Differential Diagnosis of Cough: A Comprehensive Guide for Clinicians

Cough is a prevalent symptom in healthcare, prompting approximately 30 million clinic visits annually and leading to pulmonology referrals in up to 40% of cases. This innate reflex serves as a crucial protective mechanism, safeguarding the respiratory system from foreign substances. However, cough is associated with a vast array of clinical conditions and underlying causes. Notably, the absence of objective cough measurement tools makes its evaluation inherently subjective. This article provides a detailed overview of the Differential Diagnosis Of Cough, aiming to enhance diagnostic accuracy and patient care.

Etiology of Cough

The classification of cough etiology is primarily based on its duration, a crucial factor in differential diagnosis.

• Acute Cough: Defined as cough lasting less than three weeks.
• Subacute Cough: Cough persisting between three and eight weeks.
• Chronic Cough: Cough lasting longer than eight weeks.

Common Causes of Acute Cough

Acute cough in adults is most frequently attributed to acute viral upper respiratory infections (URIs), commonly known as the common cold, and acute bronchitis. While acute bronchitis is typically viral, bacterial infections account for about 10% of cases. Other significant causes of acute cough include:

• Acute Rhinosinusitis: Inflammation of the paranasal sinus lining, responsible for roughly 16 million office visits each year. Viral infections are the usual cause if symptoms last less than ten days, while bacterial infections are more likely if symptoms persist beyond ten days. Cough in rhinosinusitis arises mainly from increased mucus production and subsequent post-nasal drip.

Alt: Person using a nasal spray to relieve sinus congestion, a common cause of cough.

• Pertussis (Whooping Cough): Characterized by paroxysmal, intense coughing fits that can last for minutes, followed by a distinctive “whooping” sound during inhalation. Bordetella pertussis infection leads to mucopurulent exudate in the respiratory tract. Pertussis progresses through three stages: catarrhal, paroxysmal, and convalescent. The catarrhal phase resembles a common cold, progressing to the paroxysmal phase with classic coughing episodes and potential post-tussive vomiting. The convalescent phase involves a lingering chronic cough. Pertussis is a serious condition, particularly for infants, and requires immediate medical attention due to high morbidity and mortality rates in this age group.

• Asthma: A complex condition involving airway inflammation, intermittent airflow obstruction, and bronchial hyperreactivity due to immune system hyperresponsiveness to environmental triggers. Asthma affects approximately 26 million individuals in the United States. Cough in asthma patients results from increased mucus secretion and airway narrowing.

• Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): COPD, affecting an estimated 32 million Americans, encompasses chronic bronchitis, emphysema, and asthma. Patients experience lung elasticity loss and air trapping, predisposing them to infections like acute bronchitis and bacterial pneumonia. Acute exacerbations worsen airway inflammation and hyperresponsiveness, leading to airway constriction, reduced lung function, and accumulation of thick mucus, triggering cough.

• Allergic Rhinitis: Nasal mucosa inflammation due to environmental allergens, causing increased mucus and post-nasal drip. The post-nasal drip irritates the airways, stimulating a cough.

• Congestive Heart Failure (CHF): Reduced heart pumping efficiency leads to fluid congestion, often starting in the left ventricle and atria, then affecting the pulmonary vasculature. Pulmonary congestion results in heavy, edematous lungs with an increased alveolar-arterial oxygen gradient, irritating the lungs and inducing cough.

• Pneumonia: Can be viral or bacterial, with various etiologies. Viral pneumonia causes airway inflammation, while bacterial pneumonia involves increased mucus and purulent secretions, further irritating the airways. Pulmonary tuberculosis typically presents with fever, productive or dry cough, and weight loss.

• Aspiration Syndromes: Occur when the glottis doesn’t close properly during swallowing, allowing food or fluids to enter the airways instead of the esophagus. This can cause irritation and potentially aspiration pneumonia.

• Pulmonary Embolism (PE): An embolus, often from a deep vein thrombosis, lodges in the pulmonary capillaries. Cough in PE develops due to blood congestion proximal to the embolus, causing lung edema and irritation. In severe cases, tissue necrosis and release of pro-inflammatory cytokines can exacerbate cough.

Subacute Cough Etiologies

Subacute cough is most commonly post-infectious, resulting from ongoing irritation of cough receptors due to resolving bronchial or sinus inflammation after a viral URI. Both acute and subacute coughs are usually self-limiting and primarily require supportive care.

Chronic Cough Differential Diagnosis

Chronic cough presents a greater diagnostic challenge, often necessitating referral to a pulmonologist or cough specialist. Potential causes are diverse and include:

• Upper Airway Cough Syndrome (UACS): Formerly known as post-nasal drip syndrome, UACS is the most common cause of chronic cough. It encompasses conditions like allergic rhinitis, non-allergic rhinitis, and chronic rhinosinusitis. Persistent post-nasal drip irritates the upper airways, triggering cough.

• Gastroesophageal Reflux Disease (GERD): Accounts for up to 40% of chronic cough cases. Stomach acid reflux into the pharynx and larynx irritates laryngeal receptors and can cause microaspiration. Cough associated with GERD often worsens at night when lying down, facilitating reflux.

• Non-asthmatic Eosinophilic Bronchitis (NAEB): Characterized by bronchial hyperresponsiveness without typical asthma findings, featuring increased eosinophils indicating immune system hyperactivity. Inflammatory cytokines from eosinophils cause airway inflammation and irritation. NAEB differs from eosinophilic asthma in mast cell localization; NAEB involves epithelial infiltration, directly irritating cough receptors, while asthma involves smooth muscle infiltration leading to airway narrowing.

• Chronic Bronchitis: Defined as cough present for at least three months per year for two consecutive years. Excessive mucus secretion and airway plugging are primary causes, with an inflammatory component also implicated. Chronic bronchitis is not infectious but increases susceptibility to bacterial infections, potentially worsening cough.

• Post-infectious Cough: Persists due to heightened cough receptor sensitivity and bronchial hyperresponsiveness following a pulmonary infection, likely related to epithelial damage from the initial infection.

• Cough Variant Asthma (CVA): Presents predominantly with cough rather than wheezing typical of asthma. Patients may have normal baseline spirometry but positive methacholine challenge tests. CVA should be considered for non-productive, repetitive cough, occurring day and night, exacerbated by exercise, cold air, or URIs. Family history of asthma or seasonal variation may be present. Cough receptors are more concentrated in proximal airways; inflammation in CVA is prominent in these areas, stimulating cough, while distal inflammation causing wheezing is less pronounced. Treatment mirrors typical asthma management.

• Malignancy: Lung tumors can cause cough through mass effect, airway obstruction, mucus accumulation, secondary infections, direct irritation of cough receptors, or secretory effects on airways.

• Interstitial Lung Diseases (ILDs): A broad group of disorders causing progressive lung tissue scarring and hardening, often due to long-term exposure to hazardous materials like asbestos, silica, coal dust, radiation, or heavy metals. Occupational exposures (e.g., nuclear plant workers, miners) and autoimmune diseases (rheumatoid arthritis, scleroderma, sarcoidosis) are risk factors. Idiopathic pulmonary fibrosis is also included.

• Obstructive Sleep Apnea (OSA): Characterized by transient airway obstruction during sleep. Increased airway resistance triggers reflexive diaphragmatic and chest muscle spasms and cough to open the airway. OSA is often due to pharyngeal muscle laxity or neck weight in obese individuals.

• Chronic Sinusitis-Induced Cough: Chronic cough results from persistent inflammation and irritation of sinus and nasal mucosa with purulent discharge, often due to bacterial pathogens. Recurrent acute sinusitis can lead to chronic sinusitis with facultative anaerobic pathogens like Staphylococcus aureus and gram-negative bacteria.

• Psychosomatic Cough: A diagnosis of exclusion, rarely diagnosed, where coughing is a habit rather than a disease symptom. It may be a learned behavior or linked to an underlying psychological condition.

Rare Causes of Cough

While less common, these causes should be considered in the differential diagnosis, particularly when common etiologies are excluded:

• Cerumen Impaction: Earwax buildup can stimulate the vagal nerve (Arnold’s nerve), triggering cough.
• Esophageal Achalasia: A motility disorder affecting the esophagus, potentially leading to cough.
• Tracheoesophageal Fistula: An abnormal connection between the trachea and esophagus.
• Oesophageal Tracheobronchial Reflex: Reflex cough initiated by esophageal stimulation.
• Ortner Syndrome: Intermittent left vocal cord paralysis due to cardiac ptosis compressing the recurrent laryngeal nerve.
• Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS): In children, streptococcal infections can trigger motor tics, including chronic cough.
• Peritoneal Dialysis: Can sometimes induce cough.
• Pneumonitis: Lung inflammation, potentially from various causes.
• Syngamus laryngeus Infection: A rare parasitic infection from a roundworm found in the Caribbean, acquired by ingesting contaminated produce. Worms reside in the larynx, causing chronic cough.
• Tracheobronchial Collapse: Weakening of the trachea and bronchi, leading to airway collapse and cough.
• Vitamin B12 Deficiency: Rarely, severe deficiency can contribute to cough.
• Zenker or Distal Esophageal Diverticulum: Pouches in the esophagus that can cause cough.

Epidemiology of Cough

Cough is the most frequent symptom prompting medical consultations. Its prevalence varies widely (5% to 40%), heavily influenced by tobacco smoking history. Specific etiologies of cough may show variations based on race and gender, but comprehensive epidemiological data are etiology-dependent.

Pathophysiology of Cough

Coughing is an involuntary protective reflex for clearing airways of mucus and irritants. The cough reflex involves:

1. Inspiration Phase: Air inhalation increases lung volume.
2. Compression Phase: Glottis closure and expiratory muscle contraction (intercostals, diaphragm, abdominals) increase intrathoracic pressure (potentially >300 mm Hg) without airflow.
3. Expiratory Phase: Rapid glottis opening results in forceful expulsion of air at high velocity (>500 mph), loosening and expelling airway secretions.

While protective, cough can become problematic if it’s excessive or ineffective, ranging from discomfort to severe hemodynamic instability.

The cough reflex is initiated by peripheral nerve receptor stimulation in the trachea, carina, large airway branch points, smaller airways, and pharynx. Laryngeal and tracheobronchial receptors respond to mechanical and chemical stimuli. Chemical receptors are sensitive to acid, heat, and capsaicin-like substances, activating type-1 capsaicin receptors. Mechanical receptors, found in auditory canals, eardrums, sinuses, pharynx, diaphragm, pleura, pericardium, and stomach, respond to touch or stretch.

Sensory receptors are categorized into:

• Rapidly Adapting Receptors (RARs): Myelinated, fast-response neurons (1-2 seconds, 4-18 m/s conduction velocity). Detect airway collapse or narrowing, responding to dynamic changes in lung compliance. Desensitize to prolonged lung inflation. Triggered by bronchospasm, mucus plugging, or biomechanical changes in airways.

• Slowly Adapting Stretch Receptors (SARs): Highly sensitive to mechanical forces, found densely in terminal bronchioles and alveoli. Slower response than RARs. Detect lung stretch (hyperinflation). Do not desensitize to chronic hyperinflation. Physiologically important in the Hering-Breuer reflex, halting inhalation and triggering exhalation at lung capacity to prevent barotrauma.

• C-fibers: Predominant afferent sensory innervation in the lungs. Unmyelinated, slow conduction (2 m/s). Relatively insensitive to mechanical stimuli, primarily respond to chemical irritants: capsaicin, bradykinin, citric acid, hypertonic saline, sulfur dioxide.

Sensory input from these receptors travels via the vagus nerve (cranial nerve X) to brain respiratory centers in the medulla and pons. The cough center is not a discrete location but rather a modulation of the respiratory center, involving the dorsal and ventral medullary groups and pontine groups (pneumotaxic and apneustic centers). The dorsal medulla controls inhalation, ventral medulla exhalation. Pontine groups modulate intensity and frequency; pneumotaxic limits inhalation, apneustic prolongs it. These groups coordinate respiration. Cough receptors project sensory input through the nucleus tractus solitarius to respiratory networks. The pre-Bötzinger complex is a pattern generator for cough response. Parts of the caudal medullary raphe nucleus are also crucial. Efferent signals are generated and travel via vagus, phrenic, and spinal motor nerves to expiratory muscles (diaphragm, intercostals, pharynx, neck) to produce cough.

History and Physical Examination in Cough Evaluation

A detailed history and physical exam are paramount in evaluating cough. Cough itself is a symptom, and patients often seek care for secondary effects. Key history components include:

• Duration of cough: Acute, subacute, or chronic.
• Smoking history: Tobacco use is a major risk factor.
• ACE inhibitor use: A common drug-induced cause of cough.
• Weight loss: Suggestive of serious underlying conditions like malignancy or tuberculosis.
• Occupation: Potential exposure to occupational irritants or allergens.
• Diurnal variation: Cough timing (e.g., nocturnal cough in GERD, OSA).
• Relieving/Aggravating factors: Triggers and alleviating measures.
• Productive vs. Non-productive cough: Sputum characteristics (color, consistency).
• Hemoptysis: Blood in sputum, warrants investigation.
• Fever: Suggests infection.
• Shortness of breath: Associated respiratory conditions.
• Preceding URI: Common trigger for acute and subacute cough.

A systemic approach is essential to identify coexisting illnesses. Cough character, timing, and sputum production can aid in differential diagnosis. Common associated symptoms include malaise, fatigue, insomnia, lifestyle changes, chest pain, hoarseness, sweating, urinary incontinence, syncope, arrhythmias, headache, subconjunctival hemorrhage, inguinal hernia, or GERD. Specific complaints guide physical exam and diagnostic workup.

Evaluation of Cough

Acute and subacute coughs often require only symptomatic treatment unless serious pathology is suspected. Chest X-rays may be indicated for severe cough or in ill-appearing patients.

Chronic cough typically necessitates diagnostic measures, including chest X-ray and pulmonary function tests. Patients with normal chest X-rays and spirometry, without clear etiology from history and physical, may need pulmonology referral for further evaluation. Chronic cough can be multifactorial. Bronchoscopy may be needed to visualize vocal cords, trachea, and airways, ruling out masses or lesions, with potential biopsy or bronchoalveolar lavage for microbiological and cytological analysis. Echocardiogram can assess cardiac function. Chest CT scans offer anatomical detail. Gastroesophageal studies, speech and swallow evaluations, esophagogastroduodenoscopy, or gastric pH monitoring may be indicated for aspiration or GERD assessment. Sleep studies are appropriate for nocturnal cough and OSA suspicion.

Alt: Normal chest X-ray, a common initial diagnostic step in cough evaluation.

Criteria for Neurogenic Cough Diagnosis:

1. Persistent daytime cough.
2. Non-productive cough.
3. Vocal fold paresis (unilateral or bilateral) on laryngeal exam.
4. Laryngeal electromyography confirming paresis.
5. Symptom resolution with appropriate treatment.

Treatment and Management of Cough

Most acute cough cases are treated empirically for symptom relief with over-the-counter cough and cold medications. However, antihistamine-decongestant combinations often show no benefit over placebo. Cough suppressants reduce cough reflex, and expectorants enhance mucus clearance. Dextromethorphan is a common suppressant, guaifenesin an expectorant. Cough is a protective reflex, so suppressing it may prolong illness recovery. Current guidelines advise against routine use of cough suppressants for acute cough due to common cold and discourage over-the-counter combinations. Sputum culture and pathogen-directed antibiotics are indicated for suspected bacterial infections. Chronic infectious upper respiratory etiologies may require prolonged (3-6 weeks) antibiotic therapy, such as amoxicillin/clavulanate. Alternatives include clindamycin, cefuroxime, cefprozil, clarithromycin, gatifloxacin, levofloxacin, or moxifloxacin.

Inhaled albuterol and ipratropium bromide can provide bronchodilation for symptomatic relief of airway constriction in urgent situations. Chronic cough management aims to treat the underlying cause rather than just suppressing cough. ACE inhibitors should be discontinued, replaced with aldosterone receptor blockers if cough is drug-induced. Reactive airway disease may require inhaled steroids or anticholinergics. Cardiac function should be optimized per cardiology recommendations for CHF-related cough. GERD management includes avoiding reflux triggers (chocolate, caffeine, alcohol, tobacco), elevating the head of the bed, avoiding late-night meals, and maximal-dose proton pump inhibitors.

Neurogenic cough treatment differs from other neuropathic conditions. For isolated cough without laryngopharyngeal reflux, tramadol or amitriptyline may be used. If laryngopharyngeal reflux is present, gabapentin is preferred, with dose escalation as needed. Combination therapy (gabapentin with low-dose amitriptyline) is common. Pregabalin and baclofen are second-line options.

Differential Diagnosis Categories for Cough

Differential diagnoses for cough are categorized by duration (acute, subacute, chronic) and include rare causes:

Acute Cough Differentials:

• Acute Bronchitis
• Acute Exacerbation of COPD
• Acute Rhinosinusitis
• Acute Viral URI
• Allergic Rhinitis
• Asthma
• Aspiration Syndromes
• Congestive Heart Failure
• Pertussis
• Pneumonia
• Pulmonary Embolism

Subacute Cough Differentials:

• Post-infectious Cough (following URI)

Chronic Cough Differentials:

• Chronic Bronchitis
• Chronic Sinusitis
• GERD
• Interstitial Lung Diseases
• ACE Inhibitor-Induced Cough
• Malignancy
• Non-asthmatic Eosinophilic Bronchitis
• Obstructive Sleep Apnea
• Post-infectious Cough
• Psychosomatic Cough
• Upper Airway Cough Syndrome

Very Rare Cough Differentials:

• Cerumen Impaction
• Esophageal Achalasia
• Tracheoesophageal Fistula
• Oesophageal Tracheobronchial Reflex
• Ortner Syndrome
• PANDAS
• Peritoneal Dialysis
• Pneumonitis
• Syngamus laryngeus Infection
• Tracheobronchial Collapse
• Vitamin B12 Deficiency
• Zenker Diverticulum

Prognosis of Cough

Cough itself is generally benign, but prognosis is heavily dependent on the underlying etiology.

Complications of Cough

Persistent or severe coughing can lead to complications:

• Sleep Disruption
• Headache
• Vomiting
• Syncope
• Excessive Sweating
• Rib Fracture
• Urinary Incontinence

Consultations for Cough

Management may require interprofessional collaboration:

• Pulmonology referral for new-onset chronic cough without clear cause.
• Cardiology referral for suspected CHF-related cough.
• Gastroenterology referral for suspected GERD-related cough.

Pearls and Key Considerations for Cough Management

• Use antibiotics for cough only if symptomatic therapy fails and bacterial sinusitis is likely (purulent nasal discharge, toothache, abnormal sinus transillumination, discolored nasal discharge).
• Bacterial sinusitis can co-occur with viral rhinitis/rhinosinusitis.
• Consider bacterial bronchitis and antibiotics for acute COPD exacerbation with worsening dyspnea or wheezing.
• Cough and vomiting suggest pertussis; antibiotics reduce infectivity but not the paroxysmal phase.
• In elderly patients, atypical presentations are common; consider pneumonia, CHF, asthma, and aspiration.
• GERD-related cough often lacks heartburn (75% of cases). Both spontaneous GERD and cough propensity are needed for GERD-induced cough. GERD is likely in patients with unexplained cough.

Enhancing Healthcare Team Outcomes in Cough Management

Effective cough management requires an interprofessional approach. Primary care providers, nurse practitioners, internists, and pulmonologists should avoid empiric anti-tussives and focus on treating the underlying cause. Thorough history is crucial. For prolonged cough with associated symptoms, referral to a pulmonologist or otolaryngologist is recommended to enhance diagnostic and therapeutic outcomes.

References

[List of references as in the original article]

Disclosures: