What is the cause of an adult or adolescent patient's persistent coughing bouts, particularly in the evening and morning, despite treatment with montelukast (leukotriene receptor antagonist), levocetirizine (antihistamine), and fexofenadine (antihistamine) 180 mg, during winter months?

Likely Diagnosis: Gastroesophageal Reflux Disease (GERD) with Possible Coexisting Asthma or Upper Airway Cough Syndrome

The most likely cause of this patient's persistent morning and evening cough during winter, despite antihistamine and leukotriene receptor antagonist therapy, is gastroesophageal reflux disease (GERD), potentially with coexisting asthma or upper airway disease. 1

Why GERD is the Primary Suspect

The specific timing pattern—coughing bouts in the evening and upon waking in the morning—is highly characteristic of reflux-related cough. 2, 1 Key diagnostic features include:

• Evening cough occurs when the lower esophageal sphincter is more relaxed before sleep, allowing reflux to trigger cough 1
• Morning cough upon waking reflects overnight reflux accumulation that manifests when the patient transitions from sleep (which suppresses cough reflex) to wakefulness 2
• Absence of dyspepsia does NOT rule out GERD—up to 75% of patients with GERD-related cough lack typical gastrointestinal symptoms (silent GERD) 1

Why Previous Treatments Failed

The patient's lack of response to montelukast, levocetirizine, and fexofenadine strongly suggests the cough is NOT primarily allergic rhinitis:

• Intranasal corticosteroids are superior to montelukast for allergic rhinitis, and montelukast alone has modest efficacy 2
• Antihistamines (levocetirizine, fexofenadine) are effective for allergic rhinitis but have limited impact on cough from other causes 2
• The failure of both antihistamine classes and a leukotriene receptor antagonist makes pure allergic rhinitis unlikely 3

Alternative or Coexisting Diagnoses to Consider

Asthma or Cough-Variant Asthma

• Cough worse in morning and evening, particularly during winter, suggests possible asthma 2
• Cold air exposure during winter is a classic asthma trigger 2
• Bronchoprovocation testing and pulmonary function tests should be performed to identify exercise-induced bronchoconstriction or asthma 2

Upper Airway Cough Syndrome (Post-Nasal Drip)

• Upper airway disease can cause cough with nasal stuffiness and sensation of post-nasal drip 2
• However, symptoms and clinical findings are not reliable discriminators, and treatment response is the recommended diagnostic approach 2

Recommended Diagnostic and Treatment Algorithm

Step 1: Initiate GERD Therapy (First-Line)

Start proton pump inhibitor (PPI) therapy immediately as the most likely diagnosis:

• Omeprazole 20-40 mg twice daily or equivalent, taken before meals for at least 8 weeks 2
• Implement lifestyle modifications: avoid eating 2-3 hours before bedtime, elevate head of bed, avoid trigger foods, weight management if overweight 1
• Response may take several months in some patients, so adequate treatment duration is essential 1

Step 2: If Inadequate Response After 4-8 Weeks

• Increase to twice-daily PPI dosing if not already prescribed 1
• Consider adding prokinetic agent (metoclopramide 10 mg three times daily) 2, 1

Step 3: Evaluate for Asthma Concurrently

• Perform pulmonary function tests and bronchoprovocation challenges to identify asthma or exercise-induced bronchoconstriction 2
• If asthma confirmed, initiate inhaled corticosteroids (dosing per standard asthma guidelines) 2
• Intranasal corticosteroids may provide additional benefit if upper airway symptoms are prominent—trial for 1 month 2

Step 4: Consider Upper Airway Disease

• If prominent nasal symptoms persist, trial topical nasal corticosteroid for 2-8 weeks 2
• Note that second-generation antihistamines have conflicting evidence for chronic cough, which explains the patient's poor response 2

Critical Clinical Pearls and Pitfalls

• Check medication list for ACE inhibitors—these are a common cause of chronic cough and should be discontinued if present 1
• Women, particularly middle-aged, have higher prevalence of chronic cough and more sensitive cough reflex 2, 1
• Winter exacerbation suggests environmental triggers (cold air for asthma) or increased time indoors with allergen exposure 2
• Cough reflex is suppressed during sleep, so cough that wakes patients suggests asthma, infection, or heart failure rather than pure GERD 2
• Multiple causes often coexist—GERD, asthma, and upper airway disease frequently overlap and may require combined treatment approaches 2