Allergic and Nonallergic Rhinitis PDF

40 Allergic and Nonallergic Rhinitis Jonathan Corren, Fuad M. Baroody, Alkis Togias CONTENTS Introduction, 636 Pathophysiology, 643 Epidemiology, 636 Treatment, 647...

40 Allergic and Nonallergic Rhinitis Jonathan Corren, Fuad M. Baroody, Alkis Togias CONTENTS Introduction, 636 Pathophysiology, 643 Epidemiology, 636 Treatment, 647 Diagnosis, 638 Summary, 651 SUMMARY OF IMPORTANT CONCEPTS International Study of Asthma and Allergies in Childhood (ISAAC) was initiated to establish the prevalence of allergic diseases in 257,800 school The incidence of chronic rhinitis has increased significantly during the last children aged 6 to 7 years and in 463,801 children aged 13 to 14 years two decades, particularly in Western countries. using standardized, validated questionnaires.1 Phase 1 of ISAAC, which Moderate to severe rhinitis adversely affects performance at work and began to enroll patients in 1992, sought to establish prevalence rates on school, thereby contributing significantly to the indirect economic costs of all continents in nearly 60 countries; Phase 2 investigated variables con- this disease. tributing to rhinitis (e.g., environmental exposures); and Phase 3 provided The presence of rhinitis has significant effects on the development and follow-up data on the patients at least 5 years after entry into the study. severity of other disorders, including bronchial asthma, sinusitis, middle In Phase 1, the prevalence rates for rhinitis collected across all centers ear disease, and dental malocclusion. ranged from 0.8% to 14.9% (median, 6.9%) in the 6- to 7-year-olds and The two most common rhinitis syndromes are allergic rhinitis and idiopathic from 1.4% to 39.7% (median, 13.6%) in the 13- to 14-year-olds.1 The rhinitis, and differentiation of these two disorders requires an assessment highest prevalence rates for rhinitis were observed in parts of Western of specific immunoglobulin E (IgE). Europe, North America, and Australia, whereas the lowest rates were A small subset of patients with rhinitis may have symptoms caused by strictly found in parts of Eastern Europe and south and central Asia. localized allergic mechanisms with no systemic evidence of specific IgE. The Phase 3 analyses revealed that the prevalence rates had increased, Although rhinitis can be treated effectively with a number of medications, with 12-month prevalence rates of 1.8% to 24.2% in children aged 6 both over-the-counter and prescription products, allergy immunotherapy to 7 years (median, 8.5%) and 1.0% to 45% (median, 14.6%) in 13- remains the only disease-modifying treatment capable of causing long-term to 14-year-olds.2 In the 6- to 7-year-old group, most centers (67%) improvement with respect to nasal symptoms and reduction in incident recorded significant increases in prevalence, 14% showed a decrease, and cases of asthma. 19% were stable. In the 13- to 14-year-old group, 45% had increases, 25% showed a decrease, and 30% were stable. These findings strongly indicate that the prevalence of rhinitis has increased over a relatively INTRODUCTION short period of time, mostly in Westernized countries with a higher Chronic rhinitis is an increasingly common condition that is now rec- standard of living. ognized to have a major impact on human health. Persistent nasal Subgroup analyses of the ISAAC cohort have provided additional dysfunction may have significant effects on physical and emotional important insights into the natural history of allergic rhinitis. In a functioning which result in absences from school and work, reduced prospective substudy following 2810 German children from age 9 to worker productivity, and impaired school performance. In addition, 11 years until age 15 to 18 years,3 the incidence of allergic rhinitis chronic nasal inflammation may aggravate or lead to the development increased from an initial rate of 7% to 14%. In a similar study of 467 of other significant disorders, including asthma, rhinosinusitis, and children assessed at age 3 years and again at 13 years, the 12-month middle ear disease. Recent improvements in our understanding of the prevalence rose from 6% to 24% in children without a family history pathologic mechanisms of rhinitis are providing key insights into the of allergy and from 13% to 44% in those with at least one allergic development of new treatments, including novel immunologic therapies. parent.4 These longitudinal data offer compelling evidence that the This chapter presents an overview of the epidemiology, diagnosis, patho- incidence of allergic rhinitis increases significantly as children grow physiology, and treatment of allergic and nonallergic rhinitis. from childhood into adolescence. Historically, the available data regarding the epidemiology of chronic EPIDEMIOLOGY rhinitis in adults are much more limited. Based on data for 15,394 adults 20 to 44 years of age, in the European Community Respiratory Health Incidence and Prevalence Survey I (ECRHS I), the prevalence of allergic rhinitis ranged from Allergic Rhinitis. The increase in the prevalence of allergic diseases 4.6% in Oviedo, Spain, to 31.8% in Melbourne, Australia.5 In the most began to garner attention from epidemiologists in the late 1980s. The recent National Health and Nutrition Examination Survey (NHANES), 636  CHAPTER 40 Allergic and Nonallergic Rhinitis 637 conducted in the U.S. between 2005 and 2006, total immunoglobulin E allergic rhinitis.14,15 Although the question of diet and allergy has not (IgE), specific IgE, and nasal symptoms were assessed in 7398 patients, been definitively answered, diets high in antioxidants and omega-3 fatty 4492 of whom were older than 20 years of age.6 The 12-month preva- acids and low in certain fats may be specifically beneficial to overall lence of rhinitis for the entire cohort was 23.5%, with a peak of 31.3% health compared with the more typical Western diet. in patients 40 to 49 years of age. For the group as a whole, 24% had seasonal rhinitis and 10% had perennial rhinitis. Of importance, 60% Quality of Life and Economic Impact of patients with rhinitis exhibited positive reactions for specific IgE. Large, population-based studies have revealed that chronic rhinitis These findings suggest that chronic rhinitis affects close to one third significantly impairs health-related quality of life. Questionnaires that of the adult population in countries like the United States and that a focus on general quality of life (as used in the SF 36 Health Survey) majority would be classified as allergic. have demonstrated significant decreases in physical functioning, energy, general health perception, social functioning, emotions, mental health, Risk Factors and pain in patients with moderate to severe perennial allergic rhinitis A number of characteristics and exposures in early childhood may act compared with control subjects.16 In particular, individuals experiencing to increase the risk of developing rhinitis (Box 40.1). Gender has been at least 1 month of rhinitis symptoms per year noted the most significant identified as a potential factor in the development of rhinitis, and an impairment of quality of life, with repeated need to blow the nose, analysis of 8486 patients who participated in the ECRHS I study revealed disrupted sleep, and inability to concentrate listed as the most severe that the crude lifelong incidence of rhinitis was approximately 14% problems.17 Sleep loss may play a key role in determining quality of life higher in women than in men; this predilection was heavily weighted in that it may lead to daytime fatigue and poor concentration in school, in adult-onset disease.7 Regarding the relationship between outdoor air resulting in learning impairment.18 pollution and development of rhinitis, conflicting data have emerged Quality-of-life questionnaires reveal that chronic rhinitis may influ- from a limited number of studies. Although a large analysis from the ence mood and cognitive function. Studies conducted during and after ISAAC study did not demonstrate a relationship between particulate air the allergy season reveal that subjects with seasonal allergic rhinitis had pollution (defined as presence of “coarse” airborne particles less than significant decreases in verbal learning, decision-making speed, psy- 10 μm in diameter [PM 10]) and the development of rhinitis,8 increased chomotor speed, reaction time tests, and positive affect scores compared levels of self-reported exposure to truck traffic were associated with with those reported for nonallergic control subjects.19 significantly higher prevalence of symptoms.9 Parental tobacco smoking, Rhinitis symptoms also have been found to impair productivity in particularly by the mother, also has been identified as a significant risk the workplace. In studies using an instrument designed and validated factor in the development of rhinitis in childhood.10 to measure the effects of rhinitis on work activities (Work Productivity A number of other factors may have a protective effect against the and Activity Impairment–Allergy Specific [WPAI-AS]), moderate to development of rhinitis (Box 40.1). The number of siblings at home severe seasonal allergic rhinitis symptoms were determined to be respon- and use of day care are inversely correlated with the risk of developing sible for 23% to 40% impairment of normal productivity at work.20,21 rhinitis.11 It is likely that sibling number is acting as a surrogate marker for viral respiratory infection frequency in early childhood, which Associated Diseases promotes a nonallergic T helper cell phenotype. Airborne allergen Asthma. Approximately 40% of patients with chronic rhinitis have exposure has been cited as another possible factor. An ecologic analysis asthma, and more than 80% of patients with asthma suffer with persis- of ISAAC data investigated the effects of pollen exposure on the preva- tent nasal symptoms.22 This close relationship suggests that modulation lence of allergic rhinitis in 13- to 14-year-olds. A significant inverse of nasal function and/or nasal inflammation may have an impact on association was found between grass pollen counts and lifetime preva- the lower airways. In histopathologic terms, both allergic rhinitis and lence of the symptoms of allergic rhinitis.12 Rather than a direct effect asthma are chronic inflammatory diseases of the airways sharing similar of pollen, this relationship has been attributed to the effects of rural mediators, patterns of cellular infiltration, and immunologic regulation. living and the likely presence of endotoxins in the immediate environ- In patients with allergic rhinitis and no clinical or physiologic evidence ment.13 Dietary factors also have been implicated in the development of asthma, inflammation frequently is present in the bronchi.23 Lower of rhinitis. Specifically, a number of small, cross-sectional, population- airway inflammation in rhinitis patients has physiologic consequences: A based surveys have suggested that the so-called Mediterranean diet, significant proportion of patients with nasal allergy exhibit nonspecific which is replete with fresh fruits and vegetables and whole grains and bronchial hyperresponsiveness in the absence of asthma symptoms.24 low in saturated fats, may reduce the chances of having asthma and Some data suggest that nasal allergic responses can have a direct impact on both bronchial reactivity25 and bronchial inflammation.26 Nasal disease is an important risk factor for worsening asthma in patients who have both rhinitis and asthma. The frequency of both BOX 40.1 Factors That Influence the emergency department visits and hospitalizations is greater in patients Development of Allergic Rhinitis with moderate to severe rhinitis than in patients who have mild or no rhinitis.27 Allergic rhinitis, particularly perennial disease, also is a sig- Increased Risk nificant independent risk factor for the development of asthma.28 Small Female gender studies indicate that patients with rhinitis who have concomitant bron- Particulate air pollution chial hyperresponsiveness are at highest risk for this outcome.29 Maternal smoking Decreased Risk Rhinosinusitis. Rhinosinusitis is common in patients with allergic Increased number of siblings rhinitis. As many as 30% of patients with acute sinusitis, 67% with Grass pollen counts unilateral chronic sinusitis, and 80% with bilateral chronic sinusitis Farm environment have allergic rhinitis.30 Nasal allergy most likely precipitates acute sinusitis Mediterranean diet by inducing sinus ostial edema, resulting in impairment of sinus drain- age, a shift to anaerobic conditions inside of the sinus cavity, and finally 638 SECTION E Respiratory Tract bacterial proliferation. The relationship between allergy and chronic suggests the presence of IgE-mediated allergy. Along with these protein- sinus disease is more complex and involves antistaphylococcal IgE anti- based allergens, other triggers include airborne substances traditionally bodies in some patients.31 categorized as irritants, including volatile organic compounds (e.g., perfumes, paint, cleaning fluids, cooking odors)42 and particulates (e.g., Otitis Media With Effusion. A considerable proportion of patients outdoor air pollution, road dust, construction dust), which appear to with allergic rhinitis have concomitant otitis media with effusion be important in provoking nonallergic rhinitis but may affect allergic (OME).32 Pollen exposure causes eustachian tube dysfunction, which patients as well. Changes in climatic factors, such as temperature, humid- induces negative pressure in the middle ear space, followed by transu- ity, and barometric pressure, are similarly important in nonallergic dation of fluid.33 rhinitis.43 The possibility of work-related symptoms should always be investigated, followed when indicated by a thorough review of potential Sleep Disorders. Adults and children with allergic rhinitis frequently triggers in the workplace. Finally, a complete list of current medications have poor-quality sleep, including difficulty getting to sleep, waking up should be collected, because the principal cause of nasal symptoms may during the night, and lack of a “good night’s sleep.”34 Nasal obstruction be drug-related (see Table 40.2).44 associated with allergic rhinitis is a risk factor for a variety of problems during sleep, including microarousals, hypopneas, and apnea. Physical Examination Routine Examination. The routine physical examination provides Dental Malocclusion. Persistent, severe rhinitis in children may cause important information regarding both the cause and severity of rhinitis, chronic mouth breathing, which has been linked to alterations in the as well as potential comorbid conditions, such as conjunctivitis, otitis, palatal anatomy and dental malocclusion.35 Although a more recent asthma, and atopic dermatitis. Additionally, in young children the study did not demonstrate an association between allergic rhinitis and examination may suggest the presence of dental malocclusion and/or malocclusive disease,36 this question has yet to be fully resolved. facial deformities (e.g., retracted mandible, high-arched palate) that may result from chronic, severe nasal obstruction.45 DIAGNOSIS The nose should first be examined for outward signs of prior bony fractures (seen as deformities of the nasal bridge), asymmetry of the History nostrils, and in children, a transverse crease over the lower portion of Typical signs and symptoms of chronic rhinitis include some combina- the nose caused by repetitive pushing of the nose upward in response tion of congestion, sneezing, rhinorrhea (anterior and/or posterior), to nasal itching or discharge. The interior of each nostril should be and pruritus of the nose, eyes, oral mucosa, or face. Nasal congestion carefully examined using either a handheld otoscope or nasal speculum frequently alternates between both sides of the nose as a function of and headlamp. In patients with moderate to severe mucosal swelling the physiologic nasal cycle.37 In addition, during sleep, the dependent of the inferior or middle turbinates, the examination also should be side of the nose may become preferentially obstructed.38 Persistent uni- conducted after the instillation of a topical decongestant such as phenyl- lateral obstruction strongly suggests the possibility of an anatomic defect ephrine. The nasal airway should be examined systematically, to look (e.g., nasal septal deviation, concha bullosa of the middle turbinate), for and establish the degree of swelling and color of the mucosa; the inflammatory mass (e.g., nasal polyp), or tumor. Sneezing may be presence, color, and consistency of secretions; alterations in internal extremely variable but in allergic disease is often marked by explosive structures (e.g., septal deviation or perforation); and the presence of paroxysms of 5 to 10 sneezes or more. In most of the rhinitis syndromes, any abnormal mass lesions (e.g., nasal polyp) or foreign body. The rhinorrhea fluid most often is clear to white in color, and the presence mucosa in patients with symptomatic nasal allergy or nonallergic rhinitis of purulent secretions strongly indicates the possibility of chronic sinusitis with eosinophilia most often is swollen and pale in color, whereas patients or atrophic rhinitis. Ocular signs and symptoms, including redness, with idiopathic rhinitis more typically have pink or erythematous mucous itching, and watering, constitute a major cause of suffering in at least membranes. Great variability in appearance of the nasal airway is the half of the patients with allergic rhinitis,39 the presence of which will rule, however, and these characteristics are not reliable for establishing dramatically alter which therapy is selected. Other signs and symptoms, a diagnosis. In patients with most forms of chronic rhinitis, the discharge such as headache, a feeling of facial fullness, reduction in or loss of is clear to white in color; the presence of discolored secretions suggests sense of smell, cough, and halitosis, should be noted, because presence chronic rhinosinusitis. Crusting, particularly with dried blood, should of any of these will affect both the diagnosis and choice of treatment. alert the physician to the possibility of atrophic rhinitis. An anterior When anosmia is the most prominent symptom and nasal or ocular nasal septal deviation may be easily visible, whereas more posterior symptoms are minimal or absent, primary central nervous system lesions abnormalities may be detected only with flexible rhinoscopy or com- should be considered.40 puted tomography (CT) imaging. Nasal polyps most commonly are Once the spectrum of symptoms has been established, the presence seen coming from the superior portion of the airway and are not dif- of temporal patterns should be sought. Rhinitis symptoms, irrespective ficult to distinguish from turbinates by virtue of their gray, glistening, of cause, often are most intense during the early morning hours as a “grapelike” appearance. consequence of circadian variations in inflammation.41 A decrease in Examination of the eyes most often reveals conjunctival injection symptoms throughout the day, especially when the patient moves out in patients with allergic rhinitis, which may be associated with erythema of doors, suggests the presence of an indoor allergen (e.g., house-dust and bogginess of the upper and lower eyelids brought on by frequent mite, animal dander, cockroach, or mold), whereas clear-cut worsening of rubbing. Cyanosis of the infraorbital tissues (“allergic shiners”) is thought symptoms in outside environments indicates the probability of allergy to to be caused by venous stasis and may be seen with any chronic nasal an outdoor allergen (e.g., pollen, mold). Occurrence of symptoms during or sinus disorder and is not pathognomonic of allergy.46 well-demarcated seasons, as documented in the medical history, usually is diagnostic of allergic rhinitis that is related to an outdoor allergen. Fiberoptic Rhinoscopy. Visualization of the nasal airway with a Finally, determination of possible triggers may provide informa- rhinoscope may serve as a very useful adjunct to the routine examina- tion that is critical in establishing a diagnosis. Obvious precipitation of tion.47 Flexible rhinoscopes are used regularly by otorhinolaryngologists, symptoms on exposure to house dust, furry pets, mildew, or cockroaches as well as some allergists and primary care physicians, and provide an  CHAPTER 40 Allergic and Nonallergic Rhinitis 639 enhanced view of structures in the superior and posterior regions of the sensation of nasal obstruction as well as imaging studies (i.e., CT the nose. These normally unseen regions include the posterior nasal and magnetic resonance imaging [MRI]) and physiologic measure- septum, superior nasal turbinates, middle meatus, adenoid gland, and ments (i.e., posterior rhinomanometry, nasal peak inspiratory flow eustachian tube orifices. Flexible rhinoscopy should therefore be con- rate). Whereas acoustic rhinomanometry may serve as a valuable aid sidered in cases of rhinitis in which nasal obstruction is unilateral or in assessing the nasal response to provocative challenge, the expense of refractory to therapy in the absence of any discernible anatomic cause the equipment, time required to make accurate measurements, and lack on routine examination. Rigid rhinoscopes are used nearly exclusively of additional information provided by the test have limited its role in by otorhinolaryngologists for visualizing the ostiomeatal complexes of clinical practice. the paranasal sinuses as well as performing nasal or sinus surgery. Nasal function can be assessed by measuring nasal peak flow or active rhinomanometry. Nasal peak flow may be measured as either Laboratory Testing inspiratory or expiratory flow rates; both methods are simple, quick, Testing for Specific Immunoglobulin E. Assessments of allergen- and inexpensive to do. Although nasal peak inspiratory flow rate cor- specific IgE are necessary to distinguish allergic rhinitis from nonallergic relates well with subjective measurements of nasal congestion, the results rhinitis. Allergy skin testing using the prick-puncture method is con- provided may be quite variable owing to the effort-dependent nature of sidered to provide the best combination of sensitivity and specificity, the test.55 Non–effort-dependent tests of nasal function include active although in vitro testing has demonstrated comparable performance rhinomanometry, which measures nasal airway resistance or its inverse, characteristics for some, but not all, allergens48 (see Chapter 72 for a conductance.56 Posterior rhinomanometry has a higher degree of accuracy complete discussion of skin and in vitro testing). than anterior rhinomanometry but may be too technically demand- ing for some patients to perform successfully. Anterior rhinomanom- Nasal Cytology. Cytologic stains of mucus blown from the nose or etry often is easier for patients to perform but may not be accurate epithelium scraped from the inferior turbinate can be assessed for mul- when severe unilateral nasal obstruction is present. These physiologic tiple cell types, including eosinophils and neutrophils. These stained measurements provide more objective descriptions of nasal patency; smears have been proposed as a means for differentiating allergic rhi- their cost and inconvenience, however, relegate their use primarily to nitis from nonallergic rhinitis or sinusitis.49 Although the presence of clinical research. significant nasal eosinophilia (more than 10 cells per high-power field) has an approximate 80% positive predictive value for the diagnosis of Classification of Rhinitis Syndromes allergic rhinitis, other conditions also are associated with this pattern The classification of chronic rhinitis is complex, and no mutually of inflammation, including asthma without symptoms of nasal allergy, agreed-upon scheme has been established. In the following discussion, nonallergic rhinitis with eosinophilia syndrome (NARES), and chronic the categories of classification are those commonly used to describe rhinosinusitis with nasal polyposis. Although routine use of this test for various syndromes and subtypes, which relate primarily to etiology the diagnosis of chronic rhinitis is not recommended, nasal cytology (Box 40.2). may be helpful in differentiating idiopathic rhinitis from NARES and in choosing optimal therapy.50 In addition, patients with nasal eosinophilia Allergic Rhinitis. Allergic rhinitis is caused by hypersensitivity to and a negative reaction on skin or blood allergy testing would be more airborne substances and accounts for approximately 50% of rhinitis likely to suffer from local allergic rhinitis (see Local allergic rhinitis). cases. The classic cardinal symptoms and signs of allergic rhinitis are congestion, discharge (usually clear and watery), sneezing, and pruritus Blood Eosinophils and Total Serum Immunoglobulin E. Large, of the nose, palate, throat, or ears. In approximately two-thirds of patients, population-based studies reveal that mean concentrations of total serum eye symptoms and signs may be present, including itching, conjunctival IgE and circulating blood eosinophils are increased in allergic rhinitis. injection, and watering.57 Prominent nasal symptoms of itching and Although recent analyses have demonstrated utility using a combination sneezing and ocular symptoms help to distinguish allergic rhinitis from of threshold values for total IgE and blood eosinophils,51 a great deal other causes of rhinitis.58 Patients with predominant congestion and of overlap with values in asymptomatic persons is typical, thereby limit- discharge alone, however, may still have allergy as the primary cause ing the diagnostic value of these markers. of their rhinitis. Clinical diagnosis of seasonal allergic rhinitis may be straightforward in patients who live in areas where there are clearly Radiographic Imaging. The most accurate test for evaluating possible defined pollen or mold seasons and experience purely seasonal symp- sinusitis is CT.52 Frequently, mild mucoperiosteal thickening can be toms. Symptoms that occur during the spring usually are ascribed to seen in patients with uncomplicated allergic rhinitis and NARES.53 tree pollen exposure, in summer to grass and outdoor molds, and in Radiographic studies should be considered in patients with symptoms fall to weeds and outdoor molds; precise start and stop dates of specific that are not typical of chronic rhinitis, such as chronic purulent rhinor- pollination seasons vary geographically. A large number of patients, rhea, alterations in sense of smell, or headaches, and are not responsive however, do not demonstrate this clear seasonal occurrence of rhinitis to therapy for rhinitis. and may experience intermittent symptoms of variable degree. This type of pattern prompted the development of a new system for classify- Measurements of Nasal Patency. An accurate assessment of nasal ing allergic rhinitis that characterizes allergic rhinitis by severity level airway swelling is helpful in estimating the severity of the patient’s and duration22 (Fig. 40.1). rhinitis, deciding on initial therapy, and monitoring the patient’s condi- The hallmark of allergic rhinitis is evidence of specific IgE to a tion over time. Objective evaluations of the nasal airway can be made relevant allergen. Although IgE most commonly is distributed systemi- by assessing the anatomy of the airway and by measuring nasal airflow cally and can be identified by allergy skin testing or blood assays, in a or resistance. subset of patients with allergic rhinitis, specific IgE can be identified The most commonly used technical method for examining nasal only in the nose. This finding, manifesting as local allergic rhinitis, or airway anatomy is acoustic rhinometry, which uses sound impulse entopy, has been suspected for several decades but has only recently emission to determine the cross-sectional area and volume of the undergone rigorous investigation (see Local allergic rhinitis).59 Nasal nasal cavity.54 Measurements of acoustic rhinometry correlate with allergen challenge is required to clinically confirm this diagnosis, which 640 SECTION E Respiratory Tract BOX 40.2 Classification of Chronic Rhinitis TABLE 40.1 Occupations With Increased Allergic Prevalence of Work-Related Rhinitis Systemic Category Occupation Likely Trigger Local Irritant Drywall installer Gypsum dust Makeup artist Cosmetic power, Work-Related perfume Irritant Corrosive Corrosive Janitor Ammonia Chemistry technician Hydrochloric acid Immunologic Immunologic Rhinosinusitis Immunoglobulin E Baker Grain flour Allergic Furrier Animal dander Nonallergic Livestock breeder Animal dander Veterinarian Animal dander Nonallergic Food processing worker Foodstuffs Idiopathic Pharmacist Medication powders Nonallergic with eosinophilia Low molecular Boat builder Anhydrides Exercise-induced weight Cold air-induced substances Gustatory Atrophic Medication-related Work-related rhinitis may be divided into three main categories Hormonal defined by the types of implicated substances: irritant-induced, corrosive, Aging and immunologic (Box 40.2). Irritant-induced rhinitis is caused by small Systemic diseases airborne substances not typically categorized as allergens and not shown in appropriate studies to elicit a specific immune response.61 Irritant rhinitis may be associated with exposure to a wide variety of substances, including volatile organic compounds (e.g., perfume, paint fumes), par- ticulates (e.g., chalk dust, coal dust, construction dust), and smoke (e.g., Intermittent Persistent wood-burning fire, tobacco). Whereas irritant-induced rhinitis due to < ys/week > ys/week or < weeks and > weeks volatile organic compounds may cause transient symptoms that abate once the exposure is stopped, exposure involving cleaning fluids, par- ticulates, and smoke may lead to more persistent symptoms. The second category of work-related rhinitis, corrosive rhinitis, results from exposure to a high concentration of such chemical gases, causing sufficient nasal Mild Moderate/severe inflammation that the mucosa may break down and ulcerate.62 Substances Nor and that have been linked to this condition include chlorine, sulfur dioxide, and ammonia. Some patients have reported that a single large exposure s, to these types of gases resulted in long-lasting symptoms of rhinitis; this work work clinical entity has been termed reactive upper airways dysfunction syn- drome (RUDS). The final category of work-related rhinitis, immunologic rhinitis, is characterized by a specific immune response to a substance Fig. 40.1 ARIA (Allergic Rhinitis and its Impact on Asthma) study guide- found in the workplace. Substances that most commonly cause immu- line for classification of allergic rhinitis. nologic rhinitis are proteins that elicit an IgE response, such as animal danders (e.g., in laboratory workers) or grains (e.g., in bakers). Low molecular weight substances, such as anhydrides (e.g., plastics manu- is performed primarily in research settings. In the near future, this facturers), act as haptens and induce an immunologic response similar procedure may become part of the clinically accepted evaluation for to that seen in persons with occupational asthma.63 patients with suspected local allergic rhinitis. Diagnosis of work-related rhinitis relies heavily on a history of symptomatic worsening during the work week, with improvement over Work-Related Rhinitis. Rhinitis related to the workplace is charac- the weekend and during vacations, when the putative trigger is absent. terized by intermittent or persistent nasal symptoms attributable to Symptom diaries and self-administered assessments of nasal peak flow exposures incurred in a particular work environment.60 Work-related may establish a clinical pattern suggesting that the workplace is causing rhinitis may be related to immunologic hypersensitivity, including the or aggravating symptoms. Eventually, however, symptoms may eventu- presence of IgE, or may be nonallergic in etiology. The first type of ally persist during periods away from work as mucosal inflammation work-related rhinitis is occupational rhinitis, in which the primary becomes more established, making the diagnosis more difficult to estab- cause of nasal symptoms arises from exposures occurring in the work lish. In many situations, skin or blood testing for specific IgE may be environment. The second type, referred to as work-exacerbated rhinitis, very helpful, and occasionally a provocative nasal challenge may be occurs in persons with preexisting or concurrent rhinitis that is worsened required to identify a specific causative agent. by workplace exposures. Occupations that carry a high risk for develop- ment of work-related rhinitis include laboratory workers, furriers, and Chronic Rhinosinusitis With and Without Nasal Polyps. Chronic bakers and many others (Table 40.1). rhinosinusitis (CRS) is an inflammatory disease of the paranasal sinuses  CHAPTER 40 Allergic and Nonallergic Rhinitis 641 that has been present 12 weeks or longer.64 The four cardinal symptoms Atrophic Rhinitis. Atrophic rhinitis is a chronic condition character- of CRS are mucopurulent drainage, nasal obstruction, facial discomfort, ized by symptoms of crusting, purulent discharge, nasal obstruction, and decreased sense of smell; two of these must be present, along with and halitosis.76 Diagnosis is based largely on clinical characteristics, and CT or endoscopic evidence of sinus mucosal inflammation to consider this entity should be considered in any patient who complains of sig- the diagnosis. Up to one-third of patients with CRS present with nasal nificant nasal crusting. Examination may reveal an ulcerated mucosa polyps, which are likely to cause anosmia.65 covered by thick yellow, brown, or green crusts with possible evidence of bleeding.77 The nasal cavities may be enlarged, with bowing of the Idiopathic Rhinitis. Idiopathic rhinitis, also referred to as vasomotor lateral nasal wall; in advanced cases, saddle nose deformity and nasal rhinitis, manifests most often with symptoms of nasal congestion and/or septal perforation may occur.77 watery rhinorrhea that are not elicited by exposure to specific allergens Primary atrophic rhinitis is most prevalent in areas with prolonged and often worsen acutely in response to nonspecific provocateurs, such warm seasons (e.g., India, Saudi Arabia) and is unusual in North America as inhalation of cold air, noxious odors, and airborne particulates, as well and northern Europe.78 The primary form of this disease typically afflicts as consumption of alcohol and spicy foods.66,67 However, many of these middle-aged adults, is more common in women, and is not seen in same triggers may also elicit symptoms in patients with well-documented children. Although primary atrophic rhinitis has no known specific allergic rhinitis related to the presence of nonspecific mucosal hyper- cause, many patients are found to have chronic bacterial infection of responsiveness. Patients with idiopathic rhinitis have negative responses the nose and sinuses related to any of a large number of organisms, on skin or blood tests for specific IgE, although occasionally patients may including Klebsiella ozaenae, Coccobacillus foetidus ozaenae, Pseudomonas exhibit a small number of positive reactions that do not correlate with the aeruginosa, and Proteus spp. clinical pattern of symptoms and are considered clinically irrelevant. In Secondary atrophic rhinitis most commonly occurs in older patients patients with idiopathic rhinitis, samples of nasal tissue sent for cytologic who have undergone multiple nasal surgeries.76 In addition, trauma, analysis will not demonstrate eosinophils or other inflammatory cells. irradiation, and granulomatous diseases (e.g., leprosy, sarcoidosis, Wegener granulomatosis, syphilis) of the nose have been reported to Exercise-Induced Rhinitis. Exercise may induce recurrent rhinitis result in secondary atrophic rhinitis. As in the primary disease, mani- in nonatopic patients who do not normally suffer from nasal symp- festations may include crusting, obstruction, halitosis, and recurrent toms.68 The most common clinical finding is clear, watery rhinorrhea, epistaxis. The so-called empty nose syndrome often is included with but patients also may experience acute nasal congestion, itching, and secondary forms of atrophic rhinitis.79 Empty nose syndrome usually sneezing.69 Up to 20% of elite runners and swimmers experience exercise- follows aggressive resection of the inferior and occasionally middle induced nasal symptoms during routine workouts.70 turbinates and manifests with symptoms of severe nasal obstruction and inability to sense airflow through the nose despite complete patency Cold Air-Induced Rhinitis. Nasal symptoms induced by exposure of the nasal airways.79 This clinical picture may be associated with a to cold air may occur in patients with underlying chronic rhinitis as profound sense of dyspnea in the absence of any objective findings of well as those with no chronic nasal disease.71 This form of rhinitis is pulmonary disease. characterized by watery discharge, congestion, and burning of the nasal mucosa that develop within minutes of exposure to cold air and stop Rhinitis Associated With Medications. Repetitive use of topical soon after the end of exposure. It is particularly common in areas with α-adrenergic decongestant nasal sprays (e.g., oxymetazoline, phenyl- low outdoor relative humidity, and the cold air may work in conjunc- ephrine [Neo-Synephrine]) for more than a few days may result in tion with vigorous exercise to cause very severe acute rhinitis. rebound nasal congestion,80 most likely secondary to downregulation of the α-agonist receptor.81 With long-term use of these agents, usually Gustatory Rhinitis. Gustatory rhinitis is characterized by watery rhi- several months, a chronic form of rhinitis referred to as rhinitis medi- norrhea that begins soon after beginning to eat.72 Virtually all foods camentosa ensues. This disorder most often manifests with severe nasal have been reported to cause these symptoms, but hot and spicy foods congestion without other significant symptoms. Rarely, chronic overuse are implicated most commonly.73 The discharge may be unilateral but of topical decongestants may result in septal perforation.82 Cocaine use most often is bilateral and is rarely associated with other nasal symptoms. also has been implicated in causing rhinitis medicamentosa but usually Although a small number of children and adults may acquire specific results in significantly more crusting, bleeding, and ultimately septal IgE to select foods, with consequent development of acute food-induced perforation than topical decongestant drugs.83 Physical examination in rhinitis, patients who experience recurrent nasal symptoms after eating patients with rhinitis medicamentosa often reveals swollen, red nasal virtually any food are rarely found to have an atopic etiology. Gustatory mucous membranes with minimal discharge.80 rhinitis may occur in patients with underlying chronic rhinitis or may It also has been suggested that the antibacterial agent benzalkonium be an individual’s only source of nasal symptoms. chloride, which is present in many intranasal medications, can damage the nasal mucosa. A review of 18 published studies, however, did not Nonallergic Rhinitis With Eosinophilia Syndrome. Nonallergic support this assertion,84 indicating that if a harmful effect exists, it rhinitis with eosinophilia syndrome (NARES) accounts for approximately probably is not clinically significant. one-third of the cases of nonallergic rhinitis.74 Affected patients have A number of systemic medications are associated with increased perennial nasal symptoms and signs, with congestion and clear discharge nasal symptoms, particularly congestion and rhinorrhea.85 These medi- being most prominent, although significant sneezing and pruritus are cations are believed to induce changes in nasal function by causing described as well. In addition, a small percentage of patients report inflammation, through neurogenic effects, or by unknown mecha- anosmia, which is unusual in uncomplicated allergic rhinitis.75 Nasal nisms. For most classes of medications, the evidence supporting smears reveal large numbers of eosinophils, as seen in patients with this relationship is anecdotal and not supported by rigorous inves- allergic rhinitis, despite the absence of systemic allergy as assessed by tigation. General classes of medications that have been implicated in allergy skin or blood testing.74 As noted previously, these patients may causing rhinitis symptoms include antihypertensives, drugs for erec- have a local form of allergic rhinitis in which IgE is present in the nasal tile dysfunction, psychiatric drugs, and nonsteroidal antiinflammatory mucosa but absent from other body tissues. drugs (Table 40.2). 642 SECTION E Respiratory Tract TABLE 40.2 Medications Associated With BOX 40.3 Differential Diagnosis in Chronic Chronic Nasal Symptoms Rhinitis Category Example(s) Concha bullosa Antihypertensives Angiotensin-converting enzyme inhibitors Nasal septal deviation β-Adrenergic blockers Adenoidal enlargement Amiloride Nasal polyps Prazocin Nasal cancer Hydralazine Nasal foreign body Psychotropics Risperidone Chlorpromazine Amitriptyline mucosal dryness and increased nasal airway resistance in patients who Phosphodiesterase-5 Sildenafil Tadalafil have not previously experienced chronic rhinitis. inhibitors Vardenafil In patients with previously established allergic rhinitis, advancing age may be associated with a gradual diminution in clinical symp- Nonsteroidal Ibuprofen toms.95 Immunologically, both skin tests and in vitro tests for allergy antiinflammatory drugs also decrease in magnitude during long-term follow-up.95 Despite these Others Gabapentin age-related reductions in symptom severity, quality of life related to allergic rhinitis remains significantly impaired in patients older than 65 years.96 Hormonal Rhinitis. The most frequently encountered hormonal state Rhinitis Related to Systemic Disease. A number of systemic dis- associated with rhinitis is pregnancy. The most common causes of nasal eases may be occasionally associated with symptoms of rhinitis. These symptoms requiring treatment during pregnancy include rhinitis of include granulomatous diseases (e.g., granulomatosis with polyangiitis, pregnancy, allergic rhinitis, rhinitis medicamentosa, and sinusitis.86 sarcoidosis, midline granuloma), cystic fibrosis, ciliary dyskinesia syn- Between 20% and 30% of pregnant women will acquire rhinitis of dromes, and immunodeficiencies. In most of these conditions, typically pregnancy, defined as new-onset nasal symptoms (usually congestion the nose and sinuses are affected, rather than the nose alone; the symp- and/or rhinorrhea) in the absence of another known cause that lasts 6 toms often extend to involve other organ systems, particularly the lungs; or more weeks and resolves within 2 weeks after delivery.87 The patho- and associated constitutional complaints, such as fatigue and poor physiology of pregnancy rhinitis is unknown. Although the condition appetite, are common. has been attributed to changes in estrogen or progesterone, or both, little evidence has emerged to support this assertion.88 Preexisting chronic Differential Diagnosis in Chronic Rhinitis rhinitis has been reported to worsen, improve, or remain unchanged Patients presenting with chronic nasal complaints may suffer from at approximately equal rates among pregnant women.86 These findings upper airway disorders other than rhinitis (Box 40.3). A number of are similar to those in asthma, and one study found concordance between anatomic abnormalities in the nose and pharynx can cause chronic the course of asthma and that of rhinitis during pregnancy.89 This cor- symptoms of nasal obstruction without other significant symptoms. relation suggests that mechanical factors involved in both diseases may Concha bullosa (aeration of the middle turbinate bones with expansion be similarly altered during pregnancy. Uncontrolled rhinitis during of the turbinates) is present in various degrees in up to 67.5% of the pregnancy may be a cause of severe snoring, which has been associated general population; in a small number of affected persons, however, with an increased risk of gestational hypertension, preeclampsia, and the condition is extensive enough to result in unilateral or bilateral intrauterine growth retardation.90,91 nasal obstruction.97 Nasal septal deviation can be identified in nearly Although abundant data are available to link pregnancy to nasal 20% of people, and as with concha bullosa, a fraction of that group symptoms, much less is known regarding the relationship between the will present with significant symptoms.97 Adenoidal enlargement also menstrual cycle or use of exogenous ovarian hormones (i.e., oral con- is very common. In a study limited to adults, 55% of asymptomatic traceptives, hormone replacement therapy) and rhinitis.88 Although subjects had some degree of adenoidal hypertrophy, whereas 63% of exogenous estrogen and progesterone both have been suspected of patients with nasal obstructive symptoms showed signs of enlargement.98 causing nasal symptoms, at least one carefully designed clinical trial In another study in children, approximately 55%, 35%, and 14% of the showed that hormone replacement therapy had no effect on quality of subjects had grade 1, 2, and 3 hypertrophy, respectively, and only those life, nasal airway resistance, or nasal mucociliary clearance.92 with grades 2 and 3 had symptomatic obstruction.99 These findings Hypothyroidism frequently is mentioned as a cause of chronic nasal suggest that nasal anatomic defects are common in the general popu- congestion and discharge, although the evidence linking these two con- lation and should be considered in all patients presenting with nasal ditions is limited and may merely represent the concomitant occurrence obstruction. of two common disorders.93 Children presenting with chronic unilateral nasal obstruction, fre- quently but not always associated with purulent secretions, should be Rhinitis Related to Aging. As people grow older, important changes evaluated for a foreign body in the nose.100 A peanut, bead, button, in nasal physiology occur, including a general decrease in total body piece of small plastic toy, or small battery may be pushed into the nose water content, decrease in nasal blood flow, and degeneration of mucous by the child, which then falls into a posterior position and is not always glands.94 In addition, collagen fibers in cartilage and elastic fibers in visible to inspection. Purulence indicates the probable presence of the dermis become progressively more atrophic, leading to retraction sinusitis secondary to the foreign body. of the nasal columella and downward rotation of the nasal tip.94 These Nasal cancers are very rare, constituting 3% of head and neck cancers, physiologic and structural changes often result in symptoms of nasal with a prevalence of 1 case in 100,000 people.101 Nasal cancer should  CHAPTER 40 Allergic and Nonallergic Rhinitis 643 dry air) or low pH (induced by volatile acids), and TRPA1 by carbon dioxide, noxious cold, possibly mechanical stimulation, and a variety of strong odors and other volatile compounds such as those deriving from menthol, wasabi, wintergreen, cinnamon, garlic, and tobacco. Both types of receptors can also be activated by intracellular messaging through metabolic products of lipid inflammatory mediators and by G protein couple receptors, such as the H1 receptor.109 Recently, another potentially important sensory system has been identified in the human nasal mucosa, that of solitary chemosensory cells (also known as brush cells) that carry taste receptors.110 Some of these cells, at least in rodents, are contacted by trigeminal, C-fiber sensory nerve endings and can activate these neuronal terminals through the release of acetylcholine. It is hypothesized that stimulation of taste receptors on brush cells by chemical irritants, including microbial products, can generate central and axonal reflexes, but the nature of these reflexes and the role of such cells in generating pruritus and sneezing is unknown.111 Rhinorrhea. Rhinorrhea results from excessive activation of the nasal glandular apparatus producing mucus. The nasal mucosa has a plethora of nasal glands, mucous, and serous as well as goblet cells, all contribut- Fig. 40.2 Pathogenesis of allergic rhinitis. ing to nasal secretions.112 Furthermore, nasal secretions can be enriched by plasma through passive diffusion, a phenomenon that may occur at the level of fenestrated capillaries that are abundant in the nasal mucosa. be suspected in older persons with unilateral nasal obstruction and Many products of the allergic reaction, such as histamine and brady- bleeding of gradual onset. Such patients should be referred promptly kinin, produce plasma leakage.113 This also occurs in cases of intense to an otorhinolaryngologist. activation of nociceptor nerves, presumably through antidromic release of tachykinins, such as Substance P, which are present in the nasal PATHOPHYSIOLOGY mucosa.114 The plasma contribution to the secretory response is stimulus- dependent, and measuring the protein content of nasal secretions can Mechanisms of Rhinitis Symptoms inform us as to their source.115 The diagnosis and treatment of rhinitis are based on symptoms. From The nasal glands are innervated by parasympathetic, cholinergic fibers this perspective, it is important that the pathophysiology of nasal symp- deriving from the facial and then the vidian nerve, which synapse at the toms is understood. The most common rhinitis symptoms are sneezing, sphenopalatine ganglion, before final distribution to the nasal mucosa.116 nasal pruritus, nasal congestion (obstruction), and rhinorrhea. These M3 muscarinic receptors are believed to mediate the effects of cholinergic symptoms are the product of activation of various functional elements activation of nasal glands. In addition, a role for vasoactive intestinal of the nasal mucosa (Fig. 40.2), but the nervous system of the nose peptide (VIP), which colocalizes with parasympathetic nerves, has been seems to be a pivotal controller.102 These symptoms are common in postulated in nasal glandular activation.117 Activation of the parasympa- both allergic and nonallergic rhinitis, although sneezing and pruritus thetic nasal nerve fibers can occur through central nasal reflexes originat- tend to be more prevalent in the former. ing at the nasal mucosa, as described previously. Histamine, for example, triggers such reflexes. Axonal reflexes involving antidromic stimulation of Sneezing and Pruritus. Sneezing and pruritus result from neural sensory nerve endings and release of tachykinins may also activate nasal activation triggered by external, environmental stimuli (irritants), or by glands.118 Finally, it is likely that the nasal glandular apparatus can be biologic products of a local inflammatory process. Sneezing is a central directly triggered to release mucus by some local biologic products.119,120 reflex, the afferent arm of which begins at the nasal mucosa and the efferent arm involves the motor nerves that innervate the diaphragm, Nasal Congestion. Nasal congestion occurs as a result of engorge- the accessory respiratory muscles and the larynx. Nasal pruritus is also ment of the venous sinusoids of the nasal mucosa, which are similar sensory nerve-mediated. The sensory nerves of the nose, other than to those in the cavernous bodies of erectile tissues. Sinusoids are found those for olfaction, arise from the ophthalmic (anterior ethmoidal nerve) in the inferior and middle turbinates, as well as the nasal septum.121 and maxillary branches of the trigeminal nerve.103 The terminal sensory Under conditions that promote engorgement, blood flows rapidly through nerve endings are mostly unmyelinated nociceptor C-fibers, but Aδ-fibers arteriovenous anastomoses from the nasal arterioles into the sinusoids. (and maybe even Aβ-fibers) are also present.104,105 Nociceptor nerves The flow of blood is probably controlled by a plexus of nerves, both respond to noxious environmental but also to endogenous stimuli via parasympathetic and sympathetic. Sensory nerve terminals mediating a series of receptors such as transient receptor potential vanilloid type axonal reflexes may also be involved.122 1 (TRPV1) and transient receptor potential ankyrin type 1 (TRPA1).106 Activation of sensory nerves by the products of an allergic reaction Receptors for endogenous chemicals, such as the histamine 1 (H1) recep- or by other, nonantigenic stimuli can generate central reflexes that result tor or the cysteinyl leukotriene 1 receptor (CysLTR1) are also present in nasal congestion, primarily by increased parasympathetic and pos- on nasal nerve endings.107,108 The presence of H1 receptors on nasal sibly decreased sympathetic activity induced by the efferent arm of the sensory nerve endings probably accounts for the prominent sneezing reflex.123 In addition, local production of inflammatory mediators can that occurs during allergen exposure, whereas the presence of tran- have direct effects on the vasculature. For example, leukotriene D4 can sient receptor potential channels may account for sneezing and itching induce nasal congestion without sneezing (no central reflex activity), reported upon exposure to nonantigenic irritants. For example, TRPV1 and histamine can inhibit sympathetic vasoconstriction by direct effects receptors can be activated by hypertonicity (that can be induced by very on H3 receptors.124,125 644 SECTION E Respiratory Tract have objectively documented narrowing of nasal passages 4 to 10 hours Allergic Rhinitis after antigen challenge, with a peak around 6 hours and resolution by Nasal allergen challenges (provocations) have been used for decades as 24 hours.141 a model to delineate pathophysiologic steps in allergic rhinitis. Most Humoral events. Along with increases in nasal symptoms and challenges are conducted by directly introducing allergen in extract measures of airway narrowing, increases are also observed in the levels form into the nasal cavities and have the advantage of a well-controlled of histamine, but not PGD2, in nasal secretions, suggesting that basophils, exposure. On the other hand, the doses of allergen required to elicit a which release histamine but do not produce PGD2, may be more relevant symptomatic response with direct nasal allergen challenge are high. A than mast cells in the late phase.142 more natural experimental approach is the use of environmental expo- In addition to the various preformed and newly generated inflam- sure chambers where allergen is kept airborne in a closed room under matory mediators secreted by mast cells, basophils, and other inflam- full control of atmospheric conditions and is being inhaled by study matory cells, many cytokines and chemokines have been identified in participants at normal breathing rates.126 Pathophysiologic information the nasal mucosa and in nasal secretions of allergic patients after allergen obtained from experimental models should be validated in natural provocation. Increased levels of cytokines characteristic of type 2 inflam- disease settings. This is not a simple task because, in most patients with mation, such as interleukin (IL)-4, IL-13, and IL-5 have been well allergic rhinitis, multiple allergens can be simultaneously involved, and documented in nasal secretions starting within a couple of hours after day-to-day exposure varies widely. As a result, snapshot-type evaluations allergen exposure and lasting for at least 10 hours.143 Other cytokines where an individual is only tested once have low reliability. Natural- and chemokines, such as eotaxin, granulocyte macrophage colony– setting studies need to include detailed characterization of clinical status stimulating factor (GM-CSF), IL-1, IL-6, IL-8, IL-9, and tumor necrosis and should be of longitudinal nature with multiple evaluations. factor (TNF)-α, have also been detected within several hours after provocation.144–146 Nasal biopsies following allergen challenge have con- Early Responses to Allergen. Within minutes after exposure of an firmed the presence of type 2 and other cytokines using immunohis- allergic patient to antigen, a symptomatic response occurs. The patient tochemistry for the detection of protein or in situ hybridization for the first senses tingling and pruritus, followed by sneezing, rhinorrhea, and detection of mRNA.147 With in situ hybridization, mRNA expression nasal congestion. These clinical manifestations correlate with physiologic for IL-4, IL-5, IL-13, GM-CSF, RANTES, but also for IL-10, IL-3, IL-8, changes that are measured after antigen provocation, such as increased and IL-2 but not for interferon (IFN)-γ has been reported.148 Approxi- nasal airway resistance (NAR).127 In addition to physiologic changes, mately 80% of cells positive for IL-5 mRNA were CD3+, and the rest increases are noted in the levels of several mediators including histamine, positive for tryptase.148 This indicates that T lymphocytes and mast bradykinin, tryptase, prostaglandin D2 (PGD2), leukotriene (LT) C4, LT cells are important sources of type 2 cytokines and that mast cells are B4, major basic protein (MBP), and platelet-activating factor (PAF).128–134 not only effector cells of the early allergic reaction, but also may func- Some of these mediators induce nasal symptoms by their effects on tion as immunoregulatory cells in allergic inflammation. Type 2 innate nerves and other end-organs of the nasal mucosa, as described previ- lymphoid cells may be another important source of these cytokines.149 ously. Histamine and tryptase are found in mast cell granules, and their The release of type 2 cytokines potentiates and prolongs the aftermath detection in nasal secretions after antigen provocation provides support of acute exposure to allergen. This is supported by the release of che- for mast cell degranulation during the nasal allergic reaction. PGD2 mokines, which attract new cells to the site of exposure. and the cysteinyl leukotrienes, which are newly synthesized via the Cellular events. Inflammatory cell influx occurs in the nasal mucosa arachidonic acid pathway, also are secreted by mast cells. Further evi- and in nasal secretions recovered after experimental provocation and dence for the role of nasal mast cells in the early allergic reaction is in seasonally exposed patients. Using different sampling techniques, provided by the demonstration of degranulated mast cells in nasal studies show that the predominant cell types in nasal secretions are mucosal biopsies from allergic patients after allergen challenge.135 polymorphonuclear cells and eosinophils, with mononuclear cells pre- Not all patients with rhinitis who have IgE sensitization to an allergen dominating in the nasal mucosa, raising the need for sampling both will experience an acute response upon experimental exposure to that compartments to obtain a more complete picture of the state of nasal allergen. For some allergens, such as house dust mites and grass, the inflammation.150 response to a nasal challenge can be moderately or very well predicted Typically, a small initial increase in eosinophils in nasal secretions by the magnitude of the skin test and/or the level of serum-specific is observed within 1 to 2 hours of challenge and is usually followed by IgE, whereas for other allergens, like Alternaria, predictability is poor.136–138 a peak 6 to 8 hours later. MBP, a mediator secreted by eosinophils, also This discrepancy raises the possibility that some allergens do not only is recovered in nasal lavage fluid hours after antigen provocation, and produce symptoms through IgE-mediated mechanisms or that not all its levels correlate with the number of eosinophils, suggesting that these sensitizing aeroallergens are relevant in allergic rhinitis. In considering cells influx into nasal secretions and release inflammatory mediators.151 nasal responsiveness to an allergen, additional factors should be taken Basophils constitute 1% of the recovered cells. Their number correlates into account: the nasal allergic reaction may be influenced by the reac- significantly with the levels of histamine recovered in nasal secretions tivity of the nasal mucosal end-organs to the products of the allergic during the late-phase response, supporting the concept that these cells reaction (e.g., histamine, cysteinyl-leukotrienes) as described for the are the source of the late rise in histamine.152 lower airways, by the presence of additional allergic sensitizations, as Antigen-presenting cells also accumulate in the nasal mucosa after well as by the state of the nasal epithelium, which determines the pen- allergen exposure. Dendritic cells, particularly plasmacytoid cells, can etrability of the mucosa.139,140 be detected several hours after challenge.153 These cells appear to produce less IL-10 and type 1 cytokines compared with healthy controls, and Late Responses to Allergen. The response to allergen exposure is this abnormality may perpetuate and potentiate type 2 polarization of not limited to the acute events that occur a few minutes after exposure. the immune response.154 Also following nasal allergen challenge, CD14+ Many patients continue being symptomatic for several hours, whereas monocytes, which are capable of differentiating into antigen-presenting others become relatively asymptomatic within an hour or so and then cells, are recruited within hours and appear to produce type 2 cyto- experience a late recurrence of symptoms, particularly nasal congestion, kines.155 Another important cell type in allergy, type 2 innate lymphoid which is conventionally termed late phase reaction. Several investigators cells (ILC2), is part of the population of cells recruited to the nasal  CHAPTER 40 Allergic and Nonallergic Rhinitis 645 mucosa after allergen challenge.149 ILC2s have the capacity of producing rhinitis175 and with an increased number of ILC2s in peripheral large quantities of type 2 cytokines, but what raises particular interest blood.176,177 in these cells is that they may be the conduit through which the respira- tory epithelium interacts with the immune system in bridging innate Nasal Hyperresponsiveness. Nasal hyperresponsiveness is a hallmark and adaptive immunity and promoting allergic inflammation. ILC2s of allergic rhinitis. Its clinical manifestation is reflected in the fact that carry receptors for the epithelium-derived cytokines, IL-25, IL-33, and patients complain of nasal symptoms induced not only by exposure to thymic stromal lymphopoietin (TSLP), which are collectively known allergens, but also to irritants such as strong odors and changes in as alarmins. In vitro exposure of nasal epithelial cells to various allergens atmospheric conditions.178 In the laboratory, this phenomenon has been and viruses leads to the release of alarmins through unclear mecha- studied using provocations with various stimuli, such as histamine, nisms.156 Although these cytokines are elevated in some studies testing methacholine, bradykinin, capsaicin, cold, dry air, etc. Responses are patients in natural allergic rhinitis settings and after allergen provocation compared with those of healthy controls or, in patients with seasonal in animals, it has not been clearly documented whether they are released allergic rhinitis, during and outside the pollen season. In a different upon allergen exposure in humans.146,157,158 In addition to the role played experimental setting, responses to such stimuli can be tested before by chemokines, interactions between cell-bound adhesion molecules and after provocation with allergen. and their ligands on vascular endothelial cells are probably also needed Numerous studies confirm the phenomenon of nasal hyperrespon- for cell recruitment during the late allergic response. Allergic reactions siveness using various triggers. These include histamine,179,180 metha- do upregulate adhesion molecules in the human nasal mucosa. For choline,181 capsaicin,182 AMP,183 or even chlorine gas.184 Hyperresponsiveness example, in nasal biopsy specimens, the expression of VCAM-1 is sig- is most obvious when comparing patients with perennial allergic rhinitis nificantly increased 24 hours after allergen challenge, in concert with with healthy controls but can also become evident in seasonal allergic increased eosinophils.159 Upregulation of additional adhesion molecules, rhinitis when tested in and out of season. such as ICAM-1 and E-selectin, has also been reported.160 Nasal allergen challenge in individuals with allergic rhinitis increases Systemic events. Allergen provocation also has systemic effects. nasal responsiveness to histamine and to other stimuli, compared with For example, there is evidence of increased activation of circulating baseline.185,186 Allergen-induced increases in nasal lavage eosinophils basophils, increased numbers of blood eosinophils and ILC2s that can correlate with the magnitude of the responsiveness to histamine, and be detected within a few hours, and increased serum-specific IgE against pretreatment with nasal corticosteroids suppresses allergen-induced the allergen in question that can be detected within a week.146,160–162 An histamine hyperresponsiveness.185 These studies provide clear evidence intriguing role for the effects of antigen-induced systemic inflammation that, in allergic rhinitis, hyperresponsiveness is an inducible phenom- in patients with allergic rhinitis is based on the observation that, after enon and that it is likely to be caused by allergic inflammation. nasal allergen provocation, the expression of adhesion molecules in the The nature of nasal hyperresponsiveness in allergic rhinitis is complex. bronchial vasculature also increases.160 This may explain several aspects As discussed earlier, rhinitis symptoms develop via different mechanisms of the interaction between rhinitis and asthma in patients who suffer mediated by different sets of end-organs. Furthermore, nonantigenic from both conditions.163 triggers activate different end-organs to produce a nasal response. For Recently, transcriptional signatures of immune cell genes have been example, histamine stimulates H1 receptors on nasal sensory nerves described in the peripheral blood within hours of nasal allergen provo- (most likely nociceptor nerves) and generates a central reflex leading cation, opening new opportunities for identifying mechanisms previously to sneezing and to a glandular secretory response. In addition, histamine not detectable with biased, targeted approaches.164 causes plasma leakage and, therefore, part of the secretory response Observations in natural disease settings. As discussed earlier, it may be of vascular nature. It is likely that hyperresponsiveness to his- is easier to study the pathophysiology of allergic rhinitis using experi- tamine, if measured only through induced sneezing, is related to increased mental allergen exposure, but it is important to validate the findings sensory nerve responsiveness, a phenomenon that has been extensively in natural settings. Compared with perennial allergic rhinitis, prospective studied in animal models.187 Yet, if hyperresponsiveness is measured evaluation of individuals with seasonal disease offers better confidence based on nasal secretions, the phenomenon may reflect an integration as to the validity of the pathophysiologic findings, because observations of sensory nerve hyperresponsiveness, as well as glandular and even can be made before, during, and after the pollen season, and each study vascular hyperresponsiveness.188 On the other hand, if the stimulus is participant can act as his own control. Studies on individuals with methacholine, a cholinergic agonist, hyperresponsiveness to this trigger perennial allergic rhinitis can also be conducted, but longitudinal obser- may only reflect upregulated glandular function. Although we use the vation with multiple evaluations spanning an entire year will produce term hyperresponsiveness in a generic manner, research on this topic results of higher fidelity. should be conducted under the concept that nasal hyperresponsiveness Although acute, natural exposures to allergen have not been captured is stimulus- and pathway-specific. This has significant implications if to validate the biological events associated with the early allergic response nasal hyperresponsiveness is to be targeted therapeutically. induced by a challenge, type 2 inflammation in nasal secretions and in One form of nasal hyperresponsiveness is a phenomenon known the nasal mucosa has been documented in natural allergic rhinitis, as priming, which refers to the observation that many patients with including increased numbers of mast cells in the epithelium,165,166 seasonal rhinitis report worsening symptoms as the allergy season pro- increased numbers of activated eosinophils in the epithelium and sub- gresses, despite unchanged or decreased pollen counts.189 In the experi- mucosa,165,167 and increased numbers of Langerhans cells, but not mac- mental setting, one observes a reduction in the dose of allergen required rophages in the epithelium and submucosa.168,169 As a possible mechanism to evoke a clinical response. The phenomenon was described by Connell, for cellular infiltration, enhanced expression of adhesion molecules who found that the dose of pollen necessary to create symptoms decreased such as ICAM and VCAM by the mucosal vasculature has been described more than fivefold by the fourth day of consecutive allergen challenges.190 in perennial allergic rhinitis.170 Furthermore, evidence of increased type In later studies, consecutive nasal allergen challenges using the same 2 cytokine production has been provided in nasal biopsies167,171–173 and allergen doses caused significantly more sneezing along with higher in nasal lavage fluids.174 Finally, evidence for activation of the epithelial/ concentrations of histamine and other inflammatory mediators in con- ILC2 axis has been produced with findings of IL-33 increased in nasal junction with an increase in the number of neutrophils, eosinophils, secretions both during the pollen season and in perennial allergic and basophils in nasal lavage fluid samples.191 These observations raise 646 SECTION E Respiratory Tract various hypotheses regarding the mechanisms of priming. These may spills over into the circulation and gets attached to basophils or whether involve inflammation-induced increased mucosal penetrability to allergen low-level systemic IgE production does, indeed, occur.201 and/or higher number of cellular targets for allergen leading to increased production of symptom-inducing mediators. It is also possible, however, Nonallergic Rhinitis that priming simply reflects increased mucosal end-organ responsive- The term nonallergic rhinitis encompasses many nosologic entities that ness to symptom-inducing mediators such as histamine. do not fit to a single pathophysiologic model. No systematic work to elucidate the pathophysiology of these entities has been conducted, and Integration of Pathophysiologic Events. The clinical presentation existing knowledge is rather scattered and hard to assemble into a cohe- of allergic rhinitis represents a constellation of the various pathophysi- sive framework. In summarizing this knowledge, two aspects need to ologic phenomena described previously. Sensitization of the nasal mucosa be addressed, mucosal inflammation and hyperresponsiveness or other to a certain allergen entails multiple interactions between the epithelium, functional abnormalities. ILC2s, APCs, T lymphocytes, and B cells that lead to the production of antigen-specific IgE antibodies, which then bind to mast cells and Mucosal Inflammation. The nonallergic rhinitis field suffers from basophils. Subsequent allergen exposure cross-links cell-bound specific conflicting reports regarding the presence of mucosal inflammation. IgE, leading to the release of both preformed and newly synthesized In the largest published report, among 519 consecutive patients with mediators. By acting on the end organs of the mucosa, these substances nonallergic rhinitis, 44.5% had an inferior turbinate scraping-derived produce the characteristic acute symptoms of rhinitis. In addition, cytogram that was not different from that of healthy controls (