Upper Airway Disease: Rhinitis and Rhinosinusitis

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Chapter 37 Upper Airway Disease

Rhinitis and Rhinosinusitis

Rhinitis

Rhinitis is defined as the presence of two or more symptoms of nasal discharge (anterior or posterior), blockage with sneeze, or itch for more than 1 hour on most days. It is an umbrella term that encompasses multiple diseases with distinct immunopathogenic mechanisms and correspondingly specific diagnostic and treatment strategies (Figure 37-1). Although rhinitis is subdivided into two broad categories of allergen-induced rhinitis and nonallergic rhinitis, disease overlap is common. Thus, a careful history and directed investigations are required to establish the exact diagnosis. In practice, inflammatory changes usually are continuous from nasal to sinus mucosa (see Figure 37-1); therefore, the designation rhinosinusitis is more accurate, although its use may lead to clinical confusion with the separate group of diseases that are historically classified under sinusitis. Apart from viral colds, allergic rhinitis (AR) is the most common cause of nasal symptoms.

Epidemiology, Risk Factors, and Pathophysiology

Allergic Rhinitis

Up to 30% of adults and 40% of children are affected, and worldwide the prevalence of AR continues to increase (Figure 37-2). The condition has marked effects on quality of life and is responsible for reduced school and workplace attendance (by 3% to 4%) and performance (by 30% to 40%). The resulting economic burden is high, and rhinitis and related AR are common. It is estimated that nearly 500 million people worldwide have AR, and it is one of the most common reasons for attendance with a primary care practitioner.

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Figure 37-2 Global prevalence of hay fever in 13- to 14-year-olds.

(From Strachan D, Sibbald B, Weiland S, et al: Worldwide variations in prevalence of symptoms of allergic rhinoconjunctivitis in children: the International Study of Asthma and Allergies in Childhood [ISAAC], Pediatr Allergy Immunol 8:161–176, 1997.)

The predisposition to develop AR is both genetic and environmental. Identical monozygotic twins demonstrate a 40% to 50% concordance rate, whereas dizygotic twins have a 25% concordance rate. Thus, persons with an affected parent or sibling are at increased risk but as-yet undefined environmental factors must interact with genetic predisposition for disease occurrence. Western lifestyle seems to be associated with an increased prevalence of allergic disorders in general, including asthma and eczema. Studies to identify the exact genes involved are still limited in AR, and the findings have been difficult to interpret because of lack of replication in separate population cohorts. As in asthma, multiple genes are involved, many of which code for epithelial molecules concerned with innate immunity, suggesting that an impaired mucosal barrier is relevant to development of AR, as is now confirmed in eczema.

The key immunologic event that initiates AR is binding of allergen to specific IgE on mast cells found in the nasal mucosa. Cross-linking of two or more high-affinity IgE molecules in response to allergen binding leads to mast cell activation and degranulation with release of mediators, initiating an immune cascade (Figure 37-3). This is termed the immediate response. With the release of histamine, leukotrienes, prostaglandins, bradykinin, and other mediators (platelet-activating factor, substance P, tachykinins) comes the immediate onset of symptoms of sneezing, itching, and “running,” typically seen in instances of intermittent allergen contact—for example, with hay fever. An additional immunologic event in up to 70% of affected persons is a further influx of inflammatory cells consisting predominantly of eosinophils, basophils, and T cells expressing TH2 cytokines such as interleukin (IL)-4 (B cell IgE class switching) and IL-13 (mucus hypersecretion). Clinically this process is characterized by further obstruction, decreased olfaction, and mucosal irritability with immunopathologic changes similar to those seen in chronic asthma (see Figure 37-3). Local mucosal allergen–specific IgE production by nasal B cells is now confirmed and leads to local (skin prick test–negative) rhinitis. Emerging evidence also indicates that activated nasal epithelium–derived cytokines such as thymic stromal lymphopoietin (TSLP), IL-25 (i.e., IL-17E), and IL-33 can further promote disease through initiation, enhancement, and maintenance of TH2 inflammation at the mucosal surface where allergen deposition and sampling occur. In addition, the potential for innate mucosal immune mechanisms such as Toll-like receptor (TLR) signaling system to drive or skew TH2 responses is increasingly recognized.

Common aeroallergens that can initiate AR include plant pollen, house dust mite, fungal spores, cockroach aeroallergens, and dander from domestic pets. AR was formerly categorized as seasonal, perennial, and occupational; however, the World Health Organization (WHO) Allergic Rhinitis and Impact in Asthma (ARIA) guidelines suggest that intermittent and persistent rhinitis are better subdivisions, because they are globally applicable, even in geographic regions that lack specific seasons.

In the United Kingdom and other North European countries, symptoms in the spring are frequently caused by allergy to tree pollens. The peak period for tree pollens ranges from mid-February for alder to early April. Silver birch, oak, ash, elm, willow, and poplar release pollen from late March or early April to the middle of May. Pine trees pollinate from late April to early July. In late spring and early summer—the classic hay fever season—AR results from allergy to grasses such as rye, timothy, and cocksfoot. In late summer, weed pollens, such as nettle and mugwort, are responsible, whereas in autumn, the fungi Cladosporium spp., Alternaria spp., and Aspergillus spp. provoke symptoms. In the United States, ragweed pollen allergy is a common cause of rhinitic symptoms, usually from mid-August to mid-September. Grass pollen is the most common seasonal allergen in the United Kingdom, and symptoms correlate with the presence of high airborne pollen counts.

Perennial rhinitis—in which symptoms occur throughout the year—in the United Kingdom most commonly is caused by allergy to the fecal pellets of the house dust mite (Dermatophagoides pteronyssinus), which flourishes in warm, humid environments and lives in bedding and soft furnishings. The major house dust mite allergen Der p 2 is now recognized as demonstrating molecular mimicry to the mammalian lipid-binding protein (LBP) MD-2. This feature allows Der p 2 to bind bacterial lipopolysaccharide (LPS) airway TLR-4 signaling complex, which is highly expressed on epithelium, and facilitates TLR signaling. Such signaling is important for the development of allergen-driven TH2 signaling pathways. Allergy to dander from domestic pets (such as cats, dogs, rabbits, and hamsters) can account for perennial rhinitis, whereas allergens encountered in the workplace are responsible for occupational rhinitis. Examples are sensitization to latex, flour, and grain (bakers); allergies to small mammals among laboratory workers; and allergy to wood dust, biologic products (such as antibiotic powder and enzyme-enhanced detergents), and rosin (colophony) from solder flux.

Constant or very-high-level allergen contact produces chronic obstructive symptoms, with reduced olfaction and nasal hyperreactivity, the allergic nature of which may not be recognized, because hyperreactivity to nonspecific irritants, such as inhaled fumes, dusts, and cold air, may lead to an erroneous diagnosis of “vasomotor” rhinitis. True food allergy is rarely the cause of isolated rhinitis but may be relevant in small children with multisystem allergy.

Nonallergic Rhinitis

Nonallergic Rhinitis with Eosinophilia Syndrome

Nonallergic rhinitis with eosinophilia syndrome (NARES) was described in 1981. The presence of eosinophils in nasal smears (more than 5% to 25%, according to different authorities) characterizes NARES, which probably is the counterpart of intrinsic asthma and may precede nasal polyposis and aspirin sensitivity. It typically is rapidly responsive to topical nasal corticosteroids. Recent progress in identifying local airway mucosal production of allergen-specific IgE has implications for future disease classification, and an entity termed local allergic rhinitis (LAR) has been described recently. What overlap NARES will have with LAR is not yet defined, but it is likely that with further investigation of these two NAR subtypes, common disease mechanisms will be found and the classification terminology will change further.

Aspirin hypersensitivity, or aspirin-exacerbated respiratory disease (AERD), develops usually in adult life in patients with rhinitis (often NARES), with subsequent development of nasal polyps and asthma. Mast cell and eosinophil degranulation are seen in biopsy specimens, and polyclonal local IgE production stimulated by superantigens from staphylococci has been described. Cyclooxygenase-1 (COX-1) inhibition by aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs) promotes leukotriene production, while inhibiting that of prostaglandins, including PGE2, a bronchodilator. Leukotrienes cause bronchoconstriction, mucosal swelling, and excess mucus production, and sensitivity to their effects is high in aspirin sensitivity, probably because of increased numbers of specific receptors. The clinical picture often is one of aggressive eosinophilic polyposis, severe asthma with life-threatening reactions to aspirin and other NSAIDs, and frequent need for oral corticosteroids. A subgroup reacts also to “E number” foods (i.e., additives and preservatives, such as sulfites in wine), as well as high-salicylate foods such as some herbs, spices, dried fruit, and jams.

Nonallergic Rhinitis Without Eosinophilia

Autonomic Rhinitis

The nasal mucosa receives a rich efferent innervation from both the parasympathetic and sympathetic nervous system. Nasal glandular secretion is largely mediated by the parasympathetic fibers, the main postganglionic neurotransmitter being acetylcholine (ACh) acting through muscarinic receptors (predominantly the M3 subtype). The sympathetic fibers mediate vascular tone and can regulate nasal airflow by potent effects on venous erectile tissue. The primary neurotransmitter is norepinephrine (noradrenaline). In autonomic rhinitis, there is no evidence of nasal inflammation, but of autonomic dysfunction or imbalance. Nasal and, in some patients, cardiovascular reflexes are abnormal, and there may be association with the chronic fatigue syndrome. Topical ipratropium is useful in decreasing watery rhinorrhea; capsaicin applications also may relieve symptoms for several months after a few weeks of treatment. Epinephrine (adrenaline) and other sympathomimetics lead to vasoconstriction of the nasal mucosa, with increased nasal patency. Both α- and β-adrenergic blockers increase nasal resistance and can produce symptoms of nasal stuffiness (Box 37-2). Stimulation of the parasympathetic system leads to an increase in nasal secretions. However, patients who have this condition also have increased responsiveness to both histamine and methacholine, which results in nasal blockage and rhinorrhea. It also is associated with hypertrophy of the inferior turbinates, and nasal polyps are sometimes present. Certain stimuli such as cold air, exercise, mechanical or thermal factors, and humidity changes result in rhinorrhea and other symptoms of rhinitis, and a period of nasal hyperresponsiveness often follows viral infection. This observation is consistent with general neuronal dysregulation leading to excessive and troublesome neural hyperreactivity and imbalance with certain environmental exposures.

Drug-Induced Rhinitis

The main drugs implicated in pharmacologic rhinitis are listed in Box 37-2. This entity is mostly noninflammatory—for example, antihypertensives, particularly beta blockers, can cause nasal obstruction by abrogation of the normal sympathetic tone, which maintains nasal patency. Exogenous estrogens in oral contraceptives or hormone replacement therapy also evoke rhinitis in some patients. Overuse of α-agonists results in rhinitis medicamentosa: a tachyphylaxis of α-receptors to extrinsic and intrinsic stimuli. The mucosa becomes swollen and reddened. Aspirin hypersensitivity is an inflammatory form of drug-induced rhinitis (see earlier).

Food-Induced Rhinitis

Granulomas/Vasculitis

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