What is the pathophysiology of allergic rhinitis?

Pathophysiology of Allergic Rhinitis

Allergic rhinitis is fundamentally an IgE-mediated inflammatory response of the nasal mucosa characterized by a complex allergen-driven mucosal inflammation involving early and late phase responses, with symptoms resulting from the interplay between resident and infiltrating inflammatory cells, vasoactive mediators, cytokines, and neurogenic mechanisms. 1

Sensitization Process

• Initial Exposure and Sensitization:
  • Allergens penetrate the disrupted epithelial barrier of nasal passages 2
  • Dendritic cells expressing CD1a and CD11c in the nasal mucosa process allergens 1, 3
  • Processed allergens are presented via MHC II molecules to T-cell receptors on resting CD4+ cells in regional lymph nodes 1, 3
  • With appropriate costimulatory signals, T cells proliferate into TH2-biased cells 1
  • TH2 cells produce cytokines (IL-3, IL-4, IL-5, IL-13, GM-CSF) 1, 3
  • These cytokines promote:
    • B-cell isotype switching
    • Allergen-specific IgE production by plasma cells
    • Mast cell proliferation and infiltration into airway mucosa
    • Eosinophilic infiltration into nasal mucosa and epithelium 1

Early Phase Response

• Immediate Reaction (within minutes of allergen exposure):
  • Allergen cross-links adjacent IgE molecules bound to mast cell surfaces 4
  • Mast cells degranulate, releasing:
    • Histamine (primary mediator)
    • Prostaglandins
    • Leukotrienes 1, 5
  • These mediators trigger:
    • Sneezing
    • Nasal itching
    • Rhinorrhea
    • Initial nasal congestion 1, 5, 4
  • Sensory nerve activation occurs, contributing to symptoms 1
  • Plasma leakage and congestion of venous sinusoids develop 1

Late Phase Response

• Delayed Reaction (4-8 hours after allergen exposure):
  • Initiated by mast cell mediators and cytokines 1
  • Characterized by cellular infiltration:
    • Eosinophils
    • Basophils
    • Monocytes
    • T-lymphocytes 4
  • Infiltrating cells release:
    • Leukotrienes
    • Kinins
    • Histamine
    • Additional inflammatory mediators 4
  • Cytokine production increases (IL-4, IL-5, IL-6, IL-8, GM-CSF, RANTES) from:
    • Mast cells
    • TH2 lymphocytes
    • Epithelial cells 4
  • Adhesion molecules (VCAM-1, E-selectin) facilitate cellular infiltration 4
  • Nasal congestion predominates in this phase 1

Priming Effect

• Repeated allergen challenges require less allergen to induce responses 1
• Results from influx of inflammatory cells during prolonged allergen exposure 1
• Explains why symptoms worsen with continued exposure 1
• Provides rationale for initiating anti-inflammatory therapies before allergen season 1

Neurogenic Mechanisms

• Neuronal reflexes play important roles:
  • Mediating local responses to inflammatory mediators
  • Possible involvement in T-lymphocyte activation 4
  • Substance P and other neuropeptides are released 5
  • CGRP (calcitonin gene-related peptide) contributes to late-phase nasal obstruction 1

Environmental Factors

• Allergic responses are less intense in hot, humid environments
• Responses are more marked in cold, dry environments
• These differences may relate to changes in osmolality of nasal surface fluid 4

Clinical Manifestations

• Common symptoms:
  • Nasal congestion (94.23% of patients)
  • Rhinorrhea (90.38% of patients) 2
  • Sneezing
  • Nasal itching
  • Palatal itching 1
• Associated symptoms:
  • Conjunctival involvement (itching, redness, watery discharge)
  • Ear fullness and popping
  • Itchy throat
  • Pressure over cheeks and forehead
  • Malaise, weakness, fatigue 1, 3

Classification

• Based on temporal pattern:
  • Seasonal (pollen-induced)
  • Perennial (year-round allergens like dust mites)
  • Episodic (sporadic exposures) 1
• Based on frequency:
  • Intermittent (<4 days/week or <4 weeks/year)
  • Persistent (>4 days/week and >4 weeks/year) 1
• Based on severity:
  • Mild to seriously debilitating 1

Pathophysiological Differences in Subtypes

• Seasonal allergic rhinitis:

  • Edematous and pale turbinates on examination 2
  • Typically caused by pollens with geographic and climatic variations 1

• Perennial allergic rhinitis:

  • Erythematous and inflamed turbinates with serous secretions 2
  • Commonly caused by dust mites, molds, animal allergens 1

Clinical Implications

• Understanding the pathophysiology guides treatment approaches:

  • Antihistamines target early phase mediators
  • Intranasal corticosteroids address both phases by reducing inflammation
  • Allergen avoidance prevents both phases
  • Anti-inflammatory therapies before allergen season can prevent priming 1

• The complex pathophysiology explains why some patients may require combination therapy targeting multiple pathways 6

• Recognition of the neurogenic component explains why some symptoms persist despite antihistamine therapy 5

Common Pitfalls in Understanding Allergic Rhinitis Pathophysiology

• Misattribution of symptoms: Not all rhinitis is allergic; mixed rhinitis (allergic + nonallergic) is common (44-87% of patients) 1

• Overlooking priming effect: Failure to recognize this phenomenon may lead to inadequate preventive treatment before allergen season 1

• Focusing only on histamine: While histamine is important in early phase, multiple mediators and cells are involved in the complete pathophysiology 4

• Neglecting environmental influences: Hot/humid vs. cold/dry environments can significantly affect symptom intensity 4

• Underestimating neurogenic mechanisms: Neuronal reflexes contribute significantly to symptom persistence 5, 4