
• Asthma: 25%
• Gastro-oesophageal reflux disease: 20%
• Non-asthmatic eosinophilic bronchitis: 13%.
More than one cause of chronic cough is often present. Truly idiopathic cough is rare and is a diagnosis of exclusion. Cough as a sole symptom of asthma, known as cough-variant asthma, is present in a sub-group of patients. These commonest causes account for most patients presenting to specialty clinics with chronic cough and should generally be considered first if there are no signs or symptoms pointing to alternative diagnoses. Other common causes include:
• ACE inhibitors: dry cough, typically associated with a tickling or scratching sensation in the throat, appears in 5% to 35% of ACE inhibitor users. ACE inhibitor-induced cough is more frequent in women, non-smokers, and people of Chinese origin.
• Post-infectious cough: the most common aetiology of sub-acute cough. A history typical for post- infectious cough should prompt watchful waiting and symptomatic therapy as necessary.
• Bronchitis: chronic bronchitis may be considered when an adult has history of chronic productive cough lasting for more than 3 months and for at least 2 consecutive years when other diagnoses have been ruled out. Chronic bronchitis is one of the manifestations of chronic obstructive pulmonary disease. Predisposing factors may include nicotine and marijuana smoking, second-hand exposure to nicotine smoke, and environmental exposure to toxins.
• Bordetella pertussis: when local epidemiology indicates a high rate of pertussis infection, testing for Bordetella pertussis is recommended. If tests are supportive of pertussis, specific antimicrobial therapy is indicated.
Less common aetiologies
Diagnoses to consider are those that impart cough through stimulation of airway mechanical and chemical receptors that feed into the vagus nerve, including afferent nerves located in the chest wall, diaphragm, oesophagus, abdominal wall, and external auditory meatus. Other potential causes therefore are:
• Disorders that distort or irritate the airway (e.g., bronchiectasis, chronic suppurative lung disease, endobronchial tumours, granulomatous disease, foreign bodies)
• Disorders of lung parenchyma (e.g., interstitial lung disease resulting from hypersensitivity pneumonitis, occupational/environmental exposure, or autoimmune diseases such as systemic lupus erythematosus)
• Other diseases that involve systemic processes (rheumatoid arthritis, sarcoidosis), autoimmune diseases such as systemic lupus erythematosus, or diseases that stimulate afferent nerves mentioned above
• Irritation of the external ear canal by an infection, wax, or hearing aids may produce cough, through a reflex mediated by Arnold's nerve.
Oral-pharyngeal dysphagia that results in recurrent aspiration of foods and liquids may also cause cough.
Patients with cough who report difficulty swallowing should be further evaluated for such aetiology. Zenker’s diverticulum can cause chronic cough, accompanied by dysphagia, regurgitation, aspiration, and weight loss.
Bronchiolitis should also be considered, and may result from infection or may be drug/toxin-related. Diffuse panbronchiolitis should be considered in patients who have recently lived in Japan, Korea, or China.
In areas of endemic infection with fungi or parasites, diagnostic evaluation for these should be undertaken when more common causes of cough have been ruled out. Slow enlargement of intrathoracic blood vessels, such as an aortic aneurysm, may cause chronic cough. Somatic cough syndrome (psychogenic cough) may be diagnosed after thorough evaluation has ruled out all other causes. People who work with their voice (e.g., teachers, call centre operators, actors, singers, coaches) may experience chronic cough and hoarseness.

Urgent considerations
Chronic cough as a sole symptom typically lasts for months or years before presentation and does not usually represent an urgent medical condition. A faster and more comprehensive evaluation (rather than empirical treatment) should take place if other symptoms are present (such as dyspnoea, haemoptysis, weight loss, fever, or chest pain) or if the patient has concurrent depression of the local, humoral, or cellular components of the immune system due to neutropenia, acquired immunodeficiency syndrome, or use of glucocorticoids, chemotherapy, or anti-rejection medications.
Lung carcinoma
Cough is the most common symptom of lung cancer. Lung cancer enters the differential diagnosis especially if cough is accompanied by weight loss, haemoptysis, chest pain, dyspnoea, or hoarseness and is more likely in current or prior smokers. Diagnosis is confirmed by radiography and pathology, and treatment may involve surgery, chemotherapy, and radiotherapy.
Asthma
Chronic cough accompanied by episodic dyspnoea and wheezing that worsens at night, on exposure to allergens, cold, or fumes, may indicate asthma. Diagnosis follows a structured clinical assessment, which may demonstrate the above symptoms and previous documented symptom variability, clinical findings of bronchoconstriction, and demonstration of airflow obstruction and reversibility. The 2017 National Institute for Health and Care Excellence (NICE) guideline on asthma also recommends that people with a possible diagnosis of asthma aged 17 years and over should be offered a fractional exhaled nitric oxide (FeNO) test, and that an elevated (>40 parts per billion [ppb]) fractional nitric oxide level should be considered a positive test. The NICE guideline recommends that FeNO testing is considered for children aged 5 to 16 years with a possible diagnosis of asthma, and that a level of >35 ppb is a positive test in this age group. Treatment relies on use of bronchodilators and anti-inflammatory agents.
Pneumonia
May follow a prodrome of chronic cough and, in that instance, is typically manifested with a change in the character of cough, appearance of sputum purulence, and fever. Less commonly, haemoptysis, chest pain, or dyspnoea may be present. Diagnosis is based on clinical findings of lung consolidation, along with radiographic findings of an infiltrate. Treatment consists of antibiotics.
Tuberculosis
Chronic cough accompanied by night sweats and weight loss may indicate tuberculosis, especially in a patient living in or visiting an area with high prevalence of this disease. Tuberculosis is typically accompanied by radiographic infiltrative, fibrotic, or cavernating changes and confirmed by demonstration of Mycobacterium tuberculosis bacilli in sputum.
Bordetella pertussis infection
Paroxysmal cough, inspiratory whooping, and post-tussive vomiting raise a possibility of B pertussis infection. Diagnosis is suspected in household contacts of whooping cough and confirmed with microbiological or serological testing. B pertussis infection is treated with beta-lactam, fluoroquinolone, or macrolide antibiotics.

Step-by-step diagnostic approach
Patients may present with a sub-acute cough, most commonly post-infection; however, most cases will be self-limiting. Observation and, if required, symptomatic therapy are all that may be needed in these cases. Once the cough persists for longer than 8 weeks, further evaluation is indicated. Several validated tools of cough assessment are available, although these are used mostly for research purposes. Pursuing the cause and resolution of chronic cough requires ongoing commitment to the patient. The approach to an individual patient with chronic cough may vary from full initial diagnostic evaluation for common associated diseases, to empirical but targeted therapy for common conditions known to cause chronic cough, with limited or no diagnostic efforts. Choice of the specific approach may be individualised, and depends on type and duration of symptoms, the patient's preference, and availability of resources. Limiting diagnostic testing, treating assumed aetiologies, and applying sequential empirical trials of therapy is most cost-effective, but leads to the longest time to disappearance of cough and may be associated with increased patient anxiety. In practice, diagnostic and therapeutic processes are often applied simultaneously. It is best to involve the patient in choosing the best approach and to explain the expected duration and course of diagnostic and therapeutic trials.

History and examination
A detailed history is essential, with attention to time and clinical setting of onset; exacerbating factors; associated symptoms; prior history suggestive of atopic disease; a complete medical, smoking, drug, and exposure history; occupational and family history; and attention to what measures have already been tried, and to what effect. The history heavily influences the clinician's impression as to which (if any) of the 4 most common aetiologies (upper airway cough syndrome [UACS], asthma, gastro-oesophageal reflux disease [GORD], or non-asthmatic eosinophilic bronchitis [NAEB]) are most likely. A careful examination is, unfortunately, unlikely to inform the clinician regarding the commonest causes of chronic cough, but is essential for early detection of less common causes, such as bronchiectasis, interstitial lung disease, neoplastic disorders, or chronic infectious pulmonary diseases. Laboratory assessment of sputum production is a key factor in narrowing the differential, as it can indicate presence of an infectious cause. Although no specific history or physical examination findings are reliably associated with specific aetiology of chronic cough, they may direct further testing or therapeutic trials. The symptoms and findings associated with the common causes (asthma, UACS, GORD, or NAEB) may direct further diagnostic evaluation towards confirming that cause. Asthma may present with wheezing, chest tightness, or dyspnoea apart from paroxysms of cough, or exacerbation of cough by seasonal exposures, specific irritants, or non-specific respiratory irritants such as cold air, aromatic vapours, or dusty environments. In patients who do not ever wheeze, another cause should be considered. There may be variability of symptoms, nocturnal exacerbation of cough, or a strong family history of asthma or atopic disease. Cough-variant asthma, in which cough is the sole symptom, is present in a sub-group of patients.
UACS is a clinical syndrome and diagnosis is based on the clinical picture (which includes frequent throat clearing, postnasal drip, nasal discharge, nasal obstruction, and sneezing) and response to therapy. Potential causes of UACS include allergic rhinitis, perennial non-allergic rhinitis, post-infectious rhinitis, bacterial sinusitis, allergic fungal sinusitis, rhinitis due to anatomical abnormalities, nasal polyposis, rhinitis due to physical or chemical irritants, occupational rhinitis, rhinitis medicamentosa, and rhinitis of pregnancy. GORD may present with heartburn, dysphagia, acid regurgitation, and an associated cough with slouched posture. Suggestive symptoms may include cough on phonation, cough on rising from bed, or association with certain foods or with eating in general.[8] Reflux disease is clinically silent in up to 75% of cases.
NAEB presents with a chronic, generally scantily productive or non-productive cough without prominent features of asthma or reliable cough triggers, although patients may complain of wheezing at times.
ACE inhibitor cessation
The cough from an ACE inhibitor may begin within days or months of onset of ACE inhibitor therapy. If use of ACE inhibitors is suspected as the cause, use should be stopped if at all possible. Diagnosis is then confirmed by the resolution of cough, usually within 1 to 4 weeks (although it may be up to 3 months). Angiotensin receptor blocking agents do not appear significantly related to chronic cough symptoms.

Chest x-ray (CXR)
A CXR should be obtained early in the evaluation of chronic cough. Although it is not diagnostic of the most common causes, findings may quickly divert the evaluation to causes of greater gravity. These include lung cancer, pulmonary fibrosis, tuberculosis, bronchiectasis, pneumonia, aspiration, and sarcoidosis.

Choice of diagnostic testing or therapeutic trials
Following CXR, the choice of either diagnostic testing or therapeutic trials depends on the clinician's assessed probability of a specific aetiology and the patient's preferred approach. Unless the history, physical examination, and CXR indicate otherwise, efforts should be concentrated on one or more of the 4 most common causes (asthma, UACS, GORD, NAEB). For example, if the history is most suggestive of asthma, then spirometry (to test for airway obstruction) and bronchodilator variability testing would be appropriate first tests. The 2017 National Institute for Health and Care Excellence guideline on asthma recommends that adults (aged 17 years and over) with a possible diagnosis of asthma should be offered a fractional exhaled nitric oxide (FeNO) test as a first test before spirometry, and that a level >40 parts per billion should be considered a positive test. Other investigations include bronchoprovocation challenge testing. If this proves negative, NAEB should be considered. If UACS is suspected, a therapeutic trial aimed at resolving rhinosinusitis and reducing excessive secretions is indicated. If GORD is suspected, either a therapeutic trial or diagnostic testing may be employed (taking into account both the clinician's and patient's preferences).
Therapeutic trials
Therapeutic trials are selected based on clinical impression, at times supported by diagnostic testing. The patient's response to the trial must be assessed and the cough resolved before a given aetiology may be assigned with certainty. A partial response may indicate that more than one aetiology is in play. In this event, further testing and/or additional therapeutic trials may be indicated, while the partially successful therapy should be continued. Lack of a response requires reassessment both of suspected aetiology and of treatment adherence and effectiveness. High placebo effect has been reported in empirical trials in chronic cough. Empirical therapeutic trials may be undertaken sequentially (starting with the most likely aetiology first), with subsequent selections made according to patient response. Alternatively, trials may be undertaken simultaneously when multiple aetiologies are suspected from the outset, with subsequent sequential withdrawal of therapies once the cough is controlled. The following are considered:
1. UACS: failure of response to appropriate therapeutic trials should prompt a sinus computed tomography (CT) scan and an ear, nose, and throat (ENT) referral, particularly if other aetiologies have been considered and deemed very unlikely.
2. Asthma or NAEB: failure of response to appropriate therapy should prompt careful evaluation for treatment adherence, anti-inflammatory effectiveness (measured by FeNO and peak-flow variability, as appropriate), and conditions that contribute to ongoing poor asthma control such as GORD, sinus disease, or ongoing allergen exposure.
3. GORD: failure of response to an appropriate therapeutic trial of 8 to 12 weeks should prompt confirmatory testing (if not already done), and careful assessment of effectiveness of acid suppression and/or other factors contributing to ongoing non-acid reflux.

Further diagnostic evaluation
If none of the 4 most common causes seem likely after thorough assessment, other tests to consider include:
1. High-resolution CT imaging of the chest to look for bronchiectasis (which does not always promote a productive cough) or other structural lung disease (which may not show well on CXR). Chronic suppurative lung disease is diagnosed in patients with clinical symptoms of bronchiectasis but no radiographic evidence of bronchiectasis. CT imaging may also indicate the presence of an aortic aneurysm or Zenker’s diverticulum.
Bronchoscopy to search for endobronchial pathology.
CT sinuses or nasendoscopy.
24-hour oesophageal pH and/or impedance monitoring to rule out silent GORD.
Serum ferritin and iron, because iron deficiency has been associated with chronic cough.
In addition, pulmonary and/or ENT consultation should be considered. In cases where the patient also has features of stridor, laryngospasm, or paradoxical vocal fold motion, early involvement of a speech pathologist is appropriate, because treatment directed at underlying causes may speed resolution of chronic cough as well.