Differential Diagnosis for Cough: A Comprehensive Guide for Clinicians

Introduction

Cough is an exceedingly common complaint in healthcare settings, prompting an estimated 30 million clinic visits annually in the United States alone. A significant proportion, up to 40%, of these cases are subsequently referred to pulmonologists for further evaluation. Coughing, while often perceived as a mere annoyance, is a fundamental, involuntary reflex that serves as a crucial component of the body’s defense mechanisms. It plays a vital role in clearing the respiratory tract of foreign particles, irritants, and excessive secretions. However, cough is also a non-specific symptom associated with a vast array of underlying medical conditions, ranging from benign self-limiting illnesses to serious and potentially life-threatening pathologies. The subjective nature of cough assessment, coupled with the absence of objective measurement tools and the potential for significant impact on a patient’s quality of life, necessitates a systematic and thorough approach to its evaluation. Therefore, understanding the Differential Diagnosis For Cough is paramount for clinicians to effectively manage and treat patients presenting with this common symptom. This article aims to provide a comprehensive overview of the differential diagnosis of cough, encompassing its diverse etiologies, evaluation strategies, and management principles, to aid healthcare professionals in delivering optimal patient care.

Etiology of Cough

Classifying cough by duration provides a useful framework for considering potential etiologies. This classification system categorizes cough into three primary types based on its duration: acute, subacute, and chronic.

Acute Cough: Defined as a cough lasting less than three weeks.

Subacute Cough: Refers to a cough that persists for three to eight weeks.

Chronic Cough: Designates a cough that has been present for more than eight weeks.

Understanding this temporal classification is crucial because it helps narrow down the differential diagnosis and guide the initial evaluation and management strategies.

Common Causes of Acute Cough

In adults, the most frequent causes of acute cough are typically infectious in nature. These include:

• Acute Viral Upper Respiratory Infection (URI): Commonly known as the common cold, viral URIs are the most prevalent cause of acute cough.
• Acute Bronchitis: While often viral, acute bronchitis can also be bacterial in approximately 10% of cases.
• Acute Rhinosinusitis: Inflammation of the nasal sinuses, frequently triggered by viral infections, leading to increased mucus production and post-nasal drip, which in turn induces cough.
• Pertussis (Whooping Cough): A bacterial infection characterized by paroxysmal coughing fits followed by a distinctive “whooping” sound during inhalation. Pertussis remains a significant concern, particularly in infants.
• Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): Patients with COPD are prone to acute exacerbations characterized by worsened cough, often accompanied by increased sputum production and shortness of breath.
• Allergic Rhinitis: Environmental allergies can cause nasal inflammation, leading to post-nasal drip and subsequent cough.
• Asthma: Acute asthma exacerbations can present with cough, wheezing, and shortness of breath due to airway inflammation and constriction.
• Congestive Heart Failure (CHF): Pulmonary congestion in CHF can irritate the airways and stimulate cough, often described as a dry cough.
• Pneumonia: Infections of the lung parenchyma, whether viral or bacterial, are a significant cause of acute cough, typically associated with fever, sputum production, and chest discomfort.
• Aspiration Syndromes: Inhalation of foreign material into the airways can trigger an acute cough, and in some cases, lead to aspiration pneumonia.
• Pulmonary Embolism (PE): Although less common, PE can present with acute cough, chest pain, and shortness of breath, especially in individuals with risk factors for thromboembolism.

Common Causes of Subacute Cough

Subacute cough is frequently a lingering consequence of an acute respiratory infection.

• Post-Infectious Cough: This is the most common cause of subacute cough. It arises from persistent irritation of cough receptors in the airways following a viral URI. Inflammation in the bronchi or sinuses may continue even after the acute infection has resolved, leading to ongoing cough.

Common Causes of Chronic Cough

Chronic cough presents a more complex diagnostic challenge and often requires referral to a specialist. Several conditions are commonly associated with chronic cough:

• Upper Airway Cough Syndrome (UACS): Previously known as post-nasal drip syndrome, UACS is the most frequent cause of chronic cough. It encompasses conditions like allergic and non-allergic rhinitis and chronic rhinosinusitis, all of which result in persistent post-nasal drip irritating the upper airways.
• Gastroesophageal Reflux Disease (GERD): GERD is a significant contributor to chronic cough, accounting for up to 40% of cases. Reflux of gastric acid into the esophagus and potentially the larynx and pharynx can trigger cough through irritation and microaspiration. Cough associated with GERD often worsens at night.
• Non-Asthmatic Eosinophilic Bronchitis (NAEB): NAEB is characterized by airway inflammation with eosinophils, leading to cough without the typical features of asthma like airflow obstruction.
• Chronic Bronchitis: Defined clinically by a chronic productive cough lasting for at least three months in two consecutive years, often associated with smoking history and COPD. Excessive mucus production and airway inflammation are key features.
• Post-Infectious Cough (Chronic): In some individuals, post-infectious cough can persist beyond the subacute phase and become chronic due to ongoing airway hyperresponsiveness and receptor sensitivity.
• Angiotensin-Converting Enzyme (ACE) Inhibitor-Induced Cough: ACE inhibitors, commonly used for hypertension and heart failure, are a well-known cause of chronic dry cough in a subset of patients.
• Malignancy (Lung Cancer): Lung tumors can cause cough through direct airway irritation, obstruction, secondary infections, or secretory effects. Persistent or changing cough, especially in smokers or those with risk factors, warrants consideration of malignancy.
• Interstitial Lung Diseases (ILDs): A diverse group of conditions causing lung scarring and fibrosis can lead to chronic cough. ILDs can result from occupational exposures, autoimmune diseases, or be idiopathic (idiopathic pulmonary fibrosis).
• Obstructive Sleep Apnea (OSA): OSA can trigger cough as a reflex response to airway obstruction during sleep. The increased respiratory effort and airway resistance can stimulate cough.
• Chronic Sinusitis: Prolonged sinus inflammation and purulent discharge can cause chronic post-nasal drip and cough.
• Psychosomatic Cough: Also known as habit cough or tic cough, this diagnosis is rare and should only be considered after excluding all organic causes. It is characterized by coughing as a habitual behavior, possibly linked to psychological factors.

Epidemiology of Cough

Cough is a ubiquitous symptom, making it the most common reason for patients to seek medical attention. Its prevalence is significantly influenced by tobacco smoking, with rates ranging from 5% to 40% depending on smoking status and population studied. The specific demographic distribution of cough varies based on the underlying etiology. For instance, COPD-related cough is more prevalent in smokers and older adults, while asthma-related cough is more common in individuals with allergic predispositions and may have a higher prevalence in certain age groups.

Pathophysiology of Cough

Coughing is a complex reflex mechanism crucial for airway protection and clearance. It involves a coordinated sequence of events:

1. Inspiration: A deep breath is taken to increase lung volume, providing the necessary airflow for effective expulsion.
2. Compression: The glottis closes, and expiratory muscles (intercostals, diaphragm, abdominals) contract forcefully, building up significant intrathoracic pressure (potentially exceeding 300 mm Hg).
3. Expiration: The glottis abruptly opens, releasing the pressurized air at high velocity (up to 500 mph). This forceful airflow dislodges mucus and foreign material from the airways and expels them.

This reflex is triggered by stimulation of cough receptors distributed throughout the respiratory tract and even beyond. These receptors are broadly classified as:

• Mechanical Receptors: Located in the larynx, trachea, and large airways, responding to physical stimuli like touch, pressure, and airway distortion (e.g., bronchospasm, mucus plugging). These include rapidly adapting receptors (RARs) and slowly adapting receptors (SARs). RARs are fast-responding to changes in airway mechanics, while SARs are sensitive to lung stretch and play a role in the Hering-Breuer reflex.
• Chemical Receptors (C-fibers): Predominantly found in smaller airways and alveoli, these receptors are activated by chemical irritants such as acid, heat, capsaicin, bradykinin, and inflammatory mediators.

Sensory signals from these receptors travel via the vagus nerve (cranial nerve X) to the cough center in the brainstem (medulla and pons). The cough center is not a discrete anatomical location but rather a network within the respiratory control centers. The respiratory center, composed of the dorsal and ventral medullary groups and pontine centers, modulates respiration. The pre-Bötzinger complex is thought to be a key pattern generator for cough. The integrated neural activity results in efferent signals transmitted through the vagus, phrenic, and spinal motor nerves to the expiratory muscles, orchestrating the cough sequence.

History and Physical Examination in Cough Evaluation

A detailed history and thorough physical examination are the cornerstones of cough evaluation. Cough is a symptom, and understanding its characteristics and associated features is essential for differential diagnosis. Key aspects of history taking include:

• Cough Duration: Acute, subacute, or chronic.
• Smoking History: Crucial risk factor for COPD, lung cancer, and chronic bronchitis.
• ACE Inhibitor Use: Document medication history to identify potential drug-induced cough.
• Associated Symptoms:
  • Sputum Production: Productive vs. non-productive cough, sputum color (clear, white, yellow, green, blood-tinged).
  • Hemoptysis: Coughing up blood – a red flag requiring prompt investigation.
  • Fever: Suggestive of infection.
  • Shortness of Breath (Dyspnea): Indicates potential respiratory or cardiac involvement.
  • Weight Loss: Raises concern for malignancy or chronic infection.
  • Diurnal Variation: Cough worse at night (GERD, asthma), morning (chronic bronchitis).
  • Aggravating/Relieving Factors: Triggers (allergens, exercise, cold air), alleviating factors (medications, position).
  • Upper Respiratory Tract Infection (URTI) Onset: Association with recent cold suggests post-infectious cough.

A systematic review of other organ systems is important to identify coexisting conditions that might be contributing to or causing the cough. Common associated complaints that may guide the differential diagnosis include: malaise, fatigue, insomnia, musculoskeletal chest pain, hoarseness, excessive sweating, urinary incontinence, syncope, cardiac dysrhythmias, headache, subconjunctival hemorrhage, inguinal herniation, and symptoms of GERD.

Evaluation of Cough

The diagnostic approach to cough depends on its duration and associated clinical features.

Acute and Subacute Cough: In most cases, acute and subacute coughs, particularly those associated with typical viral URIs, do not require extensive diagnostic testing. Symptomatic treatment is usually sufficient. A chest X-ray may be considered if there are signs of severe illness or suspicion of pneumonia.

Chronic Cough: Chronic cough often necessitates further investigation. Initial diagnostic tests may include:

• Chest X-ray: To screen for lung pathologies like pneumonia, lung masses, or ILD.
• Pulmonary Function Testing (PFT): Spirometry to assess for airflow obstruction (asthma, COPD) and lung volumes.

If initial investigations are non-diagnostic, or if there are specific clinical clues, further evaluation may include:

• Referral to a Pulmonologist: For specialized assessment and management of persistent cough.
• Bronchoscopy: Direct visualization of the airways to evaluate for structural abnormalities, masses, or lesions. Bronchoscopy can be combined with biopsy and bronchoalveolar lavage (BAL) for microbiological and cytological analysis.
• Echocardiogram: To assess cardiac function in suspected CHF-related cough.
• Computed Tomography (CT) Scan of the Chest: Provides detailed anatomical imaging of the lungs and mediastinum, useful for evaluating ILD, malignancy, and other structural lung diseases.
• Gastroesophageal Studies: For suspected GERD-related cough, including speech and swallow evaluations, esophagogastroduodenoscopy (EGD), and esophageal pH monitoring.
• Sleep Study (Polysomnography): If OSA is suspected based on nocturnal cough and other suggestive symptoms.

Diagnosis of Neurogenic Cough: Specific criteria for neurogenic cough include:

1. Persistent cough throughout the day.
2. Non-productive cough.
3. Vocal cord paresis (unilateral or bilateral) on laryngeal examination.
4. Laryngeal electromyography (EMG) confirmation of paresis.
5. Symptom resolution with appropriate treatment.

Treatment and Management of Cough

Management strategies for cough vary depending on the underlying etiology and duration.

Acute Cough Management: Focus is primarily on symptomatic relief.

• Over-the-Counter (OTC) Medications: Cough and cold remedies, including antihistamine-decongestants, have limited proven efficacy and are generally not recommended for acute cough due to common cold.
• Cough Suppressants (Antitussives): Such as dextromethorphan, may be used to reduce cough frequency, but should be used judiciously as coughing is a protective reflex.
• Expectorants: Like guaifenesin, are intended to thin mucus and facilitate expectoration, but their effectiveness is debated.
• Antibiotics: Generally not indicated for acute viral cough. Antibiotics are reserved for suspected bacterial infections (e.g., bacterial pneumonia, pertussis) and should be guided by sputum culture and sensitivity when appropriate. For chronic infectious upper respiratory etiologies, prolonged antibiotic courses (3-6 weeks) may be necessary. Examples include amoxicillin/clavulanate, clindamycin, cefuroxime, cefprozil, clarithromycin, gatifloxacin, levofloxacin, and moxifloxacin.
• Bronchodilators: Inhaled albuterol or ipratropium bromide may be used for symptomatic relief in acute cough associated with bronchospasm (e.g., asthma exacerbation).

Chronic Cough Management: Focus is on identifying and treating the underlying cause.

• Address Underlying Etiology: Targeted treatment is crucial. For example:
  • UACS: Intranasal corticosteroids, antihistamines, saline nasal irrigation.
  • GERD: Proton pump inhibitors (PPIs), lifestyle modifications (avoid reflux triggers, elevate head of bed).
  • Asthma: Inhaled corticosteroids, bronchodilators.
  • COPD: Bronchodilators, inhaled corticosteroids, pulmonary rehabilitation.
  • ACE Inhibitor Cough: Discontinue ACE inhibitor and switch to an angiotensin receptor blocker (ARB).
• Neurogenic Cough Treatment: Differs from other neuropathic pain conditions.
  • Tramadol: Low-dose tramadol (25mg up to four times daily) may be used.
  • Amitriptyline: Low-dose amitriptyline (10mg at bedtime).
  • Gabapentin: Preferred if laryngopharyngeal reflux is present or other symptoms exist, starting at 100mg four times daily and titrated up as needed (typically 300-500mg four times daily).
  • Combinations: Gabapentin with low-dose amitriptyline at bedtime.
  • Second-line agents: Pregabalin, baclofen.

Differential Diagnosis of Cough (Categorized by Duration)

The differential diagnosis for cough is broad, and categorizing by duration (acute, subacute, chronic) helps to narrow the possibilities.

Acute Cough Differential Diagnosis:

• Acute Bronchitis
• Acute Exacerbation of COPD
• Acute Rhinosinusitis
• Acute Viral Upper Respiratory Infection
• Allergic Rhinitis
• Asthma Exacerbation
• Aspiration Syndromes
• Congestive Heart Failure
• Pertussis
• Pneumonia (Viral, Bacterial)
• Pulmonary Embolism

Subacute Cough Differential Diagnosis:

• Post-Infectious Cough (following viral URI)

Chronic Cough Differential Diagnosis:

• Upper Airway Cough Syndrome (UACS)
• Gastroesophageal Reflux Disease (GERD)
• Non-Asthmatic Eosinophilic Bronchitis (NAEB)
• Chronic Bronchitis
• Post-Infectious Cough (Persistent)
• ACE Inhibitor-Induced Cough
• Malignancy (Lung Cancer)
• Interstitial Lung Diseases (ILDs)
• Obstructive Sleep Apnea (OSA)
• Chronic Sinusitis
• Psychosomatic Cough

Very Rare Causes of Cough (Considered When Diagnosis is Unclear):

• Cerumen Impaction (Arnold’s nerve stimulation)
• Esophageal Achalasia
• Tracheoesophageal Fistula
• Oesophageal Tracheobronchial Reflex
• Ortner Syndrome (Vocal cord paralysis due to cardiac ptosis)
• Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS)
• Peritoneal Dialysis-Related Cough
• Pneumonitis
• Syngamus laryngeus Infection (Rare parasitic infection)
• Tracheobronchial Collapse
• Vitamin B12 Deficiency
• Zenker’s Diverticulum, Distal Esophageal Diverticulum

Prognosis of Cough

Cough itself is generally a benign symptom. However, the long-term prognosis is determined by the underlying cause. For acute infections, the prognosis is typically excellent with resolution of cough within a few weeks. For chronic conditions like COPD, ILD, or lung cancer, the prognosis is more variable and depends on the severity and progression of the disease.

Complications of Cough

While cough is a protective reflex, persistent or severe coughing can lead to complications:

• Sleep Disruption
• Headache
• Vomiting
• Syncope (Cough syncope)
• Excessive Sweating
• Rib Fracture (Especially in elderly or osteoporotic individuals)
• Urinary Incontinence (Cough-induced incontinence)

Consultations

Effective cough management often requires a multidisciplinary approach. Consultations may be warranted in specific situations:

• Pulmonologist or Cough Specialist: For new-onset chronic cough without a clear etiology or for persistent cough despite initial management.
• Cardiologist: If congestive heart failure is suspected as the cause of cough.
• Gastroenterologist: For suspected GERD-related cough.
• Otolaryngologist (ENT): For evaluation of UACS, laryngeal disorders, or neurogenic cough.

Clinical Pearls and Key Considerations

• Antibiotics for Acute Cough: Reserve antibiotics for acute cough for cases with suspected bacterial infection and when symptomatic therapy fails, particularly if purulent nasal discharge, maxillary toothache, sinus tenderness, or discolored nasal discharge are present.
• Bacterial Sinusitis: Consider bacterial sinusitis in cases of persistent rhinosinusitis.
• Bacterial Bronchitis in COPD Exacerbation: Think of bacterial bronchitis in COPD exacerbations with worsening dyspnea or wheezing.
• Pertussis Suspicion: Cough and vomiting should raise suspicion for pertussis. Antibiotics for pertussis primarily reduce infectivity, not the duration of paroxysmal cough.
• Cough in the Elderly: In older adults, consider pneumonia, CHF, asthma, and aspiration even with atypical or minimal symptoms.
• GERD-Related Cough: Many patients with GERD-induced cough may not have typical heartburn symptoms. Consider GERD in unexplained chronic cough. Spontaneous GERD coughing may be less common, but GERD can increase cough propensity in susceptible individuals.

Enhancing Healthcare Team Outcomes

Managing cough effectively, especially chronic cough, often necessitates an interprofessional team approach. Primary care providers, nurse practitioners, internists, and pulmonologists play crucial roles. Empirically prescribing antitussives for all coughs is discouraged. Identifying and treating the underlying cause is paramount. A thorough history is vital. For prolonged cough or cough associated with concerning symptoms, referral to a pulmonologist or otolaryngologist is recommended to ensure comprehensive evaluation and optimal patient outcomes.

Review Questions (Please refer to the original article for review questions)

References (Same as original article)

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Disclosures: Sandeep Sharma declares no relevant financial relationships with ineligible companies.

Disclosures: Muhammad Hashmi declares no relevant financial relationships with ineligible companies.

Disclosures: Mohamed Alhajjaj declares no relevant financial relationships with ineligible companies.