It is clear that patients with nasal symptoms can have other sources for their symptoms than purely inflammation. Lund et al have recently suggested a classification of rhinitis into four types: structural; infectious; allergic; and “other.”¹ This system recognizes that anatomic and infectious factors may also play a role in the expression of symptoms among patients. Structural rhinitis, for example, involves the presence of anatomic abnormalities such as deviation of the nasal septum and hypertrophy of the inferior turbinates that can interfere with air flow through the nose. Infectious rhinitis includes both acute and chronic rhinosinusitis, which have significant impact on nasal inflammation and nasal symptoms. In fact, current classification schemes do not differentiate infectious rhinitis from infectious rhinosinusitis, recognizing the key role that nasal disease plays in the sinus pathology among these patients. The remaining two categories in the system devised by Lund et al, allergic rhinitis and “other” rhinitis, correspond to the categories of allergic and nonallergic rhinitis discussed above. While nasal obstruction due to anatomic deformity or variability can be important, surgical management of these conditions is beyond the scope of the present textbook. The management of patients with acute and chronic rhinosinusitis is presented in Chapter 4.

For the purposes of this chapter, the two primary noninfectious conditions responsible for nasal inflammatory symptoms will be discussed. It will focus on the presentation, pathophysiology, diagnosis and treatment of patients with allergic and nonallergic rhinitis.

▪ Allergic Rhinitis

The term allergic rhinitis (AR) refers to a condition manifested by nasal inflammation, and triggered by an immunologic response of the nasal and sinus mucosa. This immunologic response is primarily mediated by immunoglobulin E (IgE), and expressed through the influence of a number of humoral and cellular mediators. AR has traditionally been divided into two categories based upon the temporal course of the development and presentations of the symptoms: seasonal allergic rhinitis (SAR), which refers to immune-mediated nasal symptoms triggered by seasonal increases in environmental antigens, such as tree, grass and weed pollens and outdoor molds; and perennial allergic rhinitis (PAR), which refers to nasal symptoms occurring throughout the year, and generally attributed to indoor antigens such as animal dander, dust mites, cockroach, and indoor molds.²

(Reproduced with permission from Bousquet J, et al. Allergy 2002;57:841–855; Blackwell Publishing.)

▪ Nonallergic Rhinitis

Nonallergic rhinitis, in contrast to allergic rhinitis, refers to nonimmune-mediated nasal inflammation or irritation that promotes nasal symptoms such as congestion and rhinorrhea. Nonallergic rhinitis is a syndrome that cannot be explained by any uniform or consistent pathophysiologic mechanism. This condition involves many differing physiologic processes, and is often considered a “diagnosis of exclusion” among patients with nasal symptoms. Various triggers for the expression of nonallergic symptoms in the nose include infection, hormonal variability, pharmacologic agents, and autonomic dysregulation.⁴

Bachert recently divided nonallergic rhinitis into five categories based on their underlying etiology. He described these five categories as: (1) irritative-toxic (occupational) rhinitis; (2) hormonal rhinitis; (3) drug-induced rhinitis; (4) idiopathic (vasomotor) rhinitis; and (5) other forms (e.g., nonallergic rhinitis with eosinophilia (NARES)).⁵ Bachert provided specific information regarding the mechanisms and triggers for these various types of nonallergic rhinitis.

Irritative-toxic (Occupational) Rhinitis

Bachert described irritative-toxic rhinitis as rhinitis related to exposure to airborne irritants or toxic agents, such as chemicals, solvents, dyes, inks, and tobacco smoke. These irritative agents cause direct irritation of the nasal mucosa.

Hormonal Rhinitis

Hormonal influences are commonly associated with rhinitis. For example, nasal congestion is common during pregnancy, related to increased levels of various hormones.

Drug-induced Rhinitis

Bachert notes that many medications can affect nasal physiology. Many classes of medications, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and other antihypertensive agents, oral contraceptives, psychotropic medications, topical nasal decongestants, nonsteroidal anti-inflammatory medications, and phospodiasterase type-5 inhibitors (PDE-5) have been shown to have effects on the nose (Box 3.2).

Idiopathic (Vasomotor) Rhinitis

Vasomotor rhinitis is a common nonimmune condition associated with copious clear rhinorrhea and intermittent congestion. The etiology is difficult to determine, but appears to be associated with environmental irritants, changes in atmospheric conditions, and odors or aromas. It appears to be more prevalent in older than in younger adults or children

Nonallergic Rhinitis with Eosinophilia (NARES)

Patients with NARES present with paroxysmal sneezing episodes, profuse watery rhinorrhea, nasal pruritis, nasal congestion, and hyposmia/anosmia. In contrast to allergic rhinitis patients, however, these patients fail to demonstrate any evidence for allergy on testing, yet have numerous eosinophils on nasal smears.⁶ Although its etiology is unknown, NARES shares clinical characteristics with Samter’s triad (aspirin sensitivity, asthma, and nasal polyposis), and may reflect a variant of that disease.

Epidemiology and Burden of Rhinitis

Overview

As noted above, rhinitis can be defined as an inflammatory or irritative disorder of the nasal membranes. Rhinitis presents with a pattern of symptoms that usually includes sneezing, nasal itching, rhinorrhea, and nasal congestion.⁷ In addition, patients with rhinitis will often complain of changes in the sense of smell, facial pressure or fullness, headache, and aural blockage. During periods of increased symptoms, patient with rhinitis experience a significant impact on both function and quality of life.

While nasal symptoms of rhinitis can be bothersome to patients and significantly interfere with normal function, the comorbidities of rhinitis can be quite serious and even life-threatening. Rhinitis represents inflammation in one part of the respiratory system, and can be associated with other common and serious respiratory illnesses such as rhinosinusitis and asthma.⁸ In fact, among patients with asthma, the prevalence of rhinitis in that population approaches 90%.⁹ In addition, rhinitis appears to play a role in the severity of symptoms among individuals with obstructive sleep apnea.¹⁰ Furthermore, the treatment of patients with chronic rhinosinusitis is often less successful among patients with allergic rhinitis than it is among their nonallergic counterparts. Because of its functional impairment and its serious comorbidities, rhinitis is therefore not a trivial disease, but one that can have serious medical and functional consequences.

Burden of rhinitis

The economic impact of rhinitis is significant. Direct costs annually attributable to the treatment of allergic rhinitis alone were estimated in 2003 to range between US$2 and 5 billion.¹¹ In addition, the indirect costs of AR significantly contribute to the economic burden of the disease, with an estimated US$5–10 billion annually attributable to the morbidity of this common disease.¹¹ In another recent estimate, over US$6 billion was outlayed specifically for prescription medications used for treating the symptoms of allergic rhinitis.¹² Worldwide treatment of rhinitis would certainly account for a significant increment in these US figures.

In addition to the direct and indirect financial costs of allergic and nonallergic rhinitis, quality of life, daytime function, and sleep are frequently compromised among patients, not only by the disease states but also by treatments whose adverse effects further adversely impact function. Patients with allergic and nonallergic rhinitis experience a wide range of cognitive and social issues that can be disruptive in their daily activities and interpersonal relationships. Fatigue, confusion, distractibility and other cognitive symptoms are common among patients with rhinitis, and can be worsened by treatment with pharmacologic agents such as sedating antihistamines. Among children with allergic rhinitis similar effects can be seen, resulting in decrements in learning and attention in the classroom.¹³ In addition, patients with AR experience disruption in normal patterns of sleep, which can contribute to daytime symptoms.¹⁴

Prevalence of Rhinitis

Allergic and nonallergic rhinitis are common illnesses. Prevalence studies worldwide suggest that the rates of AR within the population vary between 10% and 20%.^15,¹⁶ It has been reported that 58 million Americans annually experience symptoms of allergic rhinitis, while 19 million Americans experience symptoms of nonallergic rhinitis.¹⁵ As was noted earlier, many patients have both nonallergic and allergic triggers for their symptoms. This mixed rhinitis can occur in up to 44% of patients with AR.¹⁵

In addition to these absolute values, there is evidence that the prevalence of AR is increasing. Several studies have shown that the rates of AR have increased at least twofold over the past two decades.^17,¹⁸ While several hypotheses have been suggested to explain this increasing prevalence, the reasons for this steady increase remain speculative.

Managing the Patient with Allergic Rhinitis

▪ Pathophysiology

Allergic rhinitis is an immune-mediated inflammatory condition that affects the mucosa of the nose, paranasal sinuses, and related mucosal structures. The primary mechanism underlying AR involves a type-I hypersensitivity reaction that is directed by various cellular and humoral agents. It is mediated through processes under the control of T-helper 2 cells, and involves a complex interaction of various inflammatory mechanisms. A full review of the immunology of the allergic response is presented in Chapter 1.

The allergic response in the nose is initiated when individuals come into contact with antigens to which they have been previously sensitized. IgE molecules that had been synthesized during the sensitization process to these antigens are present on the surface of mast cells, and have specific determinants available to bind to these antigens. When antigen particles bind to adjacent IgE molecules, a sequence of biochemical events occurs, resulting in degranulation of mast cells and release of preformed mediators such as histamine into the nasal tissues. This process of degranulation and histamine release is the primary process responsible for initiation of the immediate allergic response.¹⁹

Histamine binds to specific histamine-1 (H1) receptors on the surface of target cells in the nose, leading to local effects in the nasal mucosa, including transudation of plasma, engorgement and edema of the mucosa, stimulation of mucous glands to produce increased mucus secretions, and other direct inflammatory events.²⁰ In addition, histamine, as well as other mediators and neuropeptides released during the allergic response, cause stimulation of fine sensory nerves in the nasal mucosa, resulting in irritative effects such as sneezing and itching (Figure 3.2).² These events occur rapidly after exposure to a sensitized antigen, often leading to the development of symptoms within 5–10 minutes of contact. Symptoms of allergic rhinitis, such as sneezing, itching, rhinorrhea, and nasal congestion, occur as a result of these inflammatory processes that occur after exposure, and characterize the “early-phase” response to allergic stimulation.

Figure 3.2 Acute-phase mucosal response to antigen.

(Reproduced with permission from Holgate ST. Allergy, 2nd edn, figure 4.9, p. 59, published by Mosby, 2001.)

In addition to these immediate effects that occur rapidly after exposure, a second, delayed process of inflammation occurs in many patients with AR. This delayed expression of nasal symptoms is referred to as the “late-phase” response, and results in expression of symptoms at 2–4 hours after exposure or more. While the early phase response occurs primarily as a response to histamine, the late phase response is directed by other mediators such as cysteinyl leukotrienes and inflammatory cells such as eosinophils and basophils.² An appreciation of this biphasic response in AR is important in understanding the method of presentation among patients with AR and various treatment options specific for these inflammatory processes.

▪ Presentation

While allergic rhinitis can develop at any age, the majority of patients with allergic rhinitis first present with symptoms in middle childhood. Recent prevalence data suggest that up to 40% of children may express symptoms of AR in early childhood.²¹ Other studies suggest that the mean age for diagnosis of allergic rhinitis is between the ages of 9 and 11 years.¹⁶ Symptoms tend to be experienced most significantly among patients between 10 and 40 years of age, and decline somewhat thereafter. It is uncommon for patients under age 2 to experience symptoms related to allergic rhinitis. In addition, while patients may first express symptoms of allergic rhinitis in their older years, the onset of rhinitis symptoms among patients older than 55 years of age would strongly favor a diagnosis of nonallergic rhinitis.

The patient with AR will classically present with a pattern of four specific nasal symptoms, which include sneezing, nasal pruritis or itching, anterior or posterior rhinorrhea, and nasal congestion. While patients with SAR will generally demonstrate irritative symptoms such as sneezing and itching most commonly, patients with PAR will often complain more frequently about nasal obstruction, congestion, and posterior rhinorrhea (also known as postnasal drip). In addition, patients with AR often complain of other irritative symptoms of the upper airway and eyes, including symptoms such as ocular irritation, conjunctival injection, tearing, palatal itching, and aural fullness. This pattern of nasal and non-nasal symptoms is common in allergic rhinitis, but is reported infrequently among patients with nonallergic rhinitis. In addition, patients with AR often complain of other atopic diseases, either currently or by history. These patients have frequently had symptoms of eczema, asthma, or other atopic illnesses in addition to their symptoms of rhinitis.

In addition, due to the significant mucosal inflammation of the nasal and sinus membranes, and due to their concurrent nasal obstruction and congestion, many patients with both AR will report a decreased sense of smell or taste, facial pressure or pain, and temporal or frontal headache.²² These symptoms of pressure and anosmia are also common among patients with chronic sinonasal polyposis and acute and chronic rhinosinusitis.

In patients with SAR, the waxing and waning of symptoms follows the pollen counts during those seasons in which the patient has allergic sensitization to the pollens present in the environment. These symptoms will usually lag for a few days following the seasonal pollen fluctuations, and can be blunted by the use of various medications. This seasonal change in patient symptoms offers an important element of the clinical history that can be used by the clinician in confirming a diagnosis of allergic rhinitis. Seasonal changes in chronically stable symptoms among patients with PAR also suggest a seasonal component to the patient’s PAR.

In those patients with PAR, symptoms are generally present throughout all seasons of the year. The diagnosis of PAR based on history alone can often be more difficult than that of SAR due to the absence of a clear seasonality to the patient’s symptoms. In addition, patients with PAR often experience a somewhat different cluster of symptoms than those noted by the patient with SAR. Among patients with PAR, nasal obstruction and postnasal drainage appear more commonly than the sneezing and itching often seen more frequently among patients with SAR.²² In addition, since both chronic rhinosinusitis and nonallergic rhinitis can have similar symptom patterns to PAR, it can be difficult to diagnose PAR without confirmatory testing.

While AR and nonallergic rhinitis both present with symptoms related to nasal inflammation and irritation, the pattern of symptoms is usually different in the two conditions. The type of symptoms noted in patients with nonallergic rhinitis depends on the pathophysiological processes involved and the mechanisms of nasal irritation or inflammation. For example, patients with vasomotor rhinitis present predominantly with clear rhinorrhea, while those with rhinitis of pregnancy present with congestion. The presentation of patients with nonallergic rhinitis will be discussed later. Table 3.1 displays some common differences between the presentations of patients with AR and nonallergic rhinitis.

TABLE 3.1 Factors distinguishing allergic and nonallergic rhinitis

▪ Diagnosis

History

The evaluation of the patient with symptoms of rhinitis in large part depends on a thorough and careful history. Patients with both allergic and nonallergic rhinitis will present with characteristic symptoms that can be elicited through the history. In addition, the patient’s history can often distinguish AR from nonallergic rhinitis (Table 3.1).

Since allergic rhinitis usually has its onset in childhood, the majority of patients with AR will report a history of atopic symptoms beginning early in life. While rhinitis may not have been present in childhood, other atopic diseases such as asthma and eczema may have been present. In addition, patients may have experienced other upper respiratory diseases such as recurrent otitis media or rhinosinusitis. The age of onset is therefore an important factor to assess in the patient’s history.

In addition to age of onset, AR is a disease with a strong genetic component. It is common for patients with AR to have one or both parents who have a history of AR specifically or other atopic diseases. While the absence of a family history does not exclude a diagnosis of AR, it is less likely to occur among patients without a clear family history of atopic disease.

While not all patients with AR complain of seasonal triggers or fluctuations related to time of the year, seasonal variability of the patient’s nasal symptoms is also important to assess. The symptoms of SAR demonstrate a clear relationship with the increase of pollen in the environment during discrete seasons of the year. This variability of symptoms is an important component of the history among patients with rhinitis, and suggests a diagnosis of SAR. Patients with PAR may also have a seasonal worsening of symptoms, but will have significant symptoms between traditional pollen seasons. Many patients with AR will present with complaints characteristic of both SAR and PAR.

Many patients with SAR and PAR will be able to identify discrete exposures that elicit the onset of symptoms. They have learned that avoidance of these factors will decrease symptoms while exposure often brings about a prominent expression of symptoms. Not all patients have awareness of these discrete triggers, however. In taking the patient’s history, the clinician should determine if the patient is aware of any discrete symptomatic triggers that will predictably create symptoms. While patients with nonallergic rhinitis will also note specific triggering stimuli that cause symptoms, these triggers are nonimmune in nature, and include factors such as tobacco smoke, scents, paints, colognes, and similar irritants. Triggers for patients with AR, by contrast, are seasonal and perennial allergens.

Physical Examination

The physical examination of the patient with symptoms of rhinitis involves not only a careful evaluation of the nose itself, but also a comprehensive evaluation of the head, neck, and chest as well. The physical examination begins with an inspection of the face. The clinician will examine the face for external signs suggesting nasal inflammation. These signs include facial puffiness, edema, facial asymmetry, or infraorbital discoloration (Figure 3.3). The eyes are examined for evidence of conjunctival injection, irritation or erythema. Infraorbital darkening of the skin implies venous stasis due to nasal congestion. Allergic patients often demonstrate fine creases in the eyelids, noted as Dennie’s lines. These fine creases occur due to spasms of Mueller’s muscles, and are often seen in children with AR.

Figure 3.3 Facial appearance of a child with rhinitis.

(Reproduced with permission from Zitelli BJ. Atlas of pediatric physical diagnosis, 3rd edn, published by Mosby, 1997.)

Since otitis media is a frequent comorbidity among both children and adults with AR, the clinician will next examine the ears using otoscopy. The appearance of the tympanic membrane is noted, including mobility and the presence or absence of retraction. The color of the drumhead is also noted, as well as whether it appears thickened or inflamed. The clinician also examines the middle ear for the presence of serous or purulent effusion.

The clinician then evaluates the internal and external nasal appearance. The external framework of the nose is examined for deformity or asymmetry. One commonly noted physical finding among patients with AR is a transverse crease in the midportion of the nasal dorsum. This finding is seen among adults and children who frequently rub the nose with their fingers or palm, creating upward force on the nasal tip and causing creasing of the skin. In addition, the clinician examines the soft tissues at the lateral portions of the nose, looking for signs of nasal collapse with inspiration.

The clinician then examines the interior structure of the nose. The anterior portion of the nasal septum is inspected for asymmetry, spurring, or presence or excoriation or perforation. The clinician notes any signs of deformity that may interfere with nasal airflow. In addition, the clinician again notes any sign of collapse of the lateral nasal soft tissues and assesses the degree of concurrent nasal obstruction. Finally the clinician assesses the size of the inferior turbinates, and estimates the degree to which they obstruct nasal airflow (Figure 3.4). It is very important for the clinician to also instill a small amount of a nasal decongestant such as oxymetazoline into the nose bilaterally to assess the reduction in the size and bulk of the turbinates after administration. A significant amount of reversibility will predict a good response to nasal medications in treating this airway obstruction.

Figure 3.4 Congested nasal mucosa and inferior turbinate.

After assessing the anatomic structure of the nose, the clinician then examines the appearance of the nasal mucosa. Among patients with AR, the nasal mucosa is generally edematous and congested, and frequently has a boggy gray-to-blue appearance on examination. In patients with severe AR, the mucosa can have a very pale, almost white appearance. By contrast, patients with nonallergic rhinitis rarely have this pale or bluish appearance to the mucosa, but will commonly demonstrate erythema and chronic irritation.

The clinician then assesses the presence, amount, quality, and character of any nasal secretions. Among patients with AR, rhinorrhea may be described as clear or cloudy, serous, mucoid, or mucopurulent. Secretions may be copious, and may be thin and watery or thick and tenacious. The presence of nasal polyps is noted, although full examination of the nose for polyps often requires the use of nasal endoscopy.

After the nasal examination is completed, the clinician then examines the oral cavity and oropharynx. The size of the tonsils is noted, as these can be enlarged in children with AR. In addition, the posterior pharyngeal wall is examined for signs of “cobblestoning.” In patients with AR, lymphoid tissue on the posterior wall of the oropharynx can be organized into raised clusters of follicular tissue, giving the area a cobblestoned appearance.

Finally, since asthma can be present in up to 40% of patients with AR,⁹ the clinician examines the chest with auscultation. While in many patients with asthma the chest examination may be unremarkable, in patients with significant disease or those undergoing an acute exacerbation of asthma, examination of the chest with both normal and forced expiration may demonstrate end-expiratory wheezing. In cases where asthma is suspected on the basis of history, pulmonary function testing may be useful in securing a diagnosis.

Allergy Testing

In many patients with rhinitis, it can be difficult from history and physical examination alone to determine whether the rhinitis symptoms are related to allergy or are a manifestation of nonallergic rhinitis. In these cases, testing can be performed to clarify the diagnosis. In addition, allergy testing can be performed to aid with environmental control, or if the clinician plans to implement immunotherapy as part of the comprehensive treatment of the patient with AR. Several methods of allergy testing have been developed and are used in clinical practice around the world. Both in vivo and in vitro techniques are available for the testing of allergic sensitivities in adults and children, and offer complementary qualities that can be used in the evaluation of specific patients. Rapid screens can be used to identify the presence or absence of allergic sensitivities, while more comprehensive testing can be used for treatment planning in those patients who are allergic.²³

The most common methods used for assessment of the patient with suspected AR involve skin testing. The skin is chosen as the most common site for testing since it is readily available, easily examined, and contains a mast cell population that reacts to the presence of antigen in a similar manner to the nasal mucosa. Skin testing can be performed using epicutaneous methods, as in prick/puncture testing, or using percutaneous techniques, as with intradermal testing.²⁴ The allergens that are used for testing are chosen on the basis of the common seasonal and perennial antigens present in the geographic locale of the patient being tested.

The most commonly employed skin tests used in both the USA and internationally for the assessment of allergy are prick tests (Figure 3.5). In prick testing, the nurse or technician introduces a small volume of each antigen to be tested into the superficial epidermis. Various devices and methods have been developed to perform these tests. When an allergic patient is exposed to an antigen on the skin to which that patient has been previously sensitized, the area into which the antigen is introduced will develop erythema and induration around the site of introduction. When used in the context of proper controls, this reaction implies the presence of an antigen-specific immune response. The presence of a reaction is recorded for each antigen tested. This reaction can simply be noted as positive or negative, or can be graded or measured. The size of the reaction can be used to estimate in a semiquantitative manner the strength of the allergic response.²⁴

Figure 3.5 Prick testing for allergen.

Intradermal testing can also be used for the assessment of allergic sensitivity. Intradermal tests can be employed as single-strength challenges following negative prick testing, or can be utilized in a sequential manner as in intradermal dilutional testing (IDT).²⁴ In intradermal testing, the nurse or technician injects a small amount of antigen into the superficial dermis in order to raise a wheal of discrete size, often 4 mm. As described with prick testing, if the patient is sensitive to the specific allergen being tested, an increase in the size of the wheal to 7 mm will be seen.

Techniques have been developed to employ a blend of prick and intradermal techniques in order to estimate quantitatively the degree of allergic sensitivity for specific antigens. One such technique, modified quantitative testing (MQT), has been used increasingly, and has shown good sensitivity, specificity, and utility.²⁴^–²⁶

In contrast to skin testing, in vitro tests can be used to assess the presence or absence of allergic sensitivity. While total IgE level has been suggested as a marker for assessing the presence of allergy, its use is of questionable utility.²⁷ The assessment of IgE levels to specific antigens, however, allows a quantitative assessment of the strength of the allergic response. These specific IgE tests, often generically referred to as “RAST tests” (radioallergosorbent testing), involve the laboratory assessment of levels of IgE antibody specific to each antigen being tested. The amount of specific IgE can be measured for each antigen, and has been shown to correlate well with the degree of responsiveness on the skin.²⁸

▪ Treatment

Overview

Treatment of the patient with AR requires a four-component strategy to maximize outcomes among patients with varying levels of disease and symptomatology. These four elements include: (1) education; (2) environmental control measures; (3) pharmacotherapy; and (4) immunotherapy. An approach to treatment based on current guidelines provides a rational strategy for managing the patient with AR through utilizing a flexible combination of these approaches based on chronicity and severity of the patient’s symptoms. Each of these four elements will be individually reviewed, followed by an integration of management strategies based on these current guidelines.

Education

Since AR is a chronic disease that will likely be present throughout most of the patient’s life, education about the nature of the disease, the patient’s individual triggers, and the need for ongoing therapy is essential to optimize outcomes. The successful treatment of the patient with AR must incorporate ongoing education around appropriate and effective disease management strategies.

AR is a chronic disease that can be controlled through the successful application of pharmacotherapeutic and adjuvant treatment methodologies. It can be considered a disease that has a similar structure to asthma, and rules that have been successful for asthma management can be useful with AR patients as well. The concept of control of disease is critical in this framework. Patients should be instructed that while AR cannot be cured with presently available treatment modalities, it can be brought under sufficient control for the patient to be asymptomatic most of the time. As with asthma, however, AR is a disease that is characterized by frequent exacerbations. It is these exacerbations that are most bothersome to patients, and they can occur in patients who have been under excellent control given exposure to sufficient antigen load. For that reason, strategies should be developed to allow the use of rescue medications for rapid relief of acute symptoms. In this way, a blend of controller methodologies and interventions for rapid rescue from acute symptoms can provide a successful method for decreasing the symptomatology and burden of AR.

For this reason, the patient must have adequate education about the causes and triggers of AR. They must know their own personal triggers, which can be determined from history or allergy testing. They must have specific plans for blending various treatment methods to maximize outcomes. When treatment plans involve immunotherapy, they must be committed to the treatment and compliant with the ongoing requirement for regular office visits and injections. If they have concurrent atopic diseases, especially asthma, they must be aware of signs of worsening symptoms and have specific plans for modifying their treatment in an appropriate manner.

The management of AR involves a multidisciplinary approach, and all parties involved in the patient’s care must provide education and encouragement. Physicians, nurses, and allied health personnel all play key roles in this process. Adequate and ongoing education is essential in assisting patients to achieve optimal control of their symptoms of AR.

Environmental Control Measures

In patients with AR, a systematic approach focused on decreasing exposure to offending antigens can be effective in decreasing the level of patient symptoms. Avoidance of antigens that are known to trigger an exacerbation of disease can reduce the total antigenic burden, and can lead to improved outcomes with fewer symptoms and improved disease-specific quality of life. Environmental control strategies are conceptually straightforward, although they can be difficult to implement successfully. While patients can often be successful in avoiding or decreasing exposure to perennial antigens such as cat dander, it may be more difficult to limit exposure to widespread environmental antigens such as pollen.²⁹ Despite the relative difficulty in applying these principles, the successful integration of environment control strategies can be useful in decreasing patient symptoms.

There have been several studies that have looked at reducing exposure to perennial antigens such as dust mite and cat dander. In one recent study, young children who implemented strict methods at reducing dust mite exposure were less likely to become sensitized to this antigen than those who did not practice such techniques.³⁰ Measures often recommended to reduce exposure to dust mite antigen include the use of allergen-impermeable covers for mattresses and pillows. In addition, the use of effective air filters, such as high-efficiency filtration (HEPA filters), can also be of benefit. In more extreme cases the removal of carpeting and curtains can be useful, although this strategy is expensive and of questionable benefit.³¹ Methods that can be effective at reducing indoor levels of mold antigen involve keeping the home at a low humidity level and the removal of indoor plants.

One of the most difficult environmental control practices to implement, yet one of the most effective, is the removal of pets from the home when a patient has been shown by testing and exposure to demonstrate significant allergic sensitivity to the animal. Patients are reluctant to remove pets from the home due to their emotional attachment. Segregating the pet into a specific portion of the home and providing a safe haven free from the pet can be of some benefit, and should certainly be encouraged as a compromise to total removal of the pet. It is also important to recognize that even though a pet may be removed from the home, it can take a number of months for the antigen to clear. In addition, patients with AR are exposed to animal dander when visiting other homes, and with dander that is attached to clothing and transported to the office or school.

Finally, with seasonal pollens, while it can be difficult to avoid these pollens completely, certain practical suggestions can be of benefit. Pollen levels tend to be lower in the evenings, as pollen is reduced at dawn and rises into the air in the morning hours. Patients with SAR should be advised to perform outdoor activities in the evening during pollen seasons. In addition, they should keep their windows closed at home and in the car and utilize air conditioners to keep pollen from entering the home. Pets should be washed after coming in from outdoors, as they can track pollen into the home. In addition, air filtration in the home and car can also be useful in decreasing exposure to pollen in patients with SAR.

Pharmacotherapy

While other methods are frequently used for the treatment of patients with AR, such as environmental control strategies and immunotherapy, pharmacotherapeutic interventions continue to be the most commonly employed treatment strategies for these individuals. Medications for AR are delivered both topically and systemically, and vary in terms of the types of symptoms they treat and the degree to which they demonstrate improvement. The current section will review each of these classes of medications.

Antihistamines

The most commonly prescribed class of medications used for the treatment of AR is the antihistamines. Antihistamines function as competitive antagonists for the H₁ receptor that is found on end-organ target cells that make up the nasal mucosa. Antihistamines bind robustly to these H₁ receptors, and deactivate the receptor both through an active mechanism of reverse agonism as well as preventing attachment of histamine released from tissue mast cells.

Antihistamines were first developed in the 1930s and 1940s, although they did not come into widespread use until the 1950s, when many of the toxic effects of the original compounds were eliminated. The initial antihistamines in common clinical use, including diphenhydramine, chlorpheniramine, and tripolidine, were noted to have clinical effect in reducing symptoms of AR, yet were accompanied by significant adverse effects such as sedation and somnolence. These early antihistamines, also described as “first-generation” antihistamines, demonstrated significant lipophilicity and can be demonstrated to freely cross the blood–brain barrier and affect central histamine receptors.³² These agents therefore had direct effect on central H₁ receptors, resulting in significant sedation, impaired cognition, and decreased psychomotor function. These agents also demonstrated poor receptor selectivity, binding to both cholinergic and muscarinic receptors. This poor selectivity is responsible for side effects such as cognitive slowing, dry mouth, blurred vision, and increased thickness of mucus.

Current antihistamines, also described as “second-generation” antihistamines, demonstrate more potent, selective binding at the level of the H₁ receptor than do the older agents. In addition, these antihistamines do not cross the blood–brain barrier in sufficient concentrations to elicit significant central effects. Their major advantage is that they lack clinically important sedation at recommended doses. These newer agents currently include loratadine, fexofenadine, cetirizine, desloratadine, ebastine, and levocetirizine. In addition, topical antihistamines for ocular and nasal use, such as azelastine and olopatadine, have little or no sedation when topically administered.

The major role for antihistamines in the management of the patient with AR is in relieving the irritative symptoms of allergic rhinitis, especially the sneezing and itching that are commonly associated with SAR. In general, antihistamines demonstrate better efficacy with SAR than they do with PAR. In addition, antihistamines demonstrate some effect on reducing rhinorrhea, although the newer agents are less effective than the first-generation antihistamines due to the anticholinergic properties of the latter. Antihistamines have little effect on nasal obstruction, however, and are therefore not appropriate monotherapy for the patient in whom nasal congestion or stuffiness is a major symptom. In these patients, antihistamines are frequently used concurrently with medications from other classes when nasal congestion is a primary symptom of AR. A major class of medications includes dual antihistamine/decongestant products, used to treat both the irritative and obstructive symptoms of rhinitis. Antihistamines do not have benefit in the management of patients with nonallergic rhinitis. Since nonallergic rhinitis is not mediated through histamine release from mast cells, antihistamines do not have clinical effect among these patients.

One antihistamine is currently available for the treatment of AR in the USA. This medication, azelastine, demonstrates good onset of action and has efficacy in relieving both irritative symptoms and congestion. It does demonstrate mild sedation, even with topical use.

While older antihistamines such as diphenhydramine continue to be available in pharmacies, current treatment guidelines for AR recommend against the use of these sedating antihistamines.³³ These agents offer no advantage in potency or treatment efficacy over the safer current medications. In those unusual circumstances in which clinicians do recommend a sedating antihistamine is preferential, they should advise their patients about the risk for significant sedation and cognitive and psychomotor impairment, and should note the reason for recommending this medication and the subsequent discussion with the patient in the medical record.

Decongestants

Oral and topical decongestants are frequently used by patients with AR for relief of their symptoms of nasal obstruction. These agents are α-adrenergic receptor agonists that exert physiological effect on the venous erectile tissue in the cavernous sinusoids found in the nasal turbinates. Both oral and topical decongestants act as vasoconstrictors, and are effective in relieving symptoms of nasal obstruction. They are generally well tolerated, although sensitive patients may experience significant adverse effects with these medications when administered through either route.

The most commonly used topical nasal decongestants are phenylephrine, oxymetazoline, and xylometazoline. When administered topically, these medications will cause a vigorous vasoconstrictive effect in the nose, resulting in increased airflow through the nose and the relief of the symptoms of congestion. While all of these topical agents show rapid and robust efficacy, they are all associated with significant tachyphylaxis, even with short-term use. Topical decongestants are recommended for only 3–5 days of use because of the significant rebound rhinitis that is noted to occur. Because of the significant risk of tachyphylaxis and dependency, topical nasal decongestants have limited utility in the management of AR.

In addition to topical decongestant medications, oral decongestants are also used commonly for nasal obstruction. The medication that has traditionally had the most widespread use is pseudoephedrine, although the ease with which it can be used to synthesize methamphetamine has restricted its availability. An alternate medication, phenylephrine, is being more widely recommended as an oral decongestant since it cannot be used for synthesis of methamphetamine. It appears to have lesser clinical efficacy than pseudoephedrine, however, in the treatment of nasal congestion. Another oral decongestant, phenylpropanolamine (PPA), was removed from the market in the USA in 2003 when it was shown to have an epidemiological association with an increased risk of hemorrhagic stroke among young women using the medication as a diet aid.³⁴

Oral decongestants demonstrate excellent efficacy in relieving nasal obstruction, and appear to have less potential to elicit rebound rhinitis and congestion than do topical decongestants. Oral decongestants, however, are associated with significant adverse events, especially in patients sensitive to the agents. These effects are related to stimulation of alpha-receptors found centrally and in the cardiovascular system in a nonselective manner. Undesirable side effects include a variety of symptoms, including central nervous system effects such as insomnia, jitteriness, nervousness, irritability, restlessness, and headache. Adverse cardiovascular effects of oral decongestants include chest palpitations, cardiac arrhythmias, hypertension, and angina. In addition, stimulation of alpha-receptors in the prostate are associated with urinary retention. These untoward systemic effects are dose related. In addition, oral decongestants are associated with increases in intraocular pressure and have been shown to precipitate or exacerbate glaucoma in susceptible individuals.

Because of these significant systemic effects associated with oral decongestants, patients with cardiac disease, uncontrolled hypertension, and glaucoma are at risk with the use of oral decongestants. These patients should avoid or severely restrict their use. As a principle, oral decongestants should be used at the lowest dose capable of relieving symptoms of nasal obstruction, and for the shortest time necessary.

Corticosteroids

Corticosteroids are highly effective in the treatment of AR, and have a role in both the management of acute exacerbations of AR as well as in the control of chronic AR. Corticosteroids can be used systemically or topically in patients with AR. While parenteral use of corticosteroids has been used frequently in the past, it is not recommended under current guidelines due to increased risk of systemic side effects when compared with oral corticosteroids.⁷ Oral corticosteroids such as prednisone and methylprednisolone are appropriate for the management of severe AR, and can be used for short periods of time with little risk. Oral corticosteroids are also of benefit in treating patient with AR who have exacerbations of chronic rhinosinusitis or asthma.

Topical intranasal corticosteroids are being used increasingly for the treatment of AR. Comparative studies have shown these agents to be more efficacious then antihistamines in the management of patients with AR.³⁵ Safety studies have demonstrated the topical intranasal corticosteroids to be safe and well tolerated.³⁶ These medications have been shown to have only limited side effects both in the nose and systemically, and newer agents such as mometasone furoate and fluticasone propionate have been demonstrated in year-long prospective studies to be free of growth suppression over one year of use in children. They also have demonstrated lower systemic absorptions and decreased systemic bioavailability and to be free of suppression of the hypothalamic–pituitary–adrenal (HPA) axis. These topical intranasal corticosteroids would therefore be predicted to be less likely to provoke systemic effects than agents with higher systemic absorptions.

Topical intranasal corticosteroids have been shown to be both safe and effective in the treatment of patient with AR. In fact, mometasone furoate has been approved as safe for use in children down to 2 years of age. These medications can be used for the treatment of the symptoms among patients with both SAR and PAR, as well as for the prophylaxis of symptoms in patients with SAR.

Mast Cell Stabilizers

Mast cell stabilizing medications have limited utility in the current management of patients with AR. The only agent available for treatment of AR is cromolyn sodium, which is a topically administered nasal spray with a very short elimination half-life. Cromolyn sodium is effective in the treatment of patients with AR, although its efficacy is limited when compared with other agents. Mast cell stabilizers work through stabilizing membranes of mast cells in the nasal mucosa, thereby inhibiting degranulation and subsequent release of histamine into the nose. Since cromolyn sodium inhibits release of histamine, it is of little utility once histamine has been released from mast cells in response to antigen exposure. It does not interfere with histamine’s effect on target organs in the mucosa. To receive maximum benefit from the use of mast cell stabilizing medications, they must be administered prior to allergen exposure.

Leukotriene modifiers

Leukotriene receptor antagonists (LTRA) have shown benefit in the treatment of both SAR and PAR. Both montelukast and zafirlukast have been shown to have benefit in the treatment of the symptoms of AR, although the only approved LTRA for the treatment of AR in the USA is montelukast. Montelukast does display efficacy in the treatment of both SAR and PAR, and relieves both nasal and non-nasal symptoms among these patients. Several studies have demonstrated that montelukast has similar efficacy in the treatment of SAR to antihistamines such as loratadine.^37,³⁸

Anti-IgE

Since the allergic response is initiated by antigen binding to IgE antibody molecules on the surface of mast cells, theoretically an agent that reduces the amount of IgE bound to these cells would be expected to decrease degranulation and histamine release. One medication that has been shown to decrease IgE in this manner, omalizumab, is available for the treatment of refractory asthma among patients with elevated serum levels of total IgE. This medication, which is administered parenterally, decreases the amount of serum IgE, resulting in decreased mast cell-bound IgE and a blunting of the allergic response. Omalizumab has shown good efficacy in the treatment of severe asthma, decreasing the number of exacerbations on an annual basis. Preliminary studies have also demonstrated efficacy in AR,³⁹ although its practical use in AR is limited by its high cost. Future applications of monoclonal anti-IgE molecules in AR will likely be developed, but at present it is not a recommended treatment for rhinitis.

Rational Pharmacotherapeutic Management of Allergic Rhinitis

As noted earlier, patients with AR have a chronic disease that will cause them to have symptoms for a significant number of years. In patients with mild SAR, intermittent use of medications during the seasons in which the individual is symptomatic would appear to be a practical and efficacious approach to therapy. In patients with irritative symptoms of SAR, oral antihistamines offer good relief and newer agents can be used safely and without adverse effects throughout the season. Short-term use of oral decongestants can be used for obstructive symptoms in these SAR patients as well. More refractory or prolonged congestion can successfully be managed using topical intranasal corticosteroids, or even a brief course of oral corticosteroid medications.

In patients with PAR, the chronic symptoms of rhinitis are present for most of the year. In these patients, the strategy for treatment must involve the concept of control of underlying chronic symptoms with effective management of exacerbations as they occur. Again, the treatment of patients with PAR would conceptually be similar to that seen in patients with persistent asthma. Among these patients with PAR, the use of topical intranasal corticosteroid medications is a reasonable strategy for the control of the chronic nasal symptoms and their underlying inflammatory processes. In many patients, these medications will control symptoms adequately as monotherapy and patients will not require additional medication. Among patients with exacerbations, the concept of using rescue medications to decrease acute symptoms is reasonable. Topical nasal decongestants can be used for several days with severe exacerbations of congestion. In addition, topical nasal antihistamines can also be effective rescue medications, with rapid onset of symptomatic relief with antigen exposure. By treating PAR as a chronic disease with exacerbations, and by conceptualizing it as treated with control and rescue medications, patients can often bring their symptoms under excellent long-term control and experience infrequent periods of significant morbidity and functional impairment.

Summary

As noted, pharmacotherapy remains the mainstay in the treatment of patients with AR. There are a variety of topical and systemic medications available for treating AR, and new medications and treatment approaches will likely be noted over the coming decade. Table 3.2 provides a summary of the currently available classes of medications used for treating the symptoms of both AR and nonallergic rhinitis, and offers an estimate of the relative efficacy of each of these classes in the treatment of the various nasal and non-nasal symptoms associated with these diseases.

TABLE 3.2 Pharmacologic options for rhinitis: effects on symptoms

Immunotherapy

Immunotherapy for AR is undertaken to desensitize the patient to those allergens to which the patient is demonstrated to be responsive. Immunotherapy involves the subcutaneous (SC) or sublingual (SL) administration of antigens to which a patient has been shown to be sensitive, generally in steadily increasing doses over time, in order to decrease the reactivity of the patient on exposure to those antigens. Immunotherapy has been shown to be an efficacious treatment strategy for patients with AR in several large-scale evidence-based reviews. It is a major component of the comprehensive treatment of the patient with AR, and an alternative that should be considered when patients are demonstrated to be unresponsive to pharmacotherapy and environmental control measures.

In traditional SC immunotherapy, very low concentrations of antigen are injected subcutaneously over a period of 3–5 years. The concentration of antigen is steadily increased over the period of several months until the patient is receiving a maximally tolerated concentration of each antigen to which the patient is allergic. This concentration is then held stable as the patient continues SC injections weekly, biweekly, or monthly over several years. While SC immunotherapy can rarely be accompanied with local or systemic adverse reactions, which at times can be serious, the safety of SC immunotherapy in treating AR has been well established.⁴⁰

A large experience from the European allergy community suggests that immunotherapy can also be safely and effectively delivered through the SL route. Several large-scale placebo-controlled studies have demonstrated the efficacy of SL immunotherapy for the treatment of AR.^41,⁴² In addition, SL immunotherapy does not appear to be associated with the risk of anaphylaxis, as can be seen with SC immunotherapy. Mild local and systemic reactions have been noted, but are generally not sufficient to discontinue treatment. The SL route of administering immunotherapy will likely become more common and mainstream within the USA over the next decade.

While the precise mechanisms through which immunotherapy is able to decrease allergic responsiveness are not fully understood, it is felt that immunotherapy decreases T-cell responsiveness, stimulates a shift from T-helper 1 to T-helper 2 populations, and decreases antibody responsiveness through decreasing specific IgE and increasing specific IgG₄ levels with treatment.⁴³ The onset of action with immunotherapy is generally seen within 3–6 months after the initiation of treatment. In order to stimulate persistent immune change, treatment for at least 3–5 years is suggested.

Guidelines-based Therapy

As can be seen through the above discussion, there are numerous treatment options available for the management of the patient with AR. While clinicians will generally select various treatment options based on their experience and familiarity, consistent approaches to the selection of therapies for AR based on evidence can improve patient outcomes. A recent study by Bousquet and colleagues suggested that adherence to guidelines-based recommendations in the treatment of AR can lead to more effective treatment and improved quality of life.⁴⁴

Several guidelines have been developed over the past two decades that can be used to effectively treat patients with AR. In 1998, the Joint Task Force on Practice Parameters reported that intranasal corticosteroids are the most effective class of treatment for the symptoms of AR. This committee also reported that nonsedating antihistamines should be utilized as appropriate first-line therapy for patients in which the irritative symptoms of AR are primary. When nasal congestion was present to a significant degree, the committee reported that either an oral decongestant or an intranasal steroid could be used as a complementary or alternative therapy.⁷ Similar guidelines were reported by the European Academy of Allergology and Clinical Immunology (EAACI).

In 2001, the World Health Organization (WHO) impaneled an international committee of allergy specialists to examine current treatment options for patients with AR. The guidelines that were developed as a result of the deliberations of this panel are published as the ARIA Guidelines.³ ARIA is an acronym for “Allergic Rhinitis and its Impact on Asthma,” and describes treatment guidelines for AR that parallel those used in the treatment of asthma. The conceptual framework for the ARIA guidelines is based on the model of the upper and lower airways as an integrated unit. ARIA argues that allergic rhinitis represents an inflammatory disease of the upper airway, just as asthma represents an inflammatory disease of the lower airway. The classification of AR follows similar rules to that used with the classification of asthma, and the treatment for AR also follows similar guidelines.

The ARIA guidelines depart from the traditional scheme of classifying AR into seasonal AR and perennial AR. They present a model in which AR is divided into four distinct categories based upon the severity and chronicity of the disease. The ARIA guidelines then recommend a stepped care approach to therapy based upon the classification of patient symptoms (Figure 3.6).