Cough

Etiology

The etiology of a cough is an arbitrary classification based largely on the duration of a cough. If a cough is presently less than three weeks, it is designated as acute. If a cough is present for three to eight weeks, it is designated as subacute. If a cough is presently greater than eight weeks, it is designated as chronic.

The most common causes of acute cough in adults are acute viral upper respiratory infection, also known as the common cold, and acute bronchitis. Acute bronchitis is typically viral in etiology, but bacterial infection is the source in approximately 10% of cases. Additional common causes of an acute cough include acute rhinosinusitis, pertussis, acute exacerbations of chronic obstructive pulmonary disorder, allergic rhinitis, asthma, congestive heart failure, pneumonia, aspiration syndromes, and pulmonary embolism.

Acute rhinosinusitis is characterized by an inflammation of the lining of the paranasal sinuses and accounts for approximately 16 million office visits per year. It is commonly due to a viral illness if present for less than ten days but may be related to bacterial infection if the illness is longer than ten days. A cough is induced here, primarily as a response to increased mucus production and post-nasal drip.[1]

Pertussis, also known as whooping cough, is an illness with a classic clinical finding of paroxysmal episodes of intense coughing lasting up to several minutes followed by a loud gasp for air. It is an infection of the respiratory tract by Bordetella pertussis, where the bacterium induces mucopurulent sanguineous exudate formation within the respiratory tract. The overall course of pertussis infection lasts up to six weeks and is characterized by three stages: a catarrhal phase, a paroxysmal phase, and a convalescent phase. The catarrhal phase is characterized by rhinorrhea, sneezing, low fever, tearing, and nasal congestion. The paroxysmal phase occurs within two weeks of colonization and is characterized by classic coughing episodes followed by post-tussive vomiting. The convalescent phase is a condition of chronic coughing that may last for weeks. This illness is a serious diagnosis that requires prompt attention as it remains one of the highest causes of infant morbidity and mortality.[2]

Asthma is a complex disease where the body’s immune system is hyperresponsive to an environmental stimulus which results in inflammation, intermittent airflow obstruction, and bronchial hyperreactivity with constriction of the airways. It impacts 26 million people in the United States. A cough is induced in these patients as a result of increased mucous secretions compounded with the narrowing of the airways.[3][4]

Acute exacerbations of chronic obstructive pulmonary disorder (COPD) are estimated to affect 32 million people in the United States alone. COPD is a classic triad of chronic bronchitis, emphysema, and asthma. These patients have a loss of lung elasticity as well as air-trapping pathologies. This predisposes them to develop infections such as acute bronchitis and bacterial pneumonia. When an acute exacerbation occurs, the lung parenchyma becomes inflamed and has increased hyperresponsiveness, leading to a constriction of the airways with a subsequent decline in lung function. This induces an accumulation of purulent and thick mucus secretions within the bronchioles and alveoli, triggering a coughing response.[5]

Allergic rhinitis is an inflammation of the nasal mucosa secondary to an allergic irritation from the environment. This irritation leads to increased mucus secretion and post-nasal drip. It is the post-nasal drip that irritates the airways, stimulating a cough.

Congestive heart failure is an illness where the heart’s efficiency in pumping blood has decreased to the point that fluid congestion begins to occur in the vasculature. Most commonly, this failure begins in the left ventricle and atria. Fluid congestion then occurs in the pulmonary vasculature. This creates edematous, heavy lungs with an increased A-a gradient and irritates the lungs, stimulating the cough.[6]

Pneumonia has many different etiologies and may be viral or bacterial. Viral pneumonia leads to inflammation and irritation of the airways, whereas bacterial pneumonia will also have increased mucous and purulent secretion irritating the airways further. Pulmonary tuberculosis typically presents with fever and productive or dry cough with weight loss.

Aspiration syndromes occur when the glottis does not close sufficiently during swallowing. This allows for the passage of food or fluid particles into the airways rather than the esophagus. In addition, to be caustic and irritating, food particles may lead to an infectious pathology known as aspiration pneumonia.

A pulmonary embolism is a pathology where an embolus forms and becomes lodged within the pulmonary capillaries. Most commonly, this occurs as a deep vein thrombosis elsewhere in the body, which becomes dislodged and travels to the pulmonary circulation.[7]

Coughing develops here in a similar fashion to congestive heart failure. Blood congestion occurs in the areas before the embolus causing edematous and heavy lung spaces. This inflames and irritates the lung spaces. Additionally, if an embolus is large enough and present for a long enough period, necrosis of tissue may occur, releasing pro-inflammatory cytokines into the lung spaces, thus further worsening a cough.

Subacute coughing is most commonly post-infectious secondary to continued irritation of cough receptors via ongoing or resolving bronchial or sinus inflammation from a preceding viral upper respiratory infection. Both acute and subacute coughs are self-limiting illnesses that typically require only supportive measures.

A chronic cough is a more difficult diagnosis to elucidate and typically will require referral to a cough specialist or a pulmonologist for evaluation. Possible causes include upper airway cough syndrome, gastroesophageal reflux disease, non-asthmatic eosinophilic bronchitis, chronic bronchitis, postinfectious cough, intolerance to angiotensin-converting enzyme inhibitor medication, malignancy, interstitial lung diseases, obstructive sleep apnea, chronic sinusitis, and psychosomatic cough.

Upper airway cough syndrome is the most common etiology of a chronic cough. There is a wide spectrum of illnesses that encompass this disease, including allergic rhinitis, non-allergic rhinitis, post-infectious, and/or bacterial or viral rhinosinusitis. Essentially, upper airway cough syndrome is a longstanding post-nasal drip that irritates the upper airway, inducing cough.[8]

Gastroesophageal reflux disease accounts for up to 40% of chronic coughs and occurs as a result of the retropulsion of acidic contents from the stomach into the pharynx and larynx. This leads to irritation of laryngeal receptors and episodic microaspiration. Often, this illness will have a cough that is worse in the evenings when the patient is lying flat, as this allows for easier reflux of the stomach.[9][10]

Non-asthmatic eosinophilic bronchitis is an illness of hyperresponsiveness of the bronchioles without classic asthma findings and has an increased eosinophilic component indicating a hyperactive immune system. Hyperactive eosinophilia leads to increased concentrations of inflammatory cytokines, causing inflammation and irritation of the airways. Eosinophilic asthma varies from non-asthmatic eosinophilic bronchitis due to a difference in the localization of mast cells within the airway wall. Smooth muscle infiltration occurs in typical asthma, which results in the narrowing of the airways. There is epithelial infiltration of non-asthmatic eosinophilic bronchitis irritating cough receptors directly.

Chronic bronchitis is, by definition, a cough that has been present for longer than three months consecutively over two years. A cough is commonly present here as a result of excessive mucous secretions causing mucous plugging of the airways. An inflammatory component has also been suggested in this etiology. Chronic bronchitis does not have an infectious component; however, it predisposes the patient to bacterial infections, which may worsen the illness, creating a positive feedback loop of coughing.

A post-infectious cough occurs due to increased cough receptor sensitivity and temporary bronchial hyperresponsiveness during the recovery from a worse pulmonary infection. This is likely closely related to developed epithelial damage from the initial pathology.

Cough variant asthma presents primarily with coughing, not wheezes, as in typical asthma. These patients will have normal spirometry at baseline, but positive methacholine challenge, when tested. This should be suspected if a cough is non-productive, repetitive, occurs day and night, and is exacerbated by exercise, cold air, or upper respiratory infection. Look for positive family history or seasonal variation. This is thought to be because cough receptors are more prevalent in the proximal airways and decrease in density as the airways get smaller. Therefore, in cough variant asthma, the inflammation is more prominent in the proximal airways where a cough is stimulated and less so distally, where inflammation and narrowing would cause wheezing and dyspnea. Treatment is the same for cough variant asthma as for typical asthma.

Malignancy may cause a mass effect with physical obstruction or collapse of the airways, thus inducing mucus accumulation and secondary infections in addition to irritation of the cough receptors directly. Additionally, some cancers may have secretory effects on the airways.

Interstitial lung diseases are a large group of disorders that cause progressive scarring and hardening of lung tissue. These occur as the result of long-term exposure to various hazardous materials, such as asbestos, silicone, coal dust, radiation, or heavy metals. This is often work-related, such as in nuclear power plant workers, coal miners, sandblasting workers, and the like. Some types of autoimmune diseases, including rheumatoid arthritis, scleroderma, dermatomyositis and polymyositis, mixed connective tissue disease, Sjogren syndrome, and sarcoidosis, can cause interstitial lung disease. Additionally, idiopathic pulmonary fibrosis may occur.[11]

Obstructive sleep apnea is characterized by a partial or complete obstruction of the airway transiently during sleep. This increase in airway resistance causes a reflexive diaphragmatic and chest muscle spasm and cough to open the obstructed airway and pull air into the lungs. This typically occurs as a result of lax musculature in the pharynx or due to the increased weight of the neck collapsing the pharynx in obese people.[12]

Chronic sinusitis-induced cough chronically as a result of prolonged inflammation and irritation of the sinus and nasal mucosa with purulent discharge secondary to a bacterial pathogen. This occurs as a result of recurrent acute sinusitis that allows for facultative anaerobic pathogens such as Staphylococcus aureus, Staphylococcus epidemicities, and other gram-negative organisms to flourish.

A psychosomatic cough is rarely diagnosed and, as an etiology, should be avoided unless no other explanation can be elucidated. This is the act of coughing as a habit rather than as part of a disease process. It may be learned as a habit or part of an underlying psychological condition.

Epidemiology

A cough is the single most prevalent symptom on presentation to a provider’s office. Prevalence is heavily influenced by the social history of smoking tobacco usage and is estimated between 5% to 40%. The exact etiology of a cough determines the predilection of race and gender impact.

Pathophysiology

Coughing is a largely uncontrolled, protective reflex mechanism responsible for mucociliary clearance of the airway and excess secretions within the airway. This reflex is characterized by the closing of the glottis apparatus with subsequent increases in the intrathoracic pressure, which often exceeds 300 mm Hg. This is followed by the forceful expulsion of the airway contents through the glottis into the pharyngeal space and out of the body. Given the forceful nature of this process, with a velocity of exhalation exceeding 500 mph in some cases, mucous secretions are loosened from the wall of the airway and expelled. While the body physiologically uses the cough reflex in a protective manner, it is possible that aberrations in normal physiology can create unfavorable conditions that are at their mildest uncomfortable or annoying to the patient and, at worst malignant to survivability with hemodynamic instability.

The reflex of coughing is initiated by a chemical irritation at peripheral nerve receptors within the trachea, main carina, branching points of large airways, and distal smaller airways. They are also present in the pharynx. Laryngeal and tracheobronchial receptors respond to mechanical and chemical stimuli. Chemical receptors are sensitive to acid, heat, and capsaicin-like compounds via activation of the type-1 capsaicin receptor. Additionally, there are multiple neural sensory receptors located within the external auditory canals, eardrums, paranasal sinuses, pharynx, diaphragm, pleura, pericardium, and stomach, which are all capable of stimulating the coughing reflex. These are mechanical receptors that stimulate secondary to triggers such as touch or stretch. These sensory receptors are classified into one of three categories: rapidly adapting receptors, slow adapting stretch receptors, and C-fibers. Rapid adapting receptors are, as the name implies, myelinated quick response sensory neurons that respond within one to two seconds. These neurons have a conduction velocity of 4 to 18 meters per second. They are specialized for sensing collapse or narrowing of the airways and are responsive to dynamic changes in lung compliance. These receptors will become desensitized to prolonged inflation of the airways and, as such, are not able to moderate chronic inflation reflexes of the lungs. Such changes might include bronchospasm with constriction of the airway, mucous plugging with obstruction of the airways or any other physiological changes in the biomechanics of the airways. Slow-adapting stretch receptors are highly sensitive to mechanical forces acting on the airways as well. However, these neurons function much more slowly than their rapid-acting counterparts. They are found in the greatest density within the terminal bronchiole tree and alveoli of the lungs. As the name implies, these are associated with a stretch sensation in the airway, as seen in hyperinflation. These neurons do not sensitize to chronic hyperinflation. These are physiologically important in initiating the Hering-Breuer reflex at the terminal portion of inhalation to cease inhalation and induce exhalation once the lungs reach a physiological set volume to prevent barotrauma. C-fibers comprise the majority of afferent sensory innervation to the pulmonary system. They are unmyelinated neurons similar to somatic sensory nerves found elsewhere in the body, with an average conduction velocity of two meters per second. Unlike rapid-acting receptors and slow-adapting stretch receptors, these neurons are relatively insensitive to mechanical stimulation providing only chemical irritation input to the central nervous system. Known chemical irritants include capsaicin, bradykinin, citric acid, hypertonic saline solution, and sulfur dioxide.

These sensory inputs from peripheral receptors travel afferently via cranial nerve X (the Vagus nerve) to the respiratory centers of the brain within the upper brain stem, medulla, and pons. While not yet fully understood, the cough center of the brain is not necessarily a centralized location. Rather it is a modulation of the inherent respiratory center of the brain.

The respiratory center of the brain is comprised of three neuron groupings: the dorsal and ventral medullary groups and the pontine grouping. The pontine grouping is further sub-classified into the pneumotaxic and apneustic centers. The dorsal medulla is responsible for inhalation; the ventral medulla is responsible for exhalation. The pontine groupings are responsible for modulating the intensity and frequency of the medullary signals, while the pneumotaxic groups limit inhalation, and the apneustic centers prolong and encourage inhalation. Each of these groups communicates with one another to concert the efforts as the pace making potential of respiration. All cough receptors project sensory input through the nucleus tractus solitarius to other parts of the respiratory networks. The pre-Botzinger complex specifically acts as a unique pattern generation center for the cough response. Parts of the caudal medullary raphe nucleus consisting primarily of the nucleus raphe obscurus and nucleus raphe magnus are essential for coughing as well. The net result of these generated intertwined action potentials results in an efferent signal generation that travels through the vagus, phrenic, and spinal motor nerves to the expiratory musculature of the diaphragm, intercostals, pharynx, and neck to produce a cough.

The mechanism of action for coughing can be subdivided into three overarching phases: the inspiration phase, the compression phase, and the expiratory phase. During the inspiration phase, inhalation occurs, generating an increase in volume within the pulmonary system. This volume is necessary for generating enough air movement to be productive. The compression phase is marked by the closure of the larynx combined with the contraction of muscles of exhalation, including the intercostals, diaphragm, and abdominals leading to a net increase in intrathoracic pressure without any air movement occurring. The expiration phase is marked by the rapid opening of the glottis resulting in rapid, high-volume expiratory airflow. This rapid airflow causes vibrations within the larynx and pharynx, inducing the characteristic sounds of a cough. Throughout this process, airway compression occurs, resulting in a net decrease in intrathoracic volume. After exhalation, rebound inhalation may occur, depending on the duration of a coughing episode as well as the volume of airflow movement, in compensation for developed hypoxia or reflexive inhalation.[4][13]

History and Physical

As with any illness, a full and detailed history collection accompanied by an appropriate physical exam is the most important aspect of any medical evaluation. The diagnosis of a cough is an obvious clinical observation. A cough is a symptom rather than a diagnosis of disease. As such, many patients present for evaluation of the secondary or underlying effects of cough rather than a cough itself. Essential components of the history-taking session should include:

• Details about duration
• Cigarette smoking
• Use of angiotensin-converting enzyme inhibitors
• Weight loss
• Occupation
• Diurnal variation
• Relieving factors
• Aggravating factors
• Productive with sputum or nonproductive, if productive, what is the color of phlegm
• Associated hemoptysis
• Associated fever
• Associated shortness of breath
• Presence of an upper respiratory tract infection at the onset of a cough

Otherwise, a systemic approach should be used to identify any coexisting illness which may be the origin or compounding factor of a cough. Interestingly, one study in 1996 found that the character and timing of a cough and the presence or absence of sputum production aid in the further specification of a differential diagnosis. Specific findings that are common and may be found with any complaint of a cough include malaise, fatigue, insomnia, lifestyle changes, musculoskeletal chest pain, hoarseness, excessive perspiration, urinary incontinence, syncope, cardiac dysrhythmias, headache, subconjunctival hemorrhage, inguinal herniation, or gastroesophageal reflux. The specific complaints should tailor the focus of a clinical physical exam and diagnostic workup to elucidate the exact etiology.[14]

Evaluation

An acute and subacute cough requires no diagnostic studies and should be treated symptomatically unless there is suspicion of an insidious pathology. A chest x-ray may be appropriate if a cough is determined to be severe or if the patient appears extremely ill.

A chronic cough may require diagnostic measures, including a chest x-ray and complete pulmonary function testing. Patients without specific clues on history and physical examination who have a normal chest x-ray and spirometry may require referral to a pulmonologist for more intense evaluation. Often, a single etiology cannot be elucidated, and chronic cough is the result of a spectrum of multiple disease processes. Bronchoscopy with direct visualization of vocal cords, trachea, and other airways may be required to rule out any vocal cord mass or lesion and endotracheal or endobronchial mass. Accordingly, one may require biopsy and or bronchoalveolar lavage to obtain samples for microbiological and cytological analysis. An echocardiogram may be indicated for cardiac function testing. CT scan of the chest may be indicated for anatomical analysis. Gastroesophageal studies may be indicated, including speech and swallow evaluations. Esophagogastroduodenoscopy or pH-probe monitoring of the stomach may be indicated for aspiration and gastroesophageal reflux analysis. If a cough is mostly at night, and the patient has signs and symptoms suggestive of obstructive sleep apnea, then one may order a sleep study to confirm the diagnosis and treat sleep apnea accordingly.

Criteria for the diagnosis of a neurogenic cough are:

1. The almost constant presence of cough during the day
2. Non-productive cough
3. Unilateral or bilateral vocal fold paresis on the laryngeal exam
4. Laryngeal electromyographic confirmation of paresis
5. Complete resolution of symptoms with appropriate treatment

Treatment / Management

Most cases of acute cough should be treated empirically and focus on symptomatic relief. This includes supportive measures of over-the-counter cough and cold medicines. However, many over-the-counter antihistamine-decongestant medications have been shown to offer no clinical benefit over placebo. Cough suppressants may be used to lessen the cough by blunting the cough reflex, and expectorants may be used when excessive mucous secretions are determined to be the primary issue to increase mucus clearance. The most commonly used suppressant is dextromethorphan, and the most common expectorant is guaifenesin. It is important to remember, however, that coughing is a basic defense mechanism and plays an important part in the body’s immune system. Therefore, decreasing the cough reflex may have detrimental impacts on the recovery time of illness. As such, the current American College of Chest Physicians guidelines does not recommend the use of peripherally or centrally-acting cough suppressants for the treatment of cough due to and discourage the use of over-the-counter combinations for the treatment of acute cough due to the common cold. Whenever an infectious etiology is suspected, sputum culture should be attempted, and antibiotic therapy tailored to the pathogen. In chronic infectious upper respiratory etiologies, prolonged antibiotic therapy for 3 to 6 weeks with an appropriately selected agent (similar to those used for acute infections) is necessary. Amoxicillin/clavulanate 875 mg orally twice a day for 3 to 6 weeks is the first line of treatment. However, alternative therapies may be used, including:

• Clindamycin 300 mg by mouth three times a day for 3 to 6 weeks
• Cefuroxime 500 mg twice a day for 3 to 6
• Cefprozil 500 mg twice a day for 3 to 6 weeks
• Clarithromycin 500 mg twice a day for 3 to 6 weeks
• Gatifloxacin 400 mg by mouth four times daily for 3 to 6 weeks
• Levofloxacin 500 mg by mouth four times daily for 3 to 6
• Moxifloxacin 400 mg by mouth four times daily for 3 to 6 weeks

Inhaled albuterol and ipratropium bromide nebulizer solutions may be used for bronchodilatory effect in a constricted airway for symptomatic relief in urgent situations. Treatment of a chronic cough should attempt to target the underlying etiology whenever possible to reduce coughing instead of suppressing the cough. If a patient is identified to be taking an angiotensin-converting enzyme inhibitor, this medicine should be discontinued, and an aldosterone-receptor-blocking medicine started in its place. In reactive airway disease, inhaled steroids or anticholinergic medications may be indicated. Cardiac function should be optimized following appropriate cardiology recommendations in a patient-specific manner. Gastroesophageal reflux should be treated aggressively by avoiding predisposing reflux substances, including chocolate, caffeine, alcohol, and tobacco. Furthermore, to prevent aspiration, patients should elevate the head of the bed and not eat for several hours before bedtime. Medical therapy should include a proton pump inhibitor at maximal dosing.

Treatment of chronic neurogenic cough is different than other neuropathic conditions. For isolated cough with no laryngopharyngeal reflux, start treatment with tramadol 25 mg up to 4 times per day when necessary or amitriptyline 10 mg at bedtime. If laryngopharyngeal reflux is present or there are other symptoms, gabapentin 100 mg four times per day is preferred with an escalation of dose as tolerated and as needed. Patients typically require 300 to 500 mg four times per day. These medications may be used alone or in combination. Typical combination therapies include gabapentin with a small dose of amitriptyline at bedtime. Pregabalin and baclofen are second-line choices used in special situations.[4][15][9][10][16]

Differential Diagnosis

Differentials to be considered in establishing the cause of cough can be divided into categories such as acute, subacute, and chronic. Besides, there are some very rare causes that should be ruled out once the diagnosis is ambiguous.

Acute

• Acute bronchitis
• Acute exacerbations of chronic obstructive pulmonary disorder
• Acute rhinosinusitis
• Acute viral upper respiratory infection
• Allergic rhinitis
• Asthma
• Aspiration syndromes
• Congestive heart failure
• Pertussis
• Pneumonia
• Pulmonary embolism

Subacute

• Post-infectious secondary to continued irritation of cough receptors via ongoing or resolving bronchial or sinus inflammation from a preceding viral upper respiratory infection

Chronic

• Chronic bronchitis
• Chronic sinusitis
• Gastroesophageal reflux disease
• Interstitial lung diseases
• Intolerance to angiotensin-converting enzyme inhibitor medication
• Malignancy
• Non-asthmatic eosinophilic bronchitis
• Obstructive sleep apnea
• A post-infectious cough
• A psychosomatic cough
• Upper airway cough syndrome

Very Rare

• Cerumen impaction- vagal nerve stimulation of the afferent branch to the ear, known as Arnold nerve
• Esophageal achalasia
• Tracheoesophageal fistula
• Oesophageal tracheobronchial reflex
• Ortner syndrome: Intermittent left vocal fold paralysis as a result of cardiac ptosis straining the ipsilateral recurrent laryngeal nerve
• Pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS): A pediatric cough where prior Streptococcus infections can trigger motor tics, including a chronic cough
• Peritoneal dialysis
• Pneumonitis
• Syngamus laryngeus: A small, roundworm indigenous to the Caribbean, Syngamus laryngeus is acquired by ingesting a contaminated fruit or vegetable. A male and female pair of worms take up residence in the subglottic larynx, and there they remain tenaciously adherent to the mucosa, except when mating. The pair may be coughed up in copula; otherwise, they can be endoscopically removed with a resolution of the host’s chronic cough.
• Tracheobronchial collapse
• Vitamin B12 deficiency
• Zenker or distal esophageal diverticulum

Prognosis

Coughing in itself is relatively benign. However, the precise prognosis a patient faces is heavily reliant on the underlying etiology.

Complications

Persistent cough or severe bouts of cough can cause complications, and these include:

• Sleep disruption
• Headache
• Vomiting
• Syncope
• Excessive sweating
• Rib fracture
• Urinary incontinence