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Disease Summaries

In-Depth Review of Allergic Rhinitis

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Updated: June 2015
Originally Posted: June 2005

Updated by:
Natalya M. Kushnir, MD
Director, Allergy and immunology Clinic of East Bay
Berkeley, CA

Michael A. Kaliner, MD FAAAAI
Medical Director, Institute for Asthma and Allergy
Wheaton and Chevy Chase, Maryland

Original authors:
Mark D. Scarupa, MD
Associate, Institute for Asthma and Allergy
Chevy Chase and Wheaton, Maryland
Clinical Instructor, Johns Hopkins Asthma and Allergy Center
Baltimore, MD

Michael A. Kaliner, MD FAAAAI
Medical Director, Institute for Asthma and Allergy
Chevy Chase and Wheaton, Maryland
Professor of Medicine, George Washington University School of Medicine
Washington, DC

Rhinitis is one of the most common chronic conditions for which medical care is sought. Allergic rhinitis is an IgE-mediated disorder of the nose caused by the interaction of airborne allergens with specific IgE type antibodies on the surface of mast cells.  The IgE-allergen interaction leads to the mast cell releasing and synthesizing a number of chemical which then cause the surrounding tissues to become inflamed. Typical symptoms which are initiated include rhinorrhea, nasal itching, sneezing and nasal congestion, although extranasal symptoms such as allergic conjunctivitis, itchy ears and palate, and asthma are commonly associated as well. Over 400 million people suffer from allergic rhinitis around the world, which to a large extent remains underdiagnosed and undertreated. In the United States it affects between 10-30% of the adult general population and up to 40% of children, making it the fifth most common chronic disease. Unfortunately the health and economic impact of allergic rhinitis historically has been grossly underestimated and it is only recently that rhinitis has been recognized as a serious issue with epidemic proportions. Direct medical costs in The US increased from $6.1 billion in 2000 to $11.2 billion in 2005, with an estimated productivity decrease of $600 per employee yearly; this cost is greater than diabetes, coronary heart disease and asthma. Indirect losses represent an even heavier burden in societies with emerging economies. In eight countries in the Asia Pacific region, the annual per-patient direct costs ranged from the equivalent of US$ 108 to US$ 1,010.62 Total per-patient costs, including productivity costs, ranged from US$ 184 to US$ 1,189.  Thus, the cost of allergic rhinitis is enormous and widely under-appreciated.

Background

The nose and nasal cavities have a number of important functions. Airflow into the nasal passages is necessary for both the senses of smell and taste. The nasal passages also act as a filter protecting the lungs from particulate matter. Furthermore, the relatively large surface area of the mucosa covered turbinates acts to warm and humidify air prior to entry into the lungs. When airflow is significantly inhibited, all of these functions can be adversely affected. In rhinitis, a combination of nasal mucosal inflammation, edema and increased mucus production can lead to such airflow obstruction.

Though rhinitis is commonly thought of as a response to the deposition of allergens on the nasal mucosa, a significant percentage of patients suffering with rhinitis are not allergic. From 44-87% of people with rhinitis have “mixed” allergic and non-allergic rhinitis. Non-allergic rhinitis is not one uniform syndrome but instead a collection of disorders that lead to the classic symptoms of rhinitis including rhinorrhea and/or nasal congestion. The differential diagnosis of rhinitis is summarized on Table 1

Non-allergic rhinitis has 8 major subtypes which include 1. nonallergic rhinopathy (previously known as vasomotor rhinitis), 2. nonallergic rhinitis with eosinophilia, 3. atrophic rhinitis, 4. senile rhinitis, 5. gustatory rhinitis, 6. drug-induced rhinitis, 7. hormonal-induced rhinitis, and 8. cerebral spinal fluid leak (Table 2).

Compared to nonallergic rhinitis, allergic rhinitis typically presents at a younger age and symptoms are usually evident by young adulthood. Symptoms can be purely seasonal, episodic or year round (perennial) depending on the sensitizing allergen or allergens and the exposure to them.  Rhinitis symptoms can disturb daily activities and sleep patterns, leading to daytime inattention, irritability and hyperactivity. In addition children with allergic sensitization are also more likely to have asthma, otitis and atopic eczema, the other major diseases of the atopic diathesis. Maternal smoking and absence of breastfeeding are stronger predictors of nonallergic rhinitis, while current wheeze and eczema are stronger predictors of allergic rhinitis. Allergic rhinitis is most prevalent during elementary school years and affects children’s and their parents’ quality of life. Children who suffer from allergic rhinitis are also frequently diagnosed with ADHD. Allergic diseases have been shown to be closely associated with parenting stress and negative relationships between mothers and their children.

The burden of rhinitis in the US adult population is estimated between 10–30%. Standardized quality of life measures have found that in 62% of patients with allergic rhinitis, the disease has a significant impact on their daily life. Studies have also shown that almost 80% of patients with allergic rhinitis report difficulty sleeping and thus increased daytime fatigue. In the U.S., allergic rhinitis contributes to approximately 2 million missed school days and 100 million missed work days annually. Furthermore, both adults and school-aged children with rhinitis have been found to have decreased levels of cognitive functioning.

Both allergic and non-allergic rhinitis can be associated with secondary complications and co-morbidities. The nasal inflammation caused by rhinitis can contribute to the development of both acute and chronic sinusitis. Sinusitis is the third leading disease for which antibiotics are prescribed in the outpatient setting. Rhinosinusitis has also been shown to contribute to asthma exacerbations and make asthma more difficult to control. Nasal mucosal inflammation can also lead to eustachian tube dysfunction and chronic otitis media and/or serous otitis. These disorders in turn can lead to speech delay in pediatric populations and in rare cases permanent hearing damage. Also in children, rhinitis can contribute to craniofacial abnormalities due to chronic mouth breathing.

Adults and children with asthma and documented concomitant AR experience more asthma-related hospitalizations and physician visits, and incur higher asthma drug costs than patients with asthma alone.

Pathophysiology

Allergic Rhinitis

Rhinitis can be induced by allergic stimuli, non-allergic triggers or both (mixed rhinitis) (Figure 1). The underlying mechanism leading to nasal symptoms thus varies depending on the type of rhinitis. Allergic rhinitis only occurs in patients with a genetic predisposition to developing allergies. Although all people are constantly exposed to environmental allergens, it is only those patients with the innate ability to become sensitized that develop symptoms. In these sensitive individuals, repeated exposure to aeroallergens causes B cell activation and maturation into plasma cells, which produce specific IgE antibodies. The IgE binds to specific receptors on the surface of basophils and mast cells. When cell bound specific IgE is cross-linked by the sensitizing allergen, the cells release or generate chemical mediators which produce the allergic symptoms. Activated mast cells release preformed histamine and generate newly synthesized leukotrienes, prostaglandins, kinins, and other compounds. The end result of this mediator release is an immediate hypersensitivity reaction with itching, sneezing, and congestion due to increased vascular permeability, vasodilatation, and increased mucus production. The vascular leakage of plasma proteins contributes to both rhinorrhea and nasal congestion.

Further release of inflammatory mediators causes a late-phase reaction that prolongs nasal symptoms after an allergen exposure. Cytokines and chemokines released and generated during this late phase reaction recruit additional inflammatory cells. These cells in turn release further inflammatory mediators which can worsen nasal symptoms and prime the nasal mucosa so that future allergen exposures lead to more rapid onset and often more severe symptoms.

Genetics

While prevalence of allergic rhinitis is increasing worldwide and environmental impact on disease is evident, some populations tend to be affected more and have more severe clinical presentation of allergic disease. Thus genetic studies are important in understanding the pathology of disease. Monozygotic twins demonstrate  concordance of 45-60% in the development of allergic rhinitis, and dizygotic twins have a concordance rate of 25%. Chromosome 3 has three regions linked to allergic rhinitis, 3q13, 3q13.31, and 3p24. A possible involved region on chromosome 4 is 4q24-q27. Single nucleotide polymorphism has been implicated. GATA3 and IL-13.9 specific HLA haplotypes have been associated with allergic responses to particular allergens. This may be due to more than just an association since HLAs present antigens to T-cells. There is also evidence that points to genetic associations of the T-cell receptor (TCR) α-chain and the high affinity IgE receptor FcεRI with increased allergy.

Non-allergic Rhinitis

The underlying mechanisms leading to non-allergic rhinitis are quite variable and less well understood. The most common form of NAR has been known as vasomotor rhinitis (VMR) and is a common syndrome where middle-aged women develop rhinorrhea and nasal congestion in response to changing environmental conditions... Nasal symptoms can be triggered by environmental irritants such as smells and particulate materials, as well as changes in weather and barometric pressure. Some patients respond to emotional stress, hormonal changes and other unidentified stimuli. VMR is also known as nonallergic rhinopathy and idiopathic rhinitis.

Chronic sinusitis also causes a variety of nasal symptoms, which must be distinguished from rhinitis in order to treat sinusitis appropriately. Most symptoms of rhinitis involve the anterior aspects of the nose while sinusitis tends to cause posterior symptoms. The multitude of other non-allergic rhinitis triggers tend to either cause mucosal vascular engorgement, lead to damage of the nasal mucosa, or act to initiate inflammatory cascades. (Table 1)

Diagnosis

Though some rhinitis medications are efficacious in the treatment of both allergic and non-allergic rhinitis, it benefits the patient to have a specific diagnosis. To adequately distinguish between allergic, non-allergic, and mixed rhinitis, a thorough history and physical followed by diagnostic testing is a necessity. Though the end results of nasal congestion and rhinorrhea may not help to distinguish between the disorders, numerous historical clues and subtle differences on physical exam coupled with allergen skin testing or specific in vitro IgE testing (sIgE) can lead to an accurate diagnosis.

Allergic rhinitis usually presents in childhood and there is typically a strong family history of atopic diseases including rhinitis, asthma, and atopic dermatitis. Conversely, 70% of patients with non-allergic rhinitis present after the age of 20 and often there is no evidence of a familial pattern. There is also a strong female predominance in non-allergic rhinitis not seen in allergic rhinitis. Furthermore, patients with non-allergic rhinitis frequently complain of perennial symptoms. Though it is possible for allergic patients to be sensitized to only perennial allergens such as cat or dust mite, most are sensitized to seasonal pollens and thus have seasonal exacerbations of symptoms. While triggers of allergic rhinitis are aeroallergens, the list of non-allergic rhinitis triggers is broad. It includes strong smells and irritants, changes in weather and barometric pressure, hormonal fluctuations, and ingestion of alcohol or food (gustatory). One proviso to the persistent nature of non-allergic rhinitis: many patients are worsened by weather changes seen in the spring and fall and may appear to have “seasonal” rhinitis.

The nature of symptoms also differs between the two disorders. Patients with non-allergic rhinitis typically complain of nasal congestion and rhinorrhea and rarely have significant pruritus or sneezing. Patients with allergic rhinitis have very significant sneezing and nasal itch. Furthermore, most allergic patients also have troublesome ocular symptoms with conjunctival injection, tearing and itch, while non-allergic rhinitis usually involves only the nose.

There are also subtle differences on physical examination. Classically, the nasal mucosa in allergic rhinitis is edematous, boggy and often with a blue-white hue. The nasal examination in non-allergic rhinitis is more variable depending on the underlying cause of the disorder. Nasal mucosa may appear essentially normal with increased clear watery secretions or may be erythematous or even atrophic.

Treatment

There is significant overlap in the pharmacologic treatment of allergic and non-allergic rhinitis. While the treatment of non-allergic rhinitis is almost solely with medications, successful treatment of allergic rhinitis can also involve allergen avoidance and immunotherapy. There are numerous non-pharmacologic measures that deserve consideration when treating rhinitis. Immunotherapy has been demonstrated to be extremely beneficial in selected patients with allergic rhinitis. Immunotherapy has no benefit for non-allergic rhinitis patients and thus it is important to distinguish these diseases before considering starting immunotherapy.

Allergen Avoidance

Specific allergens are the main starting point of allergic rhinitis pathophysiology, thus avoiding those triggers is an effective treatment. Unfortunately adequate avoidance is not always possible, as in the case of pollen allergies and for those with mixed allergic and non-allergic rhinitis. Some allergens can and should be avoided as reduction of allergen clearly correlates with clinical improvement and reduces the need for pharmacological intervention. Precautions can be taken against dust mites, especially in endemic areas. Carpet removal, using allergen-impermeable bedding covers for the mattress and pillow, vacuuming with a high-efficiency particulate air (HEPA) filter, and washing and drying bedclothes and bed sheets in hot water (60 ℃) with long high heat drying cycle may be helpful and should be a first-line approach when specific sensitization is confirmed.

Allergen specific immunotherapy involves the progressive administration of allergen extract preparations subcutaneously in order to induce immunologic and clinical immune tolerance and long-term resolution of symptoms. Immunotherapy currently is the only allergen specific treatment that has the potential for disease modification, as reflected by prevention of disease progression and new allergic sensitization. Whereas subcutaneous immunotherapy has documented efficacy in allergic rhinitis and asthma, it has a small risk of systemic side effects including rare anaphylaxis. Recently the sublingual route has emerged as an effective and safer alternative. Efficacy of SLIT in seasonal allergy especially in monosensitized patients is now well-documented in adults and children, while more studies are needed for perennial allergies and asthma, particularly in children.

Oral antihistamines are often used as first line therapy in patients with rhinitis symptoms. The use of these H1 receptor antagonists had long been limited due to sedating side effects; however the newer second-generation drugs are extremely safe and efficacious with far less sedation. These drugs block the effects of released histamine that is present in high concentrations during allergic reactions. Oral non-sedating antihistamines are most beneficial for the suppression of nasal pruritus, sneezing, rhinorrhea, and accompanying ocular symptoms. These drugs have some, but limited effects on congestion. Because of their lack of decongestant properties, and the fact that histamine is rarely involved in non-allergic rhinitis, oral antihistamines are of little benefit in treating this disorder. Some older, sedating antihistamines have more drying properties which can provide additive benefit in treating rhinorrhea and postnasal drip.

The intranasal antihistamine azelastine is indicated for both allergic rhinitis and non-allergic rhinitis. Another intranasal antihistamine, olopatadine, is approved for treating AR.  In allergic rhinitis, intranasal anithistamines works similarly to oral antihistamines, blocking the histamine receptor and thus decreasing rhinorrhea, itch, and sneeze. Intranasal anithistamines  also are effective at reducing congestion, probably because topical application places a much higher concentration of antihistamine on the nasal mucosa than is possible with oral antihistamines. In non-allergic rhinitis, azelastine likely acts by both anti-inflammatory activity and neuropeptide depletion. Because of the efficacy of topical treatment in rhinitis, there is a move towards using more topical medications such as azelastine and nasal corticosteroids whenever possible, rather than oral systemic medications.

Nasal corticosteroids are the mainstay of therapy for both non-allergic and allergic rhinitis. With potent but local anti-inflammatory effects, they are efficacious in treating most rhinitis syndromes regardless of etiology. By decreasing inflammation, nasal corticosteroids decrease mucosal edema and vascular leak improving the symptoms of rhinorrhea and nasal congestion. They also decrease the number of histamine containing mast cells in the nasal mucosa, thus decreasing nasal pruritus and sneezing. Nasal corticosteroids are extremely safe, well tolerated and systemic steroid effects are rare. The most frequent side effects are local irritation and epistaxis, both of which can typically be lessened by utilizing proper spray technique and thus avoiding the nasal septum. Perhaps the greatest difficulty with this class of medication is patient compliance. As it typically takes 1 to 2 weeks of constant use to achieve maximum relief, educating the patient about their prophylactic benefits is necessary. Using both nasal corticosteroids and topical nasal antihistamines in combination is very likely to effectively treat either allergic or non-allergic rhinitis symptoms.

Systemic corticosteroids ( by mouth or by injection) should be considered a last resort treatment option for severe or intractable symptoms. If they are used, then the oral route is preferred. Allergy “monthly shots” of depo steroidal preparations should  be discouraged due to severe long-term systemic side effects and the availability of safer treatment options. Injecting steroids into the turbinates runs the risk of inducing blindness and is rarely indicated. Recommendations on short courses of oral steroids differ from 5-7 days to no more than 3 weeks.

Nasal saline lavage (SNL)is a great non-pharmaceutical modality that has minor decongestant benefits and improves clinical outcomes. Recent studies looked at nasal saline lavage performed regularly over a limited period of up to 7 weeks: a positive effect on all investigated outcome parameters in adults and children with AR was observed. SNL produced a 27.66% improvement in nasal symptoms, a 62.1% reduction in medicine consumption, a 31.19% acceleration of mucociliary clearance time, and a 27.88% improvement in quality of life. It is well tolerated, inexpensive, easy to use, and there is no evidence showing that regular, daily SNL adversely affects the patient's health or causes unexpected side effects. When used in conjunction with intranasal steroids and nasal antihistamines it can significantly alleviate symptoms and improve nasal breathing.

Intranasal cromolyn sodium is a mast cell stabilizer indicated for allergic rhinitis. Like nasal corticosteroids, this drug must be used prophylactically and has no beneficial effect on relieving symptoms that are already present. This drug prevents the release of histamine from mast cells and thus primarily prevents sneezing, itch and rhinorrhea. Though it has an unsurpassed safety profile, cromolyn has fallen out of favor because in order to achieve significant benefit it needs to be used 3 to 5 times per day.

Antileukotrienes (LTRA) are a relatively new class of medication. These drugs were originally indicated for asthma but are now also approved in the United States for the treatment of allergic rhinitis. These medications block the effects of leukotrienes, inflammatory mediators produced through the arachidonic acid pathway. LTRA have been shown to decrease eosinophil counts and nitric oxide production from areas of allergic inflammation. The end result is nasal symptom relief similar to that of non-sedating anti-histamines with modestly decreased rhinorrhea, sneezing, and pruritus. Montelukast, the most commonly used LTRA, is extremely safe in both adults and children. While it is well tolerated, it is much less effective efficacious as compared to nasal corticosteroids.

Oral decongestants can be beneficial in short-term treatment of congestion associated with both allergic and non-allergic rhinitis; but can have significant systemic side effects such as hypertension, nervousness, insomnia, irritability, urinary hesitancy and loss of appetite. Oral pseudoephedrine hydrochloride used alone or in combination with antihistamines is the most common decongestant. Pseudoephedrine is a sympathomimetic agent that causes vasoconstriction of the superficial blood vessels in the nasal mucosa, as well in other areas of the body. This action decreases swelling of the mucosal tissue and decreases vascular leak improving both rhinorrhea and nasal congestion. Because it is not mediator specific, decongestants can be used in both allergic and non-allergic rhinitis. Unfortunately, tolerance to pseudoephedrine is variable. It is available without prescription, and it is frequently abused by patients who relay on self-treatment. Similar problems are seen with topical decongestants which can provide rapid temporary relief of nasal congestion in allergic and non-allergic rhinitis, while chronic overuse for even relatively short periods of time (>3-7 days) can lead to rebound nasal congestion. More prolonged use can lead to rhinitis medicamentosa, rebound congestion with gross changes in the nasal mucosa. Systemic side effects are the same as seen with oral decongestants. Both short-acting (phenylephrine hydrochloride) and long-acting (oxymetazoline) preparations are available.

Nasal ipratropium bromide is a topical anti-cholinergic spray that may be beneficial in certain patients with allergic and/or non-allergic rhinitis. As cholinergic stimulation can lead to rhinorrhea, this medication can be used to reduce rhinorrhea in both rhinitis and colds. Ipratropium can be beneficial in patients with difficult to treat rhinorrhea but usually does not help postnasal drip.

With so many therapeutic options, a systematic approach to the rhinitis patient is necessary. This begins with a thorough evaluation and accurate diagnosis. The general approach to the management of a patient with allergic rhinitis is to maximize allergen avoidance, minimize the number of medications to insure compliance, and to watch for potential co-morbidities or complications. Skin testing or sIgE can not only help direct allergen avoidance, but can also help customize treatment plans so that during patients' high allergen season(s), maximum therapy can be delivered. Almost all patients benefit from nasal corticosteroids. The frequency of administration (once or twice daily) largely depends on the severity of symptoms. Antihistamines can be added as an as needed medication for breakthrough itching and sneezing, or as a part of the daily regimen. The combination of nasal corticosteroids and topical nasal antihistamines has proved very useful in treating both allergic and non-allergic rhinitis. Oral decongestants can be considered primarily as an “as needed” medication in normotensive patients with nasal congestion not adequately controlled by antihistamines and corticosteroids. Antileukotrienes may also have an additive benefit and are most strongly considered in patients with concomitant asthma. Finally, allergen immunotherapy is worth considering in all patients with allergic rhinitis who have symptoms lasting more than 3-4 months per year and for whom medications are used perennially. Immunotherapy when given properly is the only treatment that can potentially affect a cure. To read an in-depth synopsis on Immunotherapy, click here.

The general approach to managing non-allergic rhinitis is to treat any underlying conditions that may be contributing to rhinitis symptoms. This may mean finding alternative medications in patients with medication-induced rhinitis, treating underlying sinus disease or hypothyroidism, or asking patients to experiment with different oral contraceptive preparations. If no underlying cause is found, nasal corticosteroids should be considered as first line therapy. Intranasal azelastine is also frequently beneficial, especially when combined with nasal corticosteroids. Like in allergic rhinitis, oral decongestants warrant consideration typically on an as needed basis for breakthrough nasal congestion.

Conclusions

Allergic and non-allergic rhinitis detrimentally affects the quality of life in a significant portion of the population. The co-morbidities associated with rhinitis can have a further negative impact on patients' wellbeing. Treatment of rhinitis requires that underlying triggers be identified and if at all possible modified. A step-wise approach using pharmacologic and non-pharmacologic therapies can then be implemented, typically with a satisfactory outcome for patients and physicians alike.


Figure 1: Relative incidence of allergic rhinitis, non-allergic rhinitis, and mixed rhinitis.

 

Table 1: Triggers of non-allergic rhinitis

1. Cold air.
2. Changes in climate (such as temperature, humidity, and barometric pressure).
3. Strong smells (such as perfume, cooking smells, flowers, and chemical odors).
4. Environmental tobacco smoke.
5. Changes in sexual hormone levels.
6. Pollutants and chemicals (e.g., volatile organics).
7. Exercise.
8. Alcohol ingestion.


Table 2. Differential Diagnosis of Rhinitis

Infections
Sinusitis
Allergic
Seasonal or Perennial
Non-allergic rhinitis
Eosinophilic non-allergic rhinitis (NARES)
Nonallergic rhinopathy (previously known as vasomotor rhinitis)
Aspirin intolerance (aspirin triad)
Rhinitis medicamentosa

Decongestants
Beta blockers
Birth control pills
Anti-hypertensives

Rhinitis secondary to:

Pregnancy
Hypothyroidism
Horner's syndrome
Wegener's granulomatosis

Non-allergic rhinitis

Eosinophilic non-allergic rhinitis (NARES)
Vasomotor rhinitis
Aspirin intolerance

Anatomical abnormalities causing rhinitis:

Decongestants
Beta blockers
Birth control pills
Anti-hypertensives

Rhinitis secondary to:

Pregnancy
Hypothyroidism
Horner's syndrome
Wegener's granulomatosis

Anatomical abnormalities causing rhinitis:

Foreign body
Nasal polyps
Nasal septal deviation
Enlarged tonsils and adenoids
Tumors
Cerebral spinal fluid rhinorrhea
Atrophic rhinitis

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