Upper Airway Disease: Rhinitis and Rhinosinusitis

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Chapter 37 Upper Airway Disease

Rhinitis and Rhinosinusitis

Glenis K. Scadding, Harsha H. Kariyawasam

Upper Airway

The upper airway is a continuous structure that extends from the nasal vestibule to the alveolar units of the lung. Although the airway traditionally has been divided into upper and lower segments by an arbitrary line drawn at the level of the vocal cords, airway disease does not restrict itself to such specific anatomic regions. In fact, upper and lower airway disease frequently coexist, and upper airway manifestations of disease often can precede lower airway involvement. Such recognition has led to the sobriquet “the United Airway,” with an emphasis on approaching patients with disease from a combined perspective on both the upper and lower airways.

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.

Figure 37-1 Classification of rhinitis. NARES/LAR, nonallergic rhinitis with eosinophilia syndrome/local allergic rhinitis.

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.

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 T_H2 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 T_H2 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 T_H2 responses is increasingly recognized.

Figure 37-3 Immunopathogenesis of allergic rhinitis. 1, Allergen impaction on the mucosal surface leads to its solubilization and diffusion to sites of mast cell (MC) residence, where cross-linking of two or more high-affinity (FcεRI) IgE receptors lead to MC activation and subsequent degranulation and release of mediators, such as histamine and leukotrienes, that initiate the immediate rhinitis symptoms (acute inflammation). Dendritic cells (DC) also take up allergen and present processed allergen peptide in the context of MHC class II to naive T cells, which then undergo activation, leading (2) to the release of T_H2 cytokines. IL-5 in particular is essential for the maturation, release, and trafficking of eosinophils from the bone marrow. 3, Intense cellular infiltration characterizes the late nasal response, which leads to (4) chronic inflammation of the epithelium and submucosa with structural cell activation, edema, and neural hyperreactivity. TLR signaling and epithelial activation, along with TSLP, IL-17, and IL-33 signaling, will further promote T_H2 signaling. Chronic symptoms of rhinitis develop. Ag, antigen; GM-CSF, granulocyte-macrophage colony-stimulating factor; IgE, immunoglobulin E; IL, interleukin; MHC, major histocompatibility complex; TLR, Toll-like receptor; TSLP, thymic stromal lymphopoietin.

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 T_H2 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.

Infectious Rhinitis

The nasal and sinus mucosa can be infected by all types of organisms: viruses, bacteria, fungi, and protozoa. Of such infections, viral infections are the most frequent.

The Common Cold (Acute Coryza)

Most people have approximately three colds per year, but small children have from six to eight. Humans spend 2 years of their lives with colds, of which 50% result from rhinoviruses, a further 20% from coronaviruses, and a further 20% from influenza virus, parainfluenza virus, adenoviruses, and respiratory syncytial virus; the remainder are caused by other viruses, including enteroviruses. Viral invasion occurs at the point of infection, usually in the posterior nasopharynx, and results in transient vasoconstriction of the mucous membrane, followed by vasodilatation and edema with mucus production. A leukocytic inflammatory infiltrate develops, followed by desquamation of mucous epithelial cells. Initially, a clear watery secretion is produced, but this is followed by epithelial desquamation with opacification of secretions—not necessarily an indication of bacterial infection, which complicates only approximately 2% of colds. Resolution occurs in a few days in uncomplicated viral infections; however, compared with nonatopic persons, allergic patients have more colds of greater severity. With rhinovirus infections in asthmatic children exposed to allergens to which they are sensitized, the odds ratio for hospitalization with asthma approaches 20.

Nonallergic Rhinitis

Nonallergic, Noninfectious Rhinitis

By definition, patients with nonallergic rhinitis (NAR) are skin prick–negative for common aeroallergens. NAR occurs in around 25% of persons with rhinitis symptoms. However, mixed rhinitis (a combination of allergic and nonallergic forms) can occur in up to 44% to 87% of patients. NAR incidence is higher in women. The nonallergic form of rhinitis incorporates a very heterogeneous group of conditions, and it is possible to further subclassify NAR into etiologic subtypes: a group for which the etiology is known and one for which it cannot be established, termed idiopathic rhinitis. The latter type is a diagnosis of exclusion, and approximately 60% of NAR cases will fall into this category. A summary of considerations in the differential diagnosis for NAR is presented in Box 37-1. An essential division is between NAR with eosinophilic inflammation in the upper airway and that without.

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.

Box 37-2

Drugs Commonly Associated With Rhinitis *

^* Although it is possible to explain the mechanism of drug-induced rhinitis for certain groups of medications, several other types of drugs have an as-yet unexplained mechanism.

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).

Hormonal Rhinitis

Hormonal rhinitis is seen in pregnancy, occasionally in relation to menstruation, and at puberty. Rhinitis is more common in the later stages of pregnancy and may be more frequent in women who smoke. The exact pathogenesis is unknown, but the effects of estrogens on nasal mucosal homeostasis in relation to vascular tone and glandular secretion are relevant, with the potential for effects on nasal tissue remodeling as well. The symptoms disappear soon after the affected woman gives birth. Chronic nasal obstruction is associated with hypothyroidism and acromegaly.

Food-Induced Rhinitis

Differential Diagnosis for Rhinitis

A summary of considerations in the differential diagnosis for rhinitis is provided in Box 37-1. Neoplasms, foreign bodies, and trauma all can produce obstruction, pain, purulent discharge, and epistaxis. In adults, the possibility of neoplasm should always be considered in patients who have persistent symptoms, particularly if these are unilateral. In children, the presence of a foreign body should be considered if the nasal discharge is unilateral and foul-smelling. Local disease in the pharynx and larynx also may involve the nose and paranasal sinuses (e.g., enlarged adenoids), as may dental disease (e.g., maxillary dental root infection), which may spread to the maxillary sinus.

Rhinosinusitis

Evolutionary developments in humans have meant that the head is now held upright, so that sinuses, which reach down to the level of the top jaw, drain at the level of the nasal bridge, against gravity. This process is dependent on efficient mucociliary clearance and a patent ostiomeatal (sinus drainage point) complex and is easily compromised by mucosal swelling or mucociliary failure from any cause. The sinus drainage pathways are illustrated in Figure 37-4.

Figure 37-4 Sinus drainage pathways. A and B, In these diagrams, the ostiomeatal complex is seen to drain the frontal, anterior ethmoid, and maxillary sinuses. A, Coronal section. B, Lateral view. C and D, Computed tomography (CT) scans. C, On a coronal image, the paranasal sinuses are clear in a patient with a deviated nasal septum. D, On a lateral view, significant thickening of the mucosal lining is evident. CT changes do not correlate well with nasal symptoms but do relate to eosinophil counts in blood and sputum and to pulmonary function in accompanying asthma.

(C and D, Courtesy Ian Mackay.)

Rhinosinusitis, which means inflammation of the lining of the nose and sinuses, is another umbrella term that incorporates a large and heterogeneous group of upper airway disorders. It is a common condition, affecting up to 15% of the population in Western countries, and is associated with significant morbidity as well as substantial socioeconomic and health care costs.

The 2007 European position paper (EP₃OS-2007) defines rhinosinusitis as inflammation of the nose and paranasal sinuses characterized by two or more symptoms, one of which should be nasal obstruction (blockage, congestion) or nasal discharge (anterior or posterior), together with either facial pressure or pain or reduction in or loss of smell. Sinus and nasal examination accomplished by endonasal inspection or CT scanning is important to confirm the diagnosis. Sinusitis is subclassified as acute or chronic disease. Chronicity is arbitrarily defined by the persistence of symptoms beyond 12 weeks. Chronic rhinosinusitis (CRS) is further broadly subdivided into CRS without nasal polyps (CRSsNP) and with nasal polyps (CRSwNP).

Acute Rhinosinusitis

Acute rhinosinusitis (ARS) is common. It can be mild, moderate, or severe. Whereas a simple upper airway viral infection often will resolve after 5 days, with ARS the symptoms worsen by then or persist beyond 10 days. In the absence of confounding factors such as allergic inflammation or anatomic abnormalities, for example, full resolution is expected within a month.

Although the nose harbors bacteria, the sinuses normally are largely sterile, possibly because of the nitric oxide (NO) concentrations therein and continuous mucociliary clearance. ARS rarely occurs directly after trauma, dental infections, and diving into polluted water but usually arises from a bacterial infection secondary to the common cold. The mucous membranes of the nose and sinuses become swollen, which leads to blockage of the ostiomeatal complex and bacterial infection of the sinuses, particularly with Haemophilus influenzae and Streptococcus pneumoniae, with other causative bacteria identified as Staphylococcus aureus, Moraxella catarrhalis, Streptococcus pyogenes, and gram-negative bacteria such as Klebsiella and Pseudomonas. Anaerobic organisms also may be involved.

Chronic Rhinosinusitis

Failure to correctly subclassify the different subtypes of CRS has prevented confirmation of their exact incidence and prevalence, but CRS without nasal polyps (CRSsNP) accounts for a majority of cases seen.

Although CRS probably occurs after failure of resolution of ARS with the same bacterial pathogens involved, other factors often are present, such as eosinophilic inflammation (in both allergic and nonallergic forms of rhinosinusitis), immune deficiency (innate or adaptive), or structural abnormalities; the role of pathogens is disputed. One possibility is persistence of organisms as a biofilm that continually stimulates a damaging mucosal immune response.

Immune Defects

Panhypogammaglobulinemia is a severe condition with variable absence of all classes of immunoglobulin; it manifests with bacterial and other infections at many sites. Initial presentation may be to the otorhinolaryngologist with symptoms of recurrent acute or chronic rhinosinusitis. It is important to make the diagnosis early before irreversible damage occurs at other sites (the lungs) and so that appropriate immunoglobulin therapy can be instituted.

Total or relative absence of IgA may be present in the absence of any obvious clinical disease. However, IgA deficiency is now known to be associated in some patients with IgG2 subclass deficiency, and such persons may be more prone to episodes of sinusitis caused by encapsulated bacteria such as H. influenzae and S. pneumoniae.

Acute, chronic, and recurrent forms of sinusitis are common in persons with human immunodeficiency virus infection, the most common causative organisms being S. pneumoniae and H. influenzae. A tendency to chronicity and to relapse has been described, and in addition, fungal (Cryptococcus spp., Alternaria spp., and Aspergillus spp.) and viral (cytomegalovirus) sinusitis may occur.

Mucus Clearance Defects

The nose and paranasal sinuses are lined with ciliated epithelium, which in a coordinated fashion moves a mucus blanket toward the nasopharynx. This mucus is important for the entrapment and removal of particulate material and toxic substances, which include bacteria and allergens. The integrity of the mucociliary clearance pathway is vital to the appropriate drainage and ventilation of the paranasal sinuses and the nose (see Figure 37-4). Primary ciliary dyskinesia is inherited as an autosomal recessive trait and is characterized by the presence of sinusitis, bronchiectasis, situs inversus (Kartagener syndrome, present in 50% of these patients), and male infertility that results from dyskinetic sperm. Various ciliary structural defects have been described (e.g., absence of inner or outer dynein arms or both), but some cilia appear normal (Young syndrome). Recent work suggests that deficiency of inducible nitric oxide synthase (iNOS) may be the common underlying abnormality. Presentation is with chronic sinusitis, bronchiectasis or bronchitis, and obstructive azoospermia.

Secondary ciliary defects may arise after viral or bacterial infections. A number of mechanisms are involved:

• Mucous membranes become swollen and inflamed, which may result in blockage of the sinus ostia, thus preventing clearance (this is particularly critical at the ostiomeatal complex).

• If viruses or bacteria damage the epithelial cell layer, the integrity of cilial clearance is destroyed.

• Some bacteria produce toxins that inhibit cilial clearance mechanisms.

• Mucus during infection becomes thick and difficult to clear.

Chronic Rhinosinusitis With Nasal Polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) represents a more distinct immune phenotype with better characterization. Nasal polyps (Figure 37-5) result from prolapse of the mucous membranes lining the nose and on examination are seen as pale, grapelike swellings arising predominantly from the middle meatus. These lesions are insensitive to pain but cause blockage and hyposmia and often are associated with asthma and aspirin hypersensitivity. They also may be infection-related, being common in persons with cystic fibrosis. Classification of polyps is similar to that of rhinitis (Box 37-3).

Figure 37-5 Speculum examination of nostril shows a pale watery-looking polyp (arrow). Polyps are insensate and grayish, unlike turbinates, which are sensitive and bluish pink.

(Courtesy St. Mary’s Hospital Audio-Visual Department.)

Nasal polyposis demonstrates a strong heritable component, with a relative risk of 18 times the normal rate of 4% in the population and 6 times the normal rate with an affected father and mother, respectively. A strong association of AERD with CRSwNP is recognized. A number of genes have been found to be associated with AERD (e.g., leukotriene C4 synthase promoter region); these vary among different populations. HLA-DQB1 is associated with allergic fungal sinusitis. The genetics of cystic fibrosis are discussed in Chapter 46; heterozygotes for cystic fibrosis are overrepresented in the chronic rhinosinusitis population. Primary ciliary dyskinesia is also genetic, with an incidence of approximately 1 in 20,000. Various structural ciliary defects have been described, but one common defect—a lack of iNOS in nasal mucosa—has recently been found.

Clinical Features

Allergic Rhinitis

AR manifests in two major patterns: (1) watery discharge, sneezing, or itching and (2) nasal blockage. Affected persons have been called “runners” (or “sneezers” or “itchers”) and “blockers,” respectively.

Running/Sneezing/Itching

With the “running/sneezing/itching” pattern of AR, symptoms tend to be intermittent and changeable and often are closely related to allergen exposure during the day. Severity varies, with symptoms ranging from trivial to extremely disabling. In addition, itching and injection of the conjunctivae may occur, with watery discharge and conjunctival swelling, and itching in the mouth, oropharynx, and ears. This form of AR tends to be a disorder of children and young adults, and up to one third of patients have associated asthma.

Blockage

The nasal passages are chronically obstructed, with little in the way of immediate allergic symptoms. Other symptoms may include facial ache, headache, nasal hyperreactivity, and loss of sense of smell. Examination of the nose reveals pale or bluish mucosa, which is boggy and swollen, and a watery discharge may be present. Careful clinical inspection of the nose is important to exclude the concomitant presence of polyps, septal deviation, prominent turbinates, and evidence of other systemic disease and tumors.

Secondary symptoms may include disturbed sleep, pharyngitis, poor concentration, cough, and exacerbation of lower respiratory tract problems.

Considerable overlap between causes of rhinitis is not uncommon, adding to the usual rhinitic symptoms; for example, AR characterized by sneezing, itching, and watery discharge results in considerable mucosal swelling, which may result in reduced sinus drainage and contribute to development of secondary infection. Both allergic and infective forms of inflammatory rhinosinusitis may be exacerbated by the presence of anatomic and mechanical defects, such as a deviated nasal septum or enlarged turbinates. It also is important to consider the possibility of serious underlying conditions, early recognition of which may be necessary to prevent later damage (e.g., defects of immunity, impaired cilial motility, vasculitic and granulomatous disease).

Rhinosinusitis frequently is associated with lower respiratory disease; for example, approximately one third of patients who have bronchiectasis also have chronic sinusitis, and patients who have cystic fibrosis invariably have sinusitis and frequently have nasal polyps develop. Rhinitis is practically ubiquitous in asthmatic persons, with 10% of adults with late-onset asthma exhibiting aspirin hypersensitivity, often with nasal polyps (Samter’s triad). Most asthma exacerbations begin with rhinitis, either infective or allergic, or both.

Nonallergic Rhinitis

Infection

Acute Coryza (The Common Cold)

The prodrome of the common cold typically consists of a feeling of dryness, itching, and heat in the nose, which may last for a few hours and often is followed by a dry, sore throat; sneezing; watery nasal discharge; and constitutional symptoms of fever and malaise. This phase is followed in a day or so by symptoms of nasal obstruction and mucopurulent discharge, which along with the fever and malaise, may continue until resolution after 5 to 10 days. The initial symptoms of AR and coryza may be difficult to distinguish from each other.

Noninfective Rhinitis

Symptoms of noninfective rhinitis are similar to those of the blockage pattern of AR, as mentioned previously. Differentiation from AR depends on skin prick or other allergy testing.

Clinical Presentations That Warrant Physician Referral

Patients with unilateral symptoms, bloody discharge, polyps manifesting for the first time, or systemic illness should be seen by an otorhinolaryngologic surgeon. Orbital cellulitis and sinusitis with severe headache or vomiting warrant urgent referral.

Acute Rhinosinusitis

Acute maxillary rhinosinusitis is characterized by facial pain, localized to the cheek, but also present in the frontal area or around the teeth, that is made worse by stooping down or straining. The pain can be unilateral or bilateral, and tenderness may be elicited over the sinus. Acute frontoethmoidal sinusitis may cause pain around the eye and in the frontal region, with overlying tenderness and erythema of the skin. There is usually fever, and toxemia may occur. The differential diagnosis for facial pain is wide in scope and includes dental disease and the numerous causes of headache. Recently, all of the clinical signs and symptoms described here have been shown to be unreliable as diagnostic aids to identify acute sinusitis; instead, the combination of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) is the best guide.

Chronic Rhinosinusitis

CRS frequently is pain-free and manifests with a sensation of congestion, poor concentration, tiredness, and malaise. Other signs and symptoms of CRS include purulent nasal discharge (often postnasal), sore throat, and a productive cough, especially in children, in whom misdiagnosis of asthma is not uncommon. Loss of the sense of smell and halitosis are additional features.

Diagnosis, Evaluation, and Tests

Examination

It frequently is possible to arrive at a diagnosis of rhinitis and rhinosinusitis on the basis of a good detailed history. Physical examination should never be omitted, and it is vitally important that chronic symptoms be appropriately investigated. Observation of the patient’s face may reveal an allergic crease or salute, deviation of the nose from midline, or more sinister collapse of the nasal bridge.

Anterior rhinoscopy performed with use of a bright light or head mirror along with a Thudicum speculum allows simple examination of the anterior nasal cavity. In addition, the mucous membrane can be viewed, and the presence of nasal polyps and disorders of the anterior part of the nasal septum can be ascertained.

Nasal endoscopy performed using either a rigid or a fiberoptic flexible endoscope allows more detailed examination and assessment. Congenital defects such as cleft palate and atresia, septal deviation and perforation, abnormalities of the turbinates, compromised state of the mucous membranes, presence of purulent secretions, polyps, neoplasms, and foreign bodies can be identified with this examination.

Coryza

Coryza normally is diagnosed on the basis of the patient’s history, and further investigations are rarely required. Viral culture or immunofluorescent techniques can identify specific viruses.

Acute Rhinosinusitis

On examination, red, swollen nasal mucous membranes are present, and pus may be seen in the middle meatus. Endoscopy, together with imaging techniques, allows assessment of the severity and extent of involvement (diagnostic antral puncture and lavage are now rarely required). Middle meatal swabs provide material for bacteriologic culture. Immunoglobulin classes and subclasses are checked in cases of recurrent or chronic sinusitis.

Imaging Techniques

Radiography is rarely needed for diagnosis, unless a tumor is suspected. A high incidence of imaging abnormalities in the general population has been recognized: One third of unselected adults and 45% of children will have such abnormalities. After a cold, computed tomography (CT) scans show changes for at least 6 weeks. The role of imaging is largely to provide a road map for the surgeon after failure of medical treatment.

Since the advent of CT, plain sinus radiographs now have only a very limited role in the diagnosis of acute rather than chronic sinusitis, because opacification or a fluid level may be seen in a sinus or gross soft tissue swelling may be evident. The imaging investigation of choice is CT, which is the best technique to demonstrate mucosal disease and underlying anatomic abnormalities (see Figure 37-4). The detailed anatomy of both bone and soft tissue is well delineated, and axial and coronal sections can be obtained. The coronal cuts provide views of the ostiomeatal complex, important for planning surgery for acute and chronic sinusitis (Figure 37-6). Preoperatively, coronal sections at 3 to 4 mm give maximal anatomic detail, whereas axial views provide vital information regarding the relation of the optic nerve to the posterior ethmoidal and sphenoid sinuses. Magnetic resonance imaging (MRI) is of very limited value, because bone is not well imaged. MRI is useful, however, in distinguishing one type of soft tissue from another and has the advantage of avoiding irradiation.

Figure 37-6 Computed tomography scan of paranasal sinuses. This coronal image shows almost complete opacification of maxillary and ethmoid sinuses with polyps that obstruct the ostiomeatal complex.

(Courtesy Ian Mackay.)

Mucociliary Function Testing

For the simplest test, known as the saccharin clearance test, one quarter of a grain of saccharin is placed on the lateral nasal wall, 1 cm behind the anterior end of the inferior turbinate. A sweet taste is detected within 20 minutes if cilial function is normal—that is, the mucociliary mechanism is able to transport the particle to the nasopharynx and the pharynx, where taste is detected. If cilial function is abnormal, more sophisticated tests of cilial activity in cells detached by brushings taken from the turbinate can be undertaken with use of phase contrast microscopy. Significant abnormalities on this test constitute an indication for electron microscopic examination of cilia. Confirmation of reports of very low nasal NO in primary ciliary dyskinesia means that a nasal NO concentration of greater than 250 parts per billion (ppb) excludes this diagnosis with 95% sensitivity.

Nasal Airway Tests

Dynamic tests include nasal inspiratory peak flow measurement (for which the patient, wearing a mask attached to a peak flow meter, sniffs hard with a closed mouth) and rhinomanometry. The latter technique is used to assess nasal airway resistance by measuring airflow across a pressure gradient with use of a pneumotachograph and face mask. Acoustic rhinometry uses a sound pulse to measure the nasal cross-sectional area.

Nasal airway resistance can change very dramatically within a few minutes. Congestion is produced by engorgement of venous erectile tissue within the nose; the mucous membrane receives dense, autonomic innervation. Nasal resistance falls with administration of epinephrine and other sympathomimetic drugs but also with exercise, rebreathing, and adoption of the erect posture. Nasal resistance increases in rhinitis and, in some persons, with ingestion of alcohol, aspirin, and other drugs, as well as when the supine posture is adopted.

Evaluation for Suspected Allergic Rhinitis

The diagnosis usually is obvious from a careful history and examination but can easily be missed in chronic blockers; thus, skin prick tests should be performed in all patients presenting to the rhinitis clinic. Skin tests that use allergen extracts to elicit IgE-mediated immediate hypersensitivity responses can be used to confirm or exclude atopy. If all of the skin test results are negative, the history may still suggest local nasal allergen-specific IgE driven disease. However, positive results on skin testing do not confirm the diagnosis, because many asymptomatic persons exhibit a positive response to common allergens. Correlation between skin prick tests and history should be sought, because occasionally it is possible to identify an allergen that can be avoided. Measurement of total IgE is not helpful; however, measurement of specific IgE levels to common aeroallergens by means of immunologic testing may be useful, and the results show a good correlation with skin test results. Occasionally, particularly where occupational rhinitis may be a possibility, nasal challenge and provocation tests (with the offending allergen, histamine, aspirin, or methacholine) may be required.

Nasal Cytology

It may be of value to determine the presence or absence of eosinophils in patients who have perennial rhinitis and negative results on skin testing and who are not atopic. Subsets of these patients have nasal eosinophilia and are more likely to demonstrate allergic features such as sneezing and congestion; they are more likely to respond to topical corticosteroids.

Treatment

Allergic Rhinitis

Treatment for AR has five major components:

• Patient education (vital)

Identify and Avoid Allergens

In practice, the identification and avoidance of allergens may be extremely difficult. House dust mites are responsible for much perennial AR. Mites flourish at temperatures of approximately 15°C and 60% to 70% relative humidity, conditions present in many homes that contain central heating. They flourish particularly in soft furnishings, mattresses, pillows, and bed covers, as well as in carpets. Allergen avoidance and measures to reduce the load (i.e., wooden floors rather than carpets, regular vacuum cleaning, and barrier covers for mattresses and pillows) effectively reduce rhinitic symptoms. Acaricides that kill the mites do not eliminate the antigen, which is present in the fecal pellets. Removal of a pet may not abolish symptoms, because allergens may persist in rooms for many months, if not years. Avoidance of pollen is difficult, but vacationing away from pollen areas or, failing that, staying indoors when the pollen count is high, closing windows, shutting car windows, and avoiding open grassy spaces may help.

Medical Suppressive Therapy

The classification system and treatment plan for AR according to ARIA are shown in Figures 37-7 and 37-8, respectively. Intermittent rhinitis is defined as that accompanied by symptoms for fewer than 4 days per week or fewer than 4 weeks in total. Persistent symptoms are defined as those present for more than 4 days per week and lasting more than 4 weeks in total duration. Classification of disease severity as mild, moderate, or severe is based on effects on day-to-day well-being and ability to sleep or work. Thus, the diagnosis takes into account severity of disease in terms of effects on quality of life, as well as disease duration, which in turn guides pharmacotherapy and immunotherapy intervention. However, in view of the spectrum of respiratory diseases (i.e., NAR) that can manifest with rhinitis symptoms and the possible need for use of allergen-specific immunotherapy, the key concept of seasonality is very useful in the diagnostic algorithm and has been retained by several guidelines and standards of care documents such as that from the British Society for Allergy Clinical Immunology (BSACI).

Figure 37-7 Classification of rhinitis by frequency and severity.

(From Bousquet J, Van Cauwenberge P, Khaltaev N, et al: Allergic rhinitis and its impact on asthma, J Allergy Clin Immunol 108[suppl]:S147–S334, 2001.)

Figure 37-8 Approach to treatment of rhinitis based on the classification shown in Figure 37-7. CS, corticosteroids; H₁, histamine receptor type H₁; LTRA, leukotriene receptor antagonist.

(From Bousquet J, Khaltaev N, Cruz AA, et al: Allergic Rhinitis and Its Impact on Asthma [ARIA] 2008 update [in collaboration with the World Health Organization, GA[2]LEN and AllerGen], Allergy 63[Suppl 86]:8–160, 2008.)

Topical Corticosteroids

Metaanalysis has shown that topical corticosteroids constitute the most effective treatment for AR. Regular use is needed, and preseasonal dosing reduces development of seasonal rhinitis symptoms. For polyps or marked nasal blockage, betamethasone drops or oral corticosteroids for the first 2 weeks of therapy may be needed, followed by a nonabsorbable drop formulation of fluticasone propionate (Flixonase Nasule), particularly in the long term for polyp management (Figure 37-9). Side effects of topical corticosteroids include local irritation and minor epistaxis. Systemic steroid absorption is low except with betamethasone and dexamethasone, which should be reserved for only short-term use.

Figure 37-9 Correct instillation of nasal drops.

(Modified from Scadding GK, Durham SR, Mirakian R, et al: BSACI guidelines for the management of allergic and non-allergic rhinitis, Clin Exp Allergy 38:19–42, 2008.)

Sodium cromoglycate is less effective when given nasally but may be suitable for small children, whereas severe conjunctival symptoms are best treated with sodium cromoglycate or nedocromil sodium. Corticosteroid eye drops are to be avoided.

Antihistamines

Antihistamines provide excellent relief of sneezing, itching, and rhinorrhea, but not congestion; oral ones have the advantage of being effective for mouth and eye symptoms. Chlorpheniramine is best avoided because it is sedating and reduces driving ability and academic performance. Newer histamine H₁ antagonists are largely nonsedating. Certain molecules—terfenadine, astemizole, and diphenhydramine in particular—can produce QT prolongation and fatal cardiac arrhythmias, especially with high blood levels from overdosing or combination of an antihistamine with another hepatically metabolized drug. Fexofenadine, cetirizine, levocetirizine, and desloratadine seem safe in this respect and possess some measurable nasal unblocking activity. Azelastine and levocabastine are useful topical antihistamines. Rupatadine can block both histamine and platelet-activating factor.

Other Agents

Vasoconstrictors are useful in the short term for relief of marked congestion, but long-term use must be avoided because of the risk of rhinitis medicamentosa. Anticholinergics such as ipratropium bromide may be useful if extensive, watery secretion is a major problem. Antileukotrienes are similar in efficacy to antihistamines for treatment of AR, with no major benefits from a combination of the two. In some patients with polyps, however, these agents can reduce symptoms and polyp size when used with a topical steroid. Douching the nose with isotonic saline can reduce AR symptoms and improve endoscopic appearance and quality of life in chronic rhinosinusitis.

Immunotherapy

Immunotherapy is the only treatment that has been shown to influence the course of disease. Three years of treatment reduces symptoms for several years thereafter. In children with rhinitis, subcutaneous immunotherapy reduces progression to asthma as determined by follow-up evaluation at 3, 5, and 10 years. Reduction in the rate of new allergic sensitization also has been noted.

Desensitization involves the administration of increasing doses of relevant allergen extract by subcutaneous injection over a period of months and has been shown to effectively diminish symptoms of allergic seasonal rhinitis in response to grass pollen, ragweed pollen, and birch pollen. Some studies also suggest efficacy with house dust mite and some animal danders. Desensitization has largely been superseded by the success of effective medical therapy in the suppression of allergic inflammation and is therefore reserved for nonresponders with severe disease. It is not always effective, and concerns have been raised regarding occasional anaphylactic reactions and deaths after the procedure, so it must be undertaken by well-trained personnel in a hospital setting with cardiorespiratory resuscitation facilities at hand.

Safer sublingual approaches have now been demonstrated to be effective, and grass pollen tablets are now available; trials with house dust mite sublingual preparations are ongoing. The first sublingual dose needs to be given under medical supervision; thereafter, each dose is taken every day at home. Eight weeks of preseasonal therapy followed by continuation throughout the pollen season is suggested, with subsequent continuation of this treatment for 3 years. However, pre- and co-seasonal therapy repeated over 3 years may suffice. The benefits of grass pollen sublingual immunotherapy last for at least 2 years after cessation of treatment.

Surgical Intervention

When medical treatment is only partly successful, a full otorhinolaryngologic assessment is performed, because correction of a deviated nasal septum or reduction of hypertrophied mucosa may help relieve the symptoms. With coexistent chronic sinus infection, functional endoscopic sinus surgery (FESS) techniques may be necessary to facilitate sinus drainage, aeration, and access for medications, although a recent study showed that medical therapy with corticosteroids and long-term macrolides was equally effective. Both resulted in improved control of concomitant asthma.

Infections

Acute Coryza (The Common Cold)

Treatment is essentially symptomatic, with analgesics, antipyretics, rest, and broad-spectrum antibiotics if secondary infection is present. Oral or topical nasal zinc may decrease symptoms and their duration.

Noninfectious Causes

Intrinsic Rhinitis

Anticholinergics (e.g., ipratropium bromide) are useful for troublesome rhinorrhea (i.e., intrinsic rhinitis) (Figure 37-10), particularly when eosinophils are absent from nasal secretions. When eosinophilia is present, a response to topical corticosteroid therapy is usual. α-Agonist decongestants, such as pseudoephedrine and xylometazoline, should be used sparingly. Surgical procedures may help if nasal obstruction is predominant.

Figure 37-10 Management of chronic rhinosinusitis without nasal polyps (CRSsNP). ACE, angiotensin-converting enzyme; ANCA, antineutrophil cytoplasmic antibodies; CBC, complete blood count; CT, computed tomography; ENT, ear-nose-throat; ESR, erythrocyte sedimentation rate; LRT, lower respiratory tract; OME, otitis media with effusion; PCD, primary ciliary dyskinesia.

(Modified from Scadding GK, Durham SR, Mirakian R, et al: BSACI guidelines for the management of allergic and non-allergic rhinitis, Clin Exp Allergy 38:19–42, 2008.)

Structural Defects

Occasionally, topical corticosteroid therapy may ameliorate rhinitis secondary to structural defects, but normally surgical correction is required.

Immune Defects

Therapy of immune-related rhinitis is directed toward correction of the underlying defect.

Mucus Clearance Defect

It is not possible to correct the underlying mucus clearance defect, so therapy relies on regular douching, improved drainage and aeration, and prevention of secondary infection.

Granulomas

Appropriate, specific antimicrobial therapy is required for infectious causes of granulomatous disease. Sarcoidosis that involves the nose responds to either local or systemic glucocorticoid therapy. Each case will require a specific targeted approach.

Drug-Induced Disease

A careful drug history must be taken and the incriminated drug excluded.

Acute Rhinosinusitis

Most cases of ARS resolve spontaneously. Analgesics and antipyretics provide symptomatic relief, but aspirin must be avoided in persons who may be hypersensitive. Acetaminophen (paracetamol) and codeine are satisfactory alternatives. Decongestants such as oxymetazoline and xylometazoline reduce edema but compromise mucociliary activity and are not recommended. Broad-spectrum antibiotics are appropriate for severe disease with a number needed to treat of 8. These antimicrobials must have activity against the most common pathogens, namely S. pneumoniae, H. influenzae, and M. catarrhalis. Agents such as amoxicillin, trimethoprim-sulfamethoxazole (co-trimoxazole), or a macrolide such as clarithromycin are appropriate. Amoxicillin-clavulanate has the added advantage of activity against S. aureus and penicillin-resistant H. influenzae. If anaerobic infection is suspected, a combination of amoxicillin-clavulanate and metronidazole or clindamycin may be used.

Recent evidence suggests that topical nasal corticosteroids help, either in conjunction with antibiotics or alone, to reduce symptom severity and hasten recovery. There is no suggestion that they lead to more recurrences or to more adverse events. In a number of rhinosinusitis scenarios, acute intervention will be required, as shown in the EPOS guidelines (Figure 37-11, A and B).

Figure 37-11 Treatment schemes for acute rhinosinusitis (ARS): A, in children; B, general approach. CT, computed tomography; IV, intravenous.

(From Fokkens W, Lund V, Mullol J, et al: European position paper on nasal polyps 2007, Rhinology 45[Suppl 20]:1–136, 2007.)

Chronic Rhinosinusitis

With CRS, the aims of treatment are to remedy any underlying cause (e.g., immunologic defect, anatomic abnormality that prevents drainage) and to restore the integrity of the mucous membranes to allow normal ventilation of the sinuses and drainage. Nasal douching with saline relieves symptoms and improves the endoscopic appearance. Topical corticosteroids may help to reduce mucous membrane swelling and improve drainage. Initially, betamethasone drops taken in the head-down position (see Figure 37-9) are briefly used, but nonabsorbed fluticasone propionate (Flixonase Nasule) is safer for long-term use. Prolonged courses of macrolide antibiotics produced improvements equivalent to those achieved with FESS, possibly because of their antiinflammatory activity. Amphotericin douching is ineffective.

Surgical Interventions for Acute and Chronic Rhinosinusitis

Major changes have occurred in recent years as a result of the advent of high-resolution CT scans and FESS. Better demonstration of the nasal and sinus anatomy is achieved with CT scans, as well as of the important ostiomeatal complex, the vital region in which sinus drainage by mucociliary clearance occurs. Obstruction in this zone is very important in the generation of chronic sinus disease. The main aim of FESS is to restore adequate drainage for the frontal, maxillary, and ethmoidal sinuses (see Figure 37-4). When this fails, more radical sinus surgery may be needed, but complete investigation for underlying medical factors (e.g., immune deficiency) should be undertaken first.

Nasal Polyps

Unilateral nasal polyps (Figure 37-12) warrant appropriate investigation to exclude transitional cell papilloma, squamous cell carcinoma, encephalocele, or other pathologic conditions. In the absence of contraindications and clinical suspicion regarding the nature of the polyp, a medical polypectomy accomplished with use of prednisolone (0.5 mg/kg, enteric-coated) plus betamethasone drops (two in each nostril three times a day with the head upside down) for 5 days, up to 14 days as indicated by clinical need, can be as effective as surgery and is superior with respect to control of concomitant asthma. This should be followed by long-term corticosteroid drops—initially betamethasone for 2 weeks, then almost nonabsorbed fluticasone propionate. Subsequently, a trial of a leukotriene receptor antagonist should be undertaken for 2 to 4 weeks, with continuation if beneficial. Other measures being evaluated include regular saline douching and topical lysine aspirin in patients sensitive to this on nasal challenge. Failure of medical treatment is an indication for surgery.

Figure 37-12 Treatment of chronic rhinosinusitis with nasal polyps (CRSwNP). Symptoms and signs are rated using a visual analogue scale. See Figure 37-10. CT, computed tomography; ENT, ear-nose-throat; LRT, lower respiratory tract; LTRA, leukotriene receptor antagonist.

(Modified from Scadding GK, Durham SR, Mirakian R, et al: BSACI guidelines for the management of rhinosinusitis and nasal polyposis, Clin Exp Allergy 38:260–275, 2008.)

Patients with aspirin-exacerbated respiratory disease should be warned to avoid all COX-1 inhibitors and to watch for exacerbation by similar substances: “E number” foods, preservatives, high-salicylate foods. Most patients can tolerate paracetamol 500 mg or a COX-2 inhibitor.