Internal Medicine/Cough

Introduction to Cough
Cough, as a physiological response, plays a crucial role in safeguarding our respiratory system. It serves as a protective mechanism, helping to clear the airways and lungs of irritants, secretions, or foreign substances that might otherwise pose a threat to our respiratory health. Without an effective cough reflex, we would be at risk of retaining airway secretions and aspirating materials, potentially leading to infections, atelectasis (partial lung collapse), and respiratory compromise.

At the other end of the spectrum, excessive coughing can have detrimental effects. It can be exhausting, causing significant fatigue and discomfort. Prolonged or severe coughing episodes can lead to complications such as emesis (vomiting), syncope (fainting), muscular pain, or even rib fractures. In some cases, it can exacerbate pre-existing conditions like low back pain, abdominal or inguinal hernias, and urinary incontinence. Moreover, excessive coughing can be socially isolating, hindering normal interactions and causing discomfort to both the person with the cough and those around them.

Cough is often an early indicator of respiratory disease. In many instances, it manifests as an expected and accepted symptom of various respiratory conditions, especially during acute respiratory tract infections. However, when cough persists in the absence of other significant respiratory symptoms, it frequently prompts individuals to seek medical attention, signaling the potential presence of an underlying issue.

Understanding the Cough Mechanism
Coughing is not a simple reflex but a complex physiological process involving multiple sensory and motor components. It can be triggered by various stimuli, including both chemical and mechanical factors. Chemical stimuli, such as capsaicin, and mechanical factors, like mucus or particulates in air pollution, can initiate the cough reflex.

Sensory neuronal receptors, including cationic channels like transient receptor potential channels and adenosine triphosphate-activated ion channels (P2X3), play essential roles in detecting these stimuli. These receptors are primarily located in the pharynx, larynx, and airways, extending deep into the lung parenchyma. Interestingly, they can also be found in unexpected places, such as the external auditory canal and the esophagus.

The sensory signals from these receptors travel along the vagus and superior laryngeal nerves to a specific region in the brainstem known as the nucleus tractus solitarius. Here, integrated neural networks process the incoming signals, creating a conscious sensation referred to as the "urge to cough."

The efferent (outgoing) limb of the cough reflex involves a highly coordinated sequence of involuntary muscular actions. These actions include the adduction of the vocal cords, which leads to transient upper-airway occlusion. Concurrently, expiratory muscles contract, generating positive intrathoracic pressures that can reach as high as 300 mmHg. Upon the sudden release of laryngeal contraction, rapid expiratory flows are generated, surpassing the normal "envelope" of maximal expiratory flow observed on a flow-volume curve. Furthermore, bronchial smooth-muscle contraction, combined with dynamic airway compression, narrows airway lumens and maximizes the velocity of exhalation.

The kinetic energy generated by this forceful expiratory flow is critical for dislodging mucus from the inner walls of airways. This energy is directly proportional to the square of the velocity of expiratory airflow. Taking a deep breath before a cough optimizes the functioning of the expiratory muscles. In cases where multiple repetitive coughs occur at progressively lower lung volumes, they effectively sweep the point of maximal expiratory velocity further into the periphery of the lung.

Impaired Cough and Its Consequences
A weakened or ineffective cough can have serious consequences. It compromises the ability to clear lower respiratory tract secretions effectively, making individuals more susceptible to serious infections and their associated complications. When assessing cough strength, it is typically evaluated qualitatively, although objective measures such as peak expiratory flow or maximal expiratory pressure at the mouth can serve as surrogate markers for cough strength.

Various factors can contribute to impaired cough. These include weakness or paralysis of the expiratory muscles, as well as chest wall or abdominal pain. Chest wall deformities, like severe kyphoscoliosis, can also hinder the ability to produce an effective cough. Central respiratory depression, which can result from factors such as anesthesia, sedation, or neurological diseases, can further diminish cough strength.

Another critical aspect to consider is the nature of airway secretions. Abnormalities in secretions, such as abnormally viscous mucus seen in conditions like cystic fibrosis, can hinder effective clearance. Similarly, ciliary dysfunction, as seen in primary ciliary dyskinesia, or structural abnormalities of the airways, like tracheomalacia with excessive expiratory collapse of the trachea during cough, can all contribute to impaired cough function.

Symptomatic Cough and Its Diagnostic Significance
Cough often occurs in conjunction with other respiratory symptoms, which can collectively provide valuable clues for diagnosis. For instance, when cough is accompanied by wheezing, shortness of breath, and chest tightness following exposure to allergens like cat dander, it strongly suggests asthma as the underlying condition.

However, there are instances where cough takes center stage as the dominant or sole symptom of an underlying disease. In such cases, the duration and severity of the cough can offer retrospective insights into its potential etiology. Generally, cough can be categorized into three durations:


 * 1) Acute Cough (<3 weeks): Often associated with respiratory tract infections, aspiration events, or exposure to noxious chemicals or smoke.
 * 2) Subacute Cough (3–8 weeks): Commonly seen as a lingering symptom of tracheobronchitis, as in pertussis or "postviral tussive syndrome."
 * 3) Chronic Cough (>8 weeks): This form of cough can be attributed to a wide array of cardiopulmonary diseases, including inflammatory, infectious, neoplastic, and cardiovascular causes.

When a thorough initial assessment involving chest examination and radiography reveals no abnormalities, common identifiable causes of chronic cough include cough-variant asthma, gastroesophageal reflux, rhinosinusitis with excessive nasopharyngeal drainage, and medications like angiotensin-converting enzyme (ACE) inhibitors. In long-time cigarette smokers, a productive cough upon waking may suggest chronic bronchitis, while a dry, irritative cough persisting for more than two months after respiratory tract infections is often labeled as "postbronchitic cough."

However, it's worth noting that chronic cough can also manifest without an identifiable etiology. This intriguing phenomenon, recognized with increasing frequency, is believed to result from exaggerated neurologic signaling along sensory cough-reflex pathways. It is referred to as "chronic cough hypersensitivity syndrome."

Assessment of Chronic Cough
To arrive at a definitive diagnosis for chronic cough, a comprehensive approach is necessary. This includes both historical inquiries and a thorough physical examination. Key historical questions revolve around the circumstances surrounding the onset of cough, factors that exacerbate or alleviate the cough, and whether the cough produces sputum.

Physical examination plays a crucial role in identifying signs suggesting the presence of cardiopulmonary disease. Findings such as wheezing or crackles during chest examination, examination of the auditory canals and tympanic membranes to detect irritation stimulating Arnold's nerve, inspection of the nasal passages for signs of rhinitis or polyps, and examination of the nails for clubbing can all provide valuable etiologic clues. Additionally, because cough can sometimes be a manifestation of systemic diseases like sarcoidosis or vasculitis, a comprehensive general examination is equally important.

In nearly all instances, the evaluation of chronic cough should include a chest radiograph. This imaging modality is essential because the list of diseases capable of causing persistent cough without other symptoms and without detectable abnormalities on physical examination is extensive. It encompasses serious conditions such as sarcoidosis or Hodgkin's disease in young adults, lung cancer in older individuals, and, globally, pulmonary tuberculosis. If an abnormality is detected on the chest film, further evaluation is warranted to elucidate the cause of the radiographic anomaly.

In cases where chronic cough remains unexplained, despite a preserved ability to generate normal expiratory velocities, it's crucial to investigate other potential contributors. These can include abnormal airway secretions, ciliary dysfunction, or structural abnormalities of the airways, all of which can obstruct proper secretion clearance.

Chronic Cough with a Normal Chest Radiograph
It is a commonly held belief that certain factors, either alone or in combination, account for more than 90% of cases of chronic cough with a normal or noncontributory chest radiograph. These factors typically include the use of ACE inhibitors, postnasal drainage, gastroesophageal reflux, and asthma.

ACE inhibitor-induced cough, which occurs in 5–30% of patients taking these medications, is not dose-dependent. ACE inhibitors metabolize bradykinin and other tachykinins like substance P. The mechanism of ACE inhibitor-associated cough likely involves the sensitization of sensory nerve endings due to the accumulation of bradykinin. Therefore, any patient with chronic unexplained cough who is taking an ACE inhibitor should undergo a trial period without the medication, regardless of when the cough began relative to the initiation of ACE inhibitor therapy.

Postnasal drainage, which can occur due to various causes, can lead to cough as a response to the irritation of sensory receptors in the cough-reflex pathway located in the hypopharynx. Alternatively, aspiration of draining secretions into the trachea can also trigger cough. Physicians often refer to this condition as "upper airway cough syndrome." Common historical clues indicating postnasal drainage include a sensation of postnasal drip, frequent throat clearing, and symptoms like sneezing and rhinorrhea. On speculum examination of the nose, healthcare providers may observe excess mucoid or purulent secretions, inflamed and edematous nasal mucosa, and/or nasal polyps.

Linking gastroesophageal reflux to chronic cough presents similar challenges. It is hypothesized that reflux of gastric contents into the lower esophagus may initiate cough through reflex pathways originating in the esophageal mucosa. However, assessing reflux and its connection to cough is far from straightforward. Quantifying the frequency and extent of reflux necessitates somewhat invasive procedures, such as measuring esophageal pH or assessing esophageal pressures through manometry. The interpretation of test results and their ability to establish a direct link between reflux events and cough remains a matter of ongoing debate. Nevertheless, it's essential to balance the attribution of cough to gastroesophageal reflux with the understanding that many individuals with symptomatic reflux do not experience chronic cough.

Cough as the sole manifestation of asthma is more commonly observed in children than in adults. In such cases, it is referred to as "cough-variant asthma." Establishing this diagnosis typically involves a history suggestive of the onset of cough following exposure to known asthma triggers and the resolution of cough upon discontinuation of the trigger. Objective testing can help confirm or exclude asthma as the cause of cough. Such tests may include spirometry to detect airflow obstruction that varies over time or reverses in response to a bronchodilator. In cases where reliable measurements can be taken, home expiratory peak flow monitoring can be a cost-effective method to support or rule out an asthma diagnosis.

Eosinophilic bronchitis is another condition that can cause chronic cough, even when chest radiographs appear normal. This condition is characterized by sputum eosinophilia exceeding 3%, without evidence of airflow obstruction or bronchial hyperresponsiveness. The condition often responds positively to inhaled glucocorticoids. Measuring an elevated concentration of nitric oxide in exhaled breath has shown promise in detecting eosinophilic airway inflammation, potentially aiding in the diagnosis of conditions like asthma or eosinophilic bronchitis.

Symptom-Based Treatment of Cough
Treating chronic cough, especially in cases where no specific underlying cause has been identified, often involves empirical approaches targeting the most likely causes as determined by history, physical examination, and, occasionally, pulmonary function testing.

Postnasal Drainage: The treatment for cough due to postnasal drainage depends on the presumed etiology. In cases where infection, allergies, or vasomotor rhinitis are suspected, treatments may include systemic antihistamines, decongestants, antibiotics, nasal saline irrigation, and nasal pump sprays containing glucocorticoids, antihistamines, or anticholinergics.

Gastroesophageal Reflux: Addressing cough associated with gastroesophageal reflux disease (GERD) involves a multi-faceted approach. Antacids, histamine type 2 (H2) receptor antagonists, and proton pump inhibitors can help neutralize gastric acid or reduce its production. Lifestyle modifications such as dietary changes, elevating the head and torso during sleep, and medications that improve gastric emptying or impede the flow of refluxate (e.g., alginates) are additional therapeutic measures.

Cough-Variant Asthma: Patients with cough-variant asthma typically respond well to inhaled glucocorticoids and the intermittent use of inhaled β-agonist bronchodilators. These medications help manage the underlying inflammation and bronchial hyperresponsiveness that characterize asthma.

Cases That Defy Diagnosis: For individuals who do not respond to treatments targeting common causes of chronic cough or when these causes have been ruled out through appropriate diagnostic testing, it is advisable to consider a chest computed tomography (CT) scan. A chest CT can provide detailed imaging and reveal diseases that might not be evident on a chest x-ray. Such conditions may include early interstitial lung disease, bronchiectasis, tumors, or atypical mycobacterial pulmonary infections. Conversely, if a patient with chronic cough has normal findings on chest examination, lung function testing, oxygenation assessment, and chest CT, they can be reassured regarding the absence of serious pulmonary pathology.

Global Considerations in Cough
Cough is a symptom not limited to specific geographic regions, and its causes and management can vary based on environmental factors and prevalent diseases. In areas of the world where air pollution is a significant concern, exposure to pollutants can lead to chronic cough and throat clearing, along with lower respiratory tract diseases. Various forms of air pollution contribute to this issue, including smoke from cooking and heating fuels in poorly ventilated homes, toxic exposures in work environments lacking occupational safety standards, and ambient chemicals and particulates in highly polluted outdoor air.

Addressing cough related to air pollution focuses on improving environmental air quality. This can involve measures such as using stove chimneys in homes to reduce indoor smoke, implementing occupational safety standards in workplaces, and promoting the use of appropriate face masks in highly polluted outdoor areas.

In regions where tuberculosis is endemic, the presence of chronic cough raises concerns about active pulmonary tuberculosis. As such, healthcare providers must follow appropriate evaluation protocols, including chest imaging and sputum analysis, to promptly diagnose and treat cases of tuberculosis and prevent its spread.

Symptom-Based Treatment of Cough
Empirical treatment of chronic idiopathic cough has been explored using various medications, but consistent success remains elusive. Some of the medications that have been attempted include inhaled corticosteroids, inhaled anticholinergic bronchodilators, and macrolide antibiotics. However, their effectiveness in managing chronic cough has been inconsistent.

Currently available cough suppressants offer only modest relief. The most potent cough suppressants are narcotic medications like codeine, hydrocodone, or morphine. These drugs are believed to act directly on the "cough center" in the brainstem, reducing the urge to cough. However, their use is limited due to side effects such as drowsiness, constipation, and the potential for addictive dependence, making them less appealing for long-term use.

Dextromethorphan, an over-the-counter centrally acting cough suppressant, offers an alternative with fewer side effects than narcotic cough suppressants. It is believed to have a different site of action within the cough reflex pathway and can be used in combination with narcotic cough suppressants if necessary. Another option is benzonatate, which is thought to inhibit neural activity in the cough-reflex pathway. It is generally well-tolerated, but its effectiveness in suppressing cough can vary among individuals.

Inhaled lidocaine, which inhibits voltage-gated sodium channels, provides transient cough suppression. However, it carries the risk of oropharyngeal anesthesia, increasing the potential for aspiration.

Efforts to address cough hypersensitivity syndrome have primarily centered on inhibiting neural pathways. Small case series and randomized clinical trials have shown potential benefit from off-label use of medications like gabapentin, pregabalin, or amitriptyline. Recent studies have even suggested a role for behavioral modification using specialized speech therapy techniques. However, the widespread application of these therapies remains a challenge.

Future approaches to managing chronic cough involve the development of novel cough suppressants that do not possess the limitations of currently available agents. These approaches include the exploration of neurokinin-1 receptor antagonists, transient receptor protein vanilloid-1 (TRPV1) channel antagonists, a promising P2X3 channel antagonist known as gefapixant, and novel opioid and opioid-like receptor agonists.

Conclusion
Cough is a fascinating and complex physiological response with profound implications for our respiratory health and overall well-being. While it serves as a protective mechanism, its persistence or excessive manifestation can signal underlying medical issues that require careful evaluation and management. A comprehensive assessment, encompassing detailed patient history, physical examination, diagnostic imaging, and consideration of environmental factors, is essential to uncover the root causes of chronic cough and guide effective treatment strategies.

The management of chronic cough demands a patient-centered approach, considering individual factors, such as age, comorbidities, and medication tolerance. Despite the challenges posed by this symptom, ongoing research efforts continue to unravel the intricacies of cough physiology and pathology, offering hope for more effective and targeted treatments in the future. In the meantime, healthcare providers must remain vigilant in their pursuit of accurate diagnoses and symptom relief for those afflicted by chronic cough, understanding that each case presents a unique set of challenges and potential solutions.