Indications

Allergen immunotherapy is used in the treatment of allergic rhinitis, allergic asthma, and stinging insect venom hypersensitivity. The diagnosis of these diseases is made by history and physical examination supported by testing to confirm IgE sensitization. Skin testing by prick or intradermal method is the preferred objective assessment, but in vitro tests such as the radioallergosorbent test are an alternative, especially when skin testing is unable to be performed.

Candidates for venom or Hymenoptera immunotherapy include all patients who have experienced life-threatening allergic reactions or non-life-threatening systemic reactions to Hymenoptera stings. The risk of ana-phylaxis for a venom-allergy patient from an insect sting is greater than the risk of anaphylaxis from immunotherapy. In patients younger than 16 years with only urticaria to Hymenoptera stings, immunotherapy is not generally recommended. However, in patients older than 16 years with only cutaneous reactions, immunotherapy is a recommended option. Venom immunotherapy is not indicated for patients who have only had local reactions at the stinging site, even large local reactions.

Immunotherapy is also effective for pollen, mold, animal dander, dust mite, and cockroach allergies. Symptomatic patients with allergic rhinitis and asthma despite allergen avoidance and pharmacotherapy are candidates for immunotherapy. Other candidates include allergic rhinitis or asthma patients having undesirable adverse reactions to medications, or those wishing to reduce or eliminate long-term pharmacotherapy. In addition to reducing symptoms to current allergens, immunotherapy may prevent the development of sensitization to new allergens or progression of allergic rhinitis to asthma, especially in children.

Mechanism

The exact mechanism of how immunotherapy works is not fully understood, but it involves shifting a patient’s immune response to allergen from a predominantly allergic T-lymphocyte (TH2) response to a “nonallergic” T-lymphocyte (TH1) response. Lymphocytes of a TH2 phenotype typically produce IL-4 and IL-5, cytokines needed for IgE production and eosinophil survival. Findings of increased production of IFN-y and a decreased production of IL-4 and IL-5 have not, however, been consistently demonstrated after immunotherapy. What has been consistent is the increased production of allergen-specific IL-10. IL-10 causes a shift in allergen-specific IgE to allergen-specific IgG4. This change may be orchestrated by regulatory T cells that downregulate allergic immune responses in part through the release of IL-10 and T-cell growth factor alpha (TGF-a). With allergen immunotherapy, the seasonal increase in allergen-specific IgE is blunted while protective allergen-specific IgG4 production is increased. However, these changes in IgE and IgG may not correlate with clinical efficacy, so periodic skin testing or in vitro IgE antibody measurements are not always useful in evaluating responses to immunotherapy.

Contraindications

Relative contraindications for immunotherapy include medical conditions that reduce patients’ ability to survive a serious systemic allergic reaction, such as coronary artery disease or the concurrent use of P-blockers (including   eye   drops)   or   angiotensin-converting   enzyme inhibitors.

Table. Immunotherapy

b-Adrenergic blocking agents may make the treatment of immunotherapy-related systemic reactions more difficult. Despite this, immunotherapy is indicated for patients with life-threatening stinging insect hypersensitivity receiving b-blockers. Allergen immunotherapy should not be initiated in asthmatic patients unless the patient’s asthma is relatively stable with pharmacotherapy. Patients who are mentally or physically unable to communicate clearly, such as very young children, are not good candidates for immunotherapy because it may be difficult for them to report early symptoms of a systemic reaction. Pregnancy is not a contraindication for immunotherapy, but by custom immunotherapy is not initiated during pregnancy. If a patient becomes pregnant while already on immunotherapy, the dose is not increased during the pregnancy but maintained at the current level in an attempt to avoid anaphylactic reactions.

Dosing

Safety

The greatest concern with immunotherapy is safety. Local reactions at the injection site, such as redness, swelling, and warmth, are common. These reactions can be lessened with HI antagonists prior to injections. Local reactions can be managed with treatments such as cold compresses or topical corticosteroids. Large local, delayed reactions (25 mm or larger) do not appear to be predictors of developing severe systemic reactions, and generally they do not require adjustment of dosing schedules. However, some patients with a greater frequency of large local reactions (more than 10% of injections) may be at increased risk for future systemic reactions, and dosing adjustments may be necessary.

The incidence of systemic reactions, such as urticaria, angioedema, increased respiratory symptoms (nasal, pulmonary, ocular), or hypotension, ranges from 0.05% to 3.2% per injection, or 0.84% to 46.7% of patients. Risk factors for systemic reactions include errors in dosing, symptomatic asthma, a high degree of allergen hypersensitivity, concomitant use of P-blocker medications, injections from a new vial, and injections given during periods when allergic symptoms are active, especially during the allergy season. A recent survey of 1700 allergists reported that 58% of responders had an event in which a patient received an injection meant for another patient, and 74% reported that patients had received an incorrect amount of vaccine. These errors resulted in a multitude of adverse events, including local reactions, systemic reactions, and even one fatality. Thus it is extremely important to make sure patients are questioned about potential risk factors and the correct vials are used to administer immunotherapy injections.

It is unclear if premedication with antihistamines can reduce the frequency of systemic reactions in conventional immunotherapy, but in cluster or rush immunotherapy, premedication can reduce the rate of systemic reactions.

The incidence of fatalities due to immunotherapy has not changed much over the last 30 years in the United States. From 1990 to 2001, fatal reactions occurred at a rate of 1 per 2.5 million injections, with an average of 3.4 deaths per year. Most fatal reactions occurred with maintenance doses of immunotherapy. The patient population at greatest risk was poorly controlled asthmatics. In many of the fatalities, there was either a substantial delay in giving epinephrine or epinephrine was not administered at all. The incidence of near-fatal reactions (respiratory compromise, hypotension, or both, requiring epinephrine) is 2.5 times more frequent than fatal reactions.

Treatment of anaphylaxis

Systemic allergic reactions can be life threatening and need to be treated rapidly. Most systemic reactions are limited to the skin, such as urticaria. Respiratory symptoms are seen alone or with skin manifestations in 42% of systemic reactions. Epinephrine is the standard of care for severe systemic or anaphylactic reactions. Treatment of anaphylactic reactions includes placing a tourniquet above the injection sites and immediately injecting epinephrine 1:1000 intramuscularly. For adults, the dose is typically 0.2 to 0.5 mL, and for children, 0.01 mL/kg (maximum, 0.3 mg dose) every 5 to 10 minutes as needed. For convenience, subcutaneous injection at the arm (deltoid) is frequently used, but intramuscular injection into the anterolateral thigh produces higher and more rapid peak levels of epinephrine.

Immunotherapy in general practice

Efficacy and outcomes

Once maintenance dosing is achieved for venom immunotherapy, 80% to 98% of individuals will be protected from systemic symptoms upon sting challenges. Maintenance therapy is generally recommended for 3 to 5 years, with growing evidence that 5 years of treatment provides more lasting benefit. A low risk of systemic reactions to stings (approximately 10%) appears to remain for many years after discontinuing venom immunotherapy. In children who have received venom immunotherapy, the chance of systemic reaction to a sting after discontinuation of immunotherapy is even lower.

The efficacy of immunotherapy for allergic rhinitis has been clearly demonstrated in a number of clinical trials. These studies have shown significant improvements in symptoms, quality of life, medication use, and immunologic parameters. Allergen immunotherapy for allergic rhinitis is also beneficial for at least 3 to 6 years after completion of a 3-year course of treatment.

The efficacy of immunotherapy for asthma has been assessed in many trials, but some studies have been difficult to interpret either because of the use of poor quality allergen extracts or suboptimal study design. The risk/benefit ratio of immunotherapy for asthma must always be considered. Currently, professional societies recommend that patients with asthma and forced expiratory volume in 1 second (FEVj) values less than 70% should not receive immunotherapy. A Cochrane review in 2004 examined the role of allergen immunotherapy for asthma. This review of 75 trials with 3100 patients found a significant reduction in asthma symptoms and medication use, and an improvement in bronchial hyperreactivity associated with the administration of allergen-specific immunotherapy. The reviewers concluded that immunotherapy is effective in asthma, and commented that one trial found that the size of the benefit was possibly comparable to inhaled corticosteroids.

Evidence-based medicine

This study evaluates the use of immunotherapy versus placebo in 206 children, 6 to 14 years of age, with only allergic rhinitis. The children were treated for 3 years with grass and/or birch extract depending on their sensitivities. After 3 years of immunotherapy, 19 patients developed asthma; 60 did not. In the placebo arm, 32 children developed asthma over 3 years, whereas 40 did not. The odds ratio for developing asthma in those receiving placebo was 2.5 times greater than that for children treated with allergen immunotherapy. This study was the first to demonstrate clearly that allergy immunotherapy may prevent or delay the onset of asthma in children with allergic rhinitis.

This study by Golden and colleagues evaluated the long-term outcomes of venom immunotherapy in 512 sensitized children. The mean follow-up was 18 years with a mean duration of immunotherapy of 3.5 years. The rate of systemic reactions after being restung was significantly greater among patients not treated with immunotherapy (17%) compared to those treated with venom immunotherapy (3%). In those treated with immunotherapy who only had skin manifestations prior to therapy, none had systemic reactions when restung.

Conclusion

Allergen immunotherapy has been a valuable tool in treating allergic rhinitis, asthma, and stinging insect hypersensitivity for decades. Although newer pharmaco-logic agents continue to become available, immunotherapy is still the only available treatment that alters the natural course of allergic diseases. Even though there are some risks, these can be minimized when immunotherapy is given in an appropriate environment to carefully selected patients. Recent guidelines have been established to further reduce the risks by establishing a universal system of reporting dilutions and establishing appropriate dosing. Despite a large body of evidence demonstrating the positive therapeutic benefits of immunotherapy, only 3 million patients in the United States are receiving immunotherapy out of a potential 40 to 50 million allergic patients, many of whom could benefit from this therapy. Newer therapies, such as anti-IgE (omalizumab), when used with immunotherapy, may improve the efficacy and safety profile of immunotherapy in the future. In addition, newer forms of immunotherapy such as T-cell peptides or immunostimulating sequences of DNA containing CpG motifs combined with allergens are currently under investigation.

Allergen immunotherapy dosing consists of two treatment phases: the buildup phase and the maintenance phase. The prescribing physician must specify the starting immunotherapy dose, the target maintenance dose, and the immunotherapy buildup schedule. The highest concentration of vaccine projected to provide the thera-peutically effective dose is called the “maintenance” dose or concentrate. In general, the starting immunotherapy dose is 1000- to 10,000-fold less than the maintenance dose. For highly sensitive patients, the starting dose may be even lower. Dilute concentrations are more sensitive to degradation and lose potency more rapidly than the more concentrated preparations. Thus their expiration dates are much shorter and must be closely monitored.

The buildup phase involves injections with increasing amounts of allergens. The frequency of the injections can vary depending on the protocol. The most common or “conventional” protocol recommends dosing once to twice a week with at least 2 days between injections. It is customary to repeat or reduce the dose if there has been a substantial time interval between injections. Patients with greater sensitivity may require a slower buildup phase to prevent systemic reactions. With this schedule, maintenance is usually achieved after 3 to 6 months. Alternative schedules such as “rush” or “cluster” immunotherapy rapidly achieve maintenance dosing and should only be administered by an allergist/immunologist because of an increased risk for systemic reactions. Immunotherapy dosing schedules should be written by trained allergists/immunologists, and primary care physicians should seek their advice if questions or issues arise during administration.

The maintenance phase begins when the effective therapeutic dose is achieved. This final dose is based on several factors, including the specific allergen, the concentration of the extract, and how sensitive a patient is to the extract. Once maintenance is achieved, the intervals for injections range from every 2 to 6 weeks but are individualized for each patient. Clinical improvement can be demonstrated shortly after the patient reaches his or her maintenance dose. If no improvement is noted after 1 year of maintenance therapy, a reassessment should be done.

Table. Conventional immunotherapy.

Table. Typical buildup schedule for conventional immunotherapy.

Possible reasons for lack of efficacy need to be evaluated, and if none are found, discontinuation of immunotherapy should be considered. Patients should be evaluated at least every 6 to 12 months while on immunotherapy by the prescribing allergist/ immunologist. Duration of maintenance therapy is generally 3 to 5 years. Treatment may lead to prolonged clinical remission and persistent alterations in immuno-logic reactivity. The severity of disease, benefits from sustained treatment, and the convenience of treatment are all factors that are considered when deciding the length of therapy for each individual patient.

Many studies, especially from Europe, have shown that high-dose sublingual allergen immunotherapy is effective for certain patients, but this mode of therapy is not approved by the U.S. Food and Drug Administration and is considered investigational. Many questions still  remain   unanswered   on   sublingual

immunotherapy including effective dose concentrations, schedule for buildup and maintenance therapy, and timing of dosing (i.e., seasonal or continuous throughout the year). Additionally, sublingual therapy requires much larger doses of allergen, anywhere from 10 to 300 times greater, making cost an issue. Finally, the utility of sublingual immunotherapy for polysensitized patients is not yet determined.

A brief review of a patient’s current health status is recommended prior to dosing. It is important to assess any current asthma symptoms, increased allergic symptoms, any new medications, or any delayed reactions to the previous injection. In patients with asthma, peak expiratory flow rate measurements should be obtained prior to each injection.  In general, immunotherapy injections should be withheld if the patient presents with an acute asthma exacerbation or if peak flow measurements are below 20% of the patient’s baseline values. Immunotherapy may need to be decreased or held if significant allergic symptoms are present prior to an injection.

Table. Immunotherapy vaccine labeling.

Most severe reactions develop within 20 to 30 minutes after the immunotherapy injection, but reactions can occur after this time. Patients need to wait at the physician’s office for at least 20 to 30 minutes after the immunotherapy injection. In some cases, the wait may need to be longer depending on the patient’s history of previous reactions.

It is usual practice to reduce the dose of vaccine when the interval between injections is longer than prescribed. This reduction in dose should be clearly stated on the patient’s immunotherapy schedule. Because of the potential of extract degradation over time, when new vials are started the initial dose is decreased and then built back up to maintenance. When a systemic reaction occurs, the physician needs to decide if immunotherapy should be continued. This should be done in consultation with the allergist/immunologist who prescribed the immunotherapy. If the decision is to continue, the dose of the vaccine needs to be appropriately reduced to lessen the risk of a subsequent systemic reaction.

Definition and physiology

Cough is a protective mechanism to expel offending agents from the respiratory tract. The mechanics of cough can usually be characterized into four phases:

1.  Inspiration

2.  Compression (expiration against a closed glottis)

3.  Expulsion (opening of glottis with expulsive airflow)

4.  Recovery (restorative inspiration)

This combination of actions is orchestrated by an extensive neuron network. Involuntary cough is primarily initiated by the vagus afferent nerves. The pharynx is innervated by the glossopharyngeal nerve and a branch of the superior laryngeal nerve. The larynx is innervated by the superior and recurrent laryngeal nerves, which join the vagus nerve. The trachea and bronchi are innervated by three types of nerve fibers called rapid adapting receptor, slowly adapting stretch receptor (seasonal allergic rhinitis), and C fibers. RARs are triggered mainly by mechanical stimuli and some inflammatory mediators. SARs are nerve fibers that inhibit inspiration. C fibers are triggered primarily by noxious chemicals and some mechanical irritants.

Causes of cough

Symptomatic treatment of cough

The goal in treating cough is always to find the etiology. However, symptomatic relief is needed if the source of the cough is unknown or the treatment of the underlying process requires a prolonged course. Usually, the medications are divided into peripheral and central acting agents.

First-generation antihistamines have some local anti-cholinergic effects in the nasal passages and seem to have some consequence in reducing cough symptoms for upper respiratory tract infections. Inhaled iprat-ropium bromide also has peripheral cough suppressing effects for upper respiratory tract infection and COPD. Interestingly, other anti-cholinergic inhalers do not seem to have the same effect. In some studies, guaifenesin, an expectorant, decreases symptom of cough in upper respiratory tract infection and bronchiectasis.

The central acting cough suppressants are believed to act on the brainstem. Dextromethorphan is the most commonly used nonsedating, nonaddicting agent.

Codeine and other opioids have modest effects on chronic bronchitis cough. Some studies suggest codeine is not very effective for upper respiratory tract infections.

Conclusion

Cough can be a common presentation for many diseases. Because allergic diseases can affect up to 25% of the general population, atopy should always be a consideration in the differential diagnosis of cough. Allergic diseases play a significant part in upper airway cough syndrome (postnasal drip) and asthma, which are the two most common causes of cough. The advent of modern allergy medications has allowed for a powerful way of teasing out the atopic component of cough. It can be used as a diagnostic tool as well as a therapeutic treatment. Having the patient assign a percentage of effectiveness to the different medications can help distinguish between the primary and secondary causes. Thus, integrating therapeutic trials with the history and diagnostic testing can help elucidate the complex etiologies of cough.

Evidence-based medicine

Hartl D, Griese M, Nicolai T, et al. Pulmonary chemokines and their receptors differentiate children with asthma and chronic cough.

This study attempts to use bronchioalveolar lavage fluid chemokines and their receptors to distinguish between children with allergic asthmatic cough from children with chronic nonatopic cough. A total of 37 children were sampled: 12 patients with allergic asthmatic cough, 15 patients with idiopathic nonatopic chronic cough, and 10 healthy control patients, ranging from ages 3 to 17. The allergic asthmatic children had a significantly higher level of CCR4⁺CD4⁺ cells (TH2), thymus- and activation-regulated chemokine (TARC), and macrophage-derived chemokine (MDC) as compared to the nonatopic chronic cough children and control. In the nonatopic chronic cough group: CXCR3⁺CD8⁺ cells (TH1) and levels of IFN-gamma-inducible T cell alpha chemoattractant (ITAC) were significantly elevated as compared to the atopic asthmatics as well as the controls. This study helps validate the association of atopy and TH2 chemokines, providing a useful method for distinguishing atopic cough versus nonatopic cough.

This study tries to evaluate if there are unique characteristics of inflammation or remodeling as a result of asthmatic cough versus nonasthmatic cough. A group of 62 patients were subdivided into: 33 nonasthmatic chronic cough patients, 14 asthmatic cough patients, and 15 healthy controls. These patients underwent bronchoscopy with biopsies and had capsaicin cough sensitivity assessment. The group with nonasthmatic cough had significant mast cell hyperplasia, increased smooth muscle area, and increased cough sensitivity not seen in the asthmatic cough patients or the control. There was also a positive correlation between the increased cough sensitivity in relation to goblet cell hyperplasia and epithelial shedding. The asthmatic cough group had increased submucosal eosinophils and neutrophils. The results show that airway remodeling was prominent in nonasthmatic as well as asthmatic cough patients. This suggests that the chronic cough itself is the cause of the airway remodeling.

The American College of Chest Physicians’ Evidence-Based Clinical Practice Guidelines concluded from four prospective studies that these three etiologies comprised greater than 92% of patients with cough (who had normal chest radiographs, were nonsmokers and not on angiotensin-converting enzyme inhibitors).

Upper Airway Cough Syndrome (Postnasal Drip Cough)

Upper airway cough syndrome, or postnasal drip syndrome, is the most common cause of cough. The physical drainage of nasal mucus down the posterior pharynx to the larynx and upper airway induces cough. Upper airway cough syndrome includes allergic, nonallergic, and infectious rhinitis. Note that the cough may be due to more than one of these etiologies. The strategy is to discern the primary and secondary causes. The history that suggests upper airway cough syndrome includes tickling of the throat, hoarseness, throat clearing, and congestion of the throat. This type of postnasal drip cough is often alleviated by drinking or eating. The action of swallowing causes the reflexive closure of the epiglottis. A closed epiglottis shunts the postnasal drip to the esophagus bypassing the posterior pharynx and larynx. This may be the main reason why taking a cough drop and drinking water both help relieve symptoms of cough.

Allergic Rhinitis and Cough

Allergic rhinitis affects as many as 20% to 25% of the population. It is defined as an inflammatory response of the nasal mucosa to airborne antigens. This action is mediated by an IgE antibody. Allergic rhinitis often presents as postnasal drip, nasal congestion, rhinorrhea, and eustachian tube dysfunction. Postnasal drip causes both mechanical and inflammatory mediators to trigger the cough reflex in the larynx and trachea.

Table. Respiratory innervations.

Table. Causes of cough.

The history attained from the patient can usually be subdivided into seasonal versus perennial symptoms. Patients who suffer from these symptoms in spring are affected by grass and tree pollen. Symptoms occurring during the fall are typically caused by weed pollen. The perennial symptoms are usually triggered by dust mites, animal proteins, and mold spores. Itching of the nose and eyes is the key symptom that distinguishes allergic rhinitis from other causes. Although sneezing is an associated symptom, it is not unique to allergic rhinitis. Sneezing can be due to infectious, mechanical, or chemical nasal irritation.

Physical examination findings that may help in ascertaining allergic rhinitis include the appearance of posterior pharynx “cobblestoning” and/or observation of mucus draining down the posterior pharynx. Tests such as allergy skin tests and the radioallergosorbent test (radioallergosorbent test) can help establish or rule out allergic causes. However, allergy testing alone without a clinically significant history will lead to an inaccurate diagnosis. Ultimately, the use of a daily intranasal corticosteroid for 2 weeks is the most practical solution for discerning allergic rhinitis from other causes. If symptoms improve, then the likely cause is allergic rhinitis. Asking the patient to assign a percentage of improvement with this therapy is helpful in modifying the treatment plan. If the patient is still symptomatic after using the intranasal corticosteroid, adjunctive therapy with a daily leukotriene receptor antagonist for an additional 2 weeks may be beneficial.

Nonallergic Rhinitis and Cough

A significant etiology of chronic cough that is often overlooked is nonallergic rhinitis with postnasal drip. It encompasses vasomotor rhinitis, nonallergic rhinitis with eosinophilia syndrome, rhinitis medicamentosa, and gustatory rhinitis. Nonallergic rhinitis is usually perennial, triggered by irritants, and has negative IgE allergy skin tests or radioallergosorbent test.

Vasomotor Rhinitis

Vasomotor rhinitis is defined as rhinorrhea, nasal congestion, and postnasal drip cough caused by nasal mucosal autonomic nerve instability or dysfunction. The autonomic nerve instability causes vasodilation and vascular leakage leading to mucosal edema as well as triggering an overproduction of mucus. The stimuli for vasomotor rhinitis usually consist of physical and chemical irritants. These common irritants include odors, smoke, fumes, changes in temperature, and changes in barometric pressure/humidity. A positive correlation between the patient’s history and exposure to the irritants is the key to diagnosing this entity. Avoidance of the offending agent, if possible, is the first course of action. However, if this is not possible, medications can serve as a diagnostic tool as well as a treatment option.

If nasal congestion is elicited in the patient’s history, the use of azelastine nasal spray two puffs per nostril twice a day for a 2-week trial would be in order. If the nonallergic rhinitis symptom is mostly rhinorrhea, then a 2-week trial of nasal ipratropium bromide, 0.03% or 0.06% one to two puffs per nostril up to four times a day, would reduce mucus production.

Nonallergic rhinitis with eosinophilia syndrome

Nonallergic rhinitis with eosinophilia syndrome occurs when eosinophils are found in the nasal mucosa. This syndrome has all of the symptoms of vaso-motor rhinitis with the addition of itching of the nose and eyes. The IgE allergy skin test or radioallergosorbent test is negative in nonallergic rhinitis with eosinophilia syndrome. A nasal swab for eosinophils is conducted with Hansel’s stain to help make the diagnosis. nonallergic rhinitis with eosinophilia syndrome is treated with an intranasal corticosteroid to inhibit the eosinophils and inflammatory mediators.

Rhinitis Medicamentosa

Rhinitis medicamentosa is defined as paradoxical nasal congestion due to the overuse of topical nasal vasoconstrictors (e.g., oxymetazoline). The long-term use of topical vasoconstrictors (typically alpha agonists) can cause tachyphylaxis or a need for more of the drug to maintain the effect that was initially attained with the medication. Withdrawal of the topical vasoconstrictor causes a rebound vasodilatory effect, which leads to nasal congestion. Associated with this phenomenon is a postnasal drip cough due to overproduction of mucus. The treatment is cessation of the topical nasal vasoconstrictor. It may take up to 2 weeks before the congestion resolves completely.

Gustatory Rhinitis

Gustatory rhinitis is rhinorrhea, nasal congestion, and/or postnasal drip caused by the act of eating or drinking. This is a vagal reflex that causes vasodilation of the nasal mucosa and an increase in mucus production. Rhinorrhea is the most common symptom, and ipratropium bromide nasal spray is the drug of choice. Again, if there is a nasal congestion component, azelastine may be helpful.

Infectious Rhinitis and Cough

Infectious postnasal drip cough can occur with viral infection, sinusitis, and/or from a postinfectious cause. Patients who have viral infections experience malaise, clear mucus drainage, nasal congestion, postnasal drip cough, myalgia, and sometimes fevers. Treatment using saline rinses, decongestants and mucolytics usually help resolve symptoms of cough in a couple of weeks. If coughing persists, bacterial sinusitis needs to be considered.

Bacterial sinusitis can be diagnosed with a history of purulent drainage that persists for longer than 10 days and sometimes with symptoms of maxillary tooth pain. Sinus radiographs or computed tomography scans tend to be the studies of choice. The common bac-terias associated with sinusitis are Streptococcus pneumonia, Haemophilus influenzae, and Moraxella catarrhalis in children. In chronic sinusitis, anaerobic bacteria may play a role. The treatment method should consist of a three-step approach:

1.  Decrease nasal mucosa swelling with intranasal corticosteroid with or without a short burst of oral steroids to allow for proper mucus drainage.

2.  Loosen up thick mucus with a mucolytic (e.g., guaifenesin).

3.  Neutralize the bacteria with the appropriate antibiotic (e.g., amoxicillin or penicillin alternative).

Acute sinusitis requires 2 weeks of treatment; chronic sinusitis requires 4 to 6 weeks of treatment. If a sinus radiograph or computed tomography sinus is positive, and the patient does not respond to antibiotics, fungal sinusitis needs to be considered. Fungal sinusitis requires surgical resection.

Postinfectious cough can comprise 11% to 15% of upper respiratory tract infections. This is the type of cough that lingers for longer than 3 weeks. It usually resolves before the eighth week of symptoms. The two organisms of interest are Bordetella pertussis and Mycoplasma pneumoniae. Although culturing or antibody titers can be attempted, a trial of an oral macrolide for 2 weeks would be the most practical course of action.

Angiotensin-Converting Enzyme Inhibitor Cough

With the rise of diabetes and hypertension in the general population, the use of angiotensin-converting enzyme inhibitors has become more prevalent. It can cause a persistent cough in up to 35% of its users. The mechanism is believed to be the inhibition of ACE, which normally degrades bradykinin and substance P. These mediators induce upper airway cough. This class of medications is unusual because the cough can occur much later after the initial use of the medication. The cough may take up to 3 months to resolve after discontinuation of the angiotensin-converting enzyme inhibitors.

Asthma and Cough

Cough is one of many symptoms associated with asthma. However, there tends to be an overdiagnosis of asthma as the cause of chronic cough. The definition of asthma can be elusive. Its most basic definition is hyperresponsive airway disease that is reversible. This hyperresponsive airway is driven most of the time by chronic inflammation of the bronchioles triggered by atopic, physical, or chemical irritation. The chronic inflammatory mediators then cause bronchial smooth muscle constriction and an overproduction of mucus that necessitates clearing the airway with coughing.

Although symptoms of cough, dyspnea, and wheezing may suggest asthma, the need for allergy skin tests/radioallergosorbent test, pulmonary function tests, and response to treatment are important. Spirometry with pre- and post-short-acting bronchodilator agents (e.g., albuterol) showing a forced expiratory volume in 1 second (FEV,) increase of greater than 12% and 200 mL is a practical approach to showing reversible airway disease. However, if the patient is not actively having bronchospasm, the spirometry may yield a normal result. A better and more definitive test is a methacholine challenge. This test induces airway reactivity if the patient has underlying asthma. Patients are given increasing sequential doses of methacholine, and spirometry is administered after every dilution. A provocative concentration that causes a 20% reduction from the baseline forced expiratory volume in the first second (PC20FEV,) or a decrease in specific conductance of 35% to 45% from the baseline at less than 16 mg/mL of methacholine is considered a positive methacholine challenge.

An adequate trial of asthma medications is the last step to diagnosing asthma, after having considered and treated upper airway cough syndrome and other potential causes of cough. An inhaled corticosteroid used on a daily maintenance schedule with or without a long-acting beta agonist is the drug of choice depending on severity. If the patient has a severe cough or shortness of breath, using a trial of pred-nisone, 40 mg once a day for 7 days, will help control the inflammation more efficiently. Leukotriene receptor antagonists can also be added later, if symptoms persist.

Cough Variant Asthma

Cough variant asthma is a subset of asthma that can present as cough alone with a normal physical examination and a normal spirometry. Patients with Cough variant asthma tend to have a more sensitive cough reflex but less bronchial reactivity when compared to classic asthmatics. A methacholine challenge may assist in confirming bronchial reactivity, but it does not necessarily establish the diagnosis of Cough variant asthma. The definitive diagnosis depends on resolution of symptoms after being treated with asthma medications.

Nonasthmatic Eosinophilic Bronchitis

Nonasthmatic eosinophilic bronchitis is a steroid responsive chronic cough found in nonsmokers who have sputum eosinophils without variable airflow obstruction. The sputum should contain a nonsquamous cell sputum eosinophil count of greater than 3%. Methacholine challenges in patients with no asthmatic eosinophilic bronchitis usually yield a normal result. It can be associated with occupational exposures as well as allergens. The treatment is avoiding offending agents and using asthma anti-inflammatory medications.

Gastroesophageal Reflux Disease and Cough

Gastroesophageal reflux disease frequently causes a persistent cough. It is defined as a retrograde movement of gastric material from the stomach to the esophagus. Common symptoms of gastroe-sophageal reflux disease include heartburn, regurgitation, sour taste in the back of the mouth, and coughing. In a normal individual, it can occur 50 times a day. Some studies suggest that the patient may not detect symptoms of gastroesophageal reflux disease 75% of the time.

Gastroesophageal reflux disease causes cough in two ways. Gastric material (frequently acid) can make its way up the esophagus to the larynx and cause direct irritation. However, this is not always necessary. Acid or other caustic agents (e.g., pancreatic enzymes or bile) can irritate the distal esophagus. This stimulation of the vagal reflexes can cause bronchoconstriction or cough. The diagnostic procedures that may be helpful are 24-hour esophageal pH monitoring and barium esophagography. The 24-hour esophageal pH monitoring is the most sensitive and specific test for measuring acid in the esophagus. However, by itself this test does not establish causation. Barium esophagography helps determine if there is an esophageal lesion from nonacid gastroe-sophageal reflux disease. Perhaps the most helpful information for diagnosing gastroe-sophageal reflux disease is a significant resolution of the persistent cough after a 1- to 3-month trial of antireflux treatment. The preferential choice of antireflux treatment is a proton pump inhibitor. This therapy would then be followed by changes in diet and lifestyle modifications to reduce acid production.

The ear has multiple targets for allergic diseases. The external ear may be afflicted with contact dermatitis to earrings or hearing aid molds, eczema, or sensitization to ear drops or fungus. The middle ear may be plagued with persistent effusion secondary to eustachian tube dysfunction or chronic inflammatory response to allergens. The inner ear may be troubled by Meniere’s disease and cochlear hydrops, both disorders with possible allergic bases.

Allergic diseases of the external ear

Chronic Otitis Externa

The skin of the pinna and external ear may be afflicted in two major ways. Eczema of the auricle or external auditory canal may manifest as erythematous, scaling, and pruritic dermatitis. Atopic eczema is the most common type of eczema and closely associated with asthma and allergic rhinitis. The usual treatments are with emollients that maintain skin hydration and topical steroids to reduce inflammation. Another type of eczema seen is seborrheic eczema, which is most commonly seen on the scalp as dandruff but can spread to the face and ears. The condition is thought to be caused by yeast and can be treated with an antifungal cream if necessary. Chronic otitis externa that follows the use of topical antimicrobial drops, particularly those containing neomycin, can actually be a Cell and Coombs Type IV hypersensitivity reaction. Symptoms generally resolve with discontinuation of the offending agent; however, occasionally topical steroid drops may be needed to accelerate recovery.

Contact Sensitivity

Some patients may develop contact sensitivity to certain plastic molds attached to hearing aids. The problem manifests as a localized skin reaction. Boiling the hearing aid mold in water for 30 seconds, substituting a different material for the mold, or plating a thin film of gold onto the mold may reduce symptoms. Along this vein, patients may develop contact sensitivity to nickel and chromium in earrings. Treatment often involves use of earring posts of surgical stainless steel or 14-karat gold or titanium.

Dermatophytid Reaction

The auricle or external auditory canal can be the site of a dermatophytid reaction in a sensitized individual. Usually there is a primary site of fungal infection. The fungus or their aller-genic products spread hematogenously to a secondary site, causing an allergic skin eruption. Resolution requires treatment of the primary fungal infection, desensitization with an allergenic extract of the infecting fungus, and control of any secondary bacterial infections. The most common fungus involved is Trichophyton, although Candida (Oidiomycetes) and Epidermophyton have also been described. Common sites for the primary fungal infection include the nails (onychomycoses), skin, and vagina (monilial vaginitis).

Allergic diseases of the middle ear

Allergic diseases of the inner ear

Meniere’s Disease

Meniere’s disease is characterized by aural fullness, tinnitus, vertigo, and fluctuating sensorineural hearing loss. Two related variants are cochlear hydrops (fluctuating sensorineural hearing loss without vertigo) and vestibular hydrops (imbalance without fluctuating sensorineural hearing loss). The etiology of Meniere’s disease is unclear and has been attributed to anatomic, infectious, immunologic, and allergic factors. The target organ appears to be the endolymphatic sac. The mainstays of medical therapy have included diuretic therapy (particularly thiazide diuretics), carbonic anhydrase inhibitors, vasodilators, salt reduction (<1.5 g/day) and dietary restrictions. Surgical therapy is reserved for cases refractory to medical management. These include chemical labyrinthectomy (intratympanic aminoglycoside), surgical labyrinthectomy, endolymphatic shunt, and vestibular nerve section.

Both inhalant and food allergies have been linked with symptoms of Meniere’s disease and cochlear hydrops. Patients with Meniere’s disease have a 40% rate of allergy, as measured by skin or in vitro testing, which is twice as high as that reported for the general population. The success of sedating antihistamines in the treatment of Meniere’s disease is usually attributed to vestibular suppressant effects, but allergic reaction suppressant properties may also contribute to clinical improvement. Dietary restrictions on sodium, caffeine, nicotine, alcohol, and foods containing theophylline (e.g., chocolate) improve symptoms in patients with Meniere’s disease, although the mechanism has usually been attributed to fluid regulation of the endolymphatic sac. Regardless, immunotherapy and food elimination diets have mitigated both allergic and labyrinthine symptoms in Meniere’s disease.

Evidence-based medicine

Studies over the last few years have focused on the possible roles of allergy in Otitis media with effusion. Allergic rhinitis and nasal/nasopharyngeal inflammation resulting in Eustachian tube dysfunction is associated with increased rates of Otitis media with effusion. Allergy-related mediators (IL-4, IL-5, IL-6, regulated on activation, normal T-cell expressed and secreted [RANTES], eosinophil cationic protein [ECP], tryptase, IgE) isolated from middle ear effusions have been shown to be elevated. The role of food allergy in Otitis media with effusion and in other allergic diseases of the ear is under active investigation. For Otitis media with effusion and Meniere’s disease, an allergic basis of disease and treatment should be considered in cases refractory to conventional medical and/or surgical management.

Table. Otologic manifestations of allergy.

Eustachian Tube Dysfunction

Eustachian tube dysfunction is a major factor in the development of Otitis media with effusion. Upper respiratory infections and allergies contribute to Eustachian tube dysfunction, and in some cases contribute to a patulous Eustachian tube. Patients with patulous Eustachian tube may complain of autophony (abnormal awareness of their own voice), reverberation, or tinnitus resembling the sound of an ocean roar. Provocative intranasal challenges of pollen, house dust mites, and histamine worsen Eustachian tube dysfunction. Allergic rhinitis results in a significantly higher rate of Eustachian tube dysfunction, particularly during childhood, as demonstrated by nasal turbinate changes. Bernstein proposes that Eustachian tube dysfunction in the setting of allergy may be a result of retrograde spread of edema and congestion of nasal mucosa, decreased mucociliary function that permits secretions to cover the ostium and subsequent intraluminal inflammation, or obstruction of the Eustachian tube orifice from hypersecretion by seromucous glands. These symptoms can be alleviated with specific allergy therapy, including immunotherapy and elimination diets depending on the offending agent.

Otitis Media with Effusion

Otitis media with effusion often results from Eustachian tube dysfunction or can be the result of chronic inflammation or microbial infection. The causative contribution of allergy to Otitis media with effusion is unknown, with a broad range of attribution (0% to 95%) reported in the literature. The controversy regarding the role of allergy in Otitis media with effusion is reflected in different types of skin and in vitro testing, and heterogeneous types of allergens included in each study. Many would agree that Otitis media with effusion caused by allergy is most likely from Eustachian tube dysfunction secondary to an allergic reaction in the proximal Eustachian tube or nasopharynx. However, some studies have demonstrated the presence of histamine and other biologic mediators of inflammation in the middle ear fluid of patients with Otitis media with effusion, suggesting that the middle ear is also a primary target of allergic reactions.

An argument against a significant role of allergy in the pathogenesis of Otitis media with effusion is that although allergy is typically considered seasonal with regional variation, Otitis media with effusion has its highest incidence in the winter, regardless of region. In addition, an IgE-mediated reaction is brief and not typically long enough to cause significant Eustachian tube dysfunction. Also, there is no clear evidence for an intranasal challenge directly producing a middle ear effusion. Although intranasal challenges have resulted in Eustachian tube dysfunction, the duration of dysfunction is insufficient to result in Otitis media with effusion. Even complete Eustachian tube obstruction produced by sectioning the tensor veli palatine muscle in an animal model takes 1 to 4 weeks to result in a middle ear effusion. Intranasal provocative challenge persists for only several hours to a few days.

Counter arguments contend that winter is the time of year when dust and mold counts tend to be highest. Intranasal challenges of histamine, pollen, and house dust mites result in Eustachian tube dysfunction, albeit of unclear sufficient duration to cause Otitis media with effusion. Epidemiologic studies have shown that patients with Otitis media with effusion have an increased prevalence of atopic conditions, such as allergic rhinitis, eczema, and asthma. More than 50% of patients with Otitis media with effusion have allergic rhinitis, whereas 21% of patients with allergic rhinitis have Otitis media with effusion. One study of 20 patients with Otitis media with effusion refractory to medical and surgical management showed that allergy immunotherapy in patients tested with the radioallergosorbent test resulted in preservation of hearing and elimination of recurrent infections for 3 years when compared with controls. Although small, this study encourages consideration of allergic factors in patients with refractory Otitis media with effusion to conventional treatments.

Food Allergy in Otitis Media with Effusion

Few studies address the role of food antigens in Otitis media with effusion. One study of 56 children found food allergies in children with Otitis media with effusion (45%) were significantly higher than in children without complaints of food allergy or Otitis media with effusion (18%). Another study of 104 children with recurrent otitis media found that 78% had food allergy diagnosed by skin prick or IgE tests and food challenge. They reported that 86% of the children with food allergy who were treated with food elimination had significant amelioration of Otitis media with effusion, as documented by clinical examination and tympanometry. Food challenge resulted in recurrence of Otitis media with effusion in 94% of the children with food allergies who underwent challenge. A few studies have suggested that cow’s milk allergy in infancy, even when treated properly, is associated with significantly higher rates of recurrent Otitis media with effusion. A few of these studies address possible mechanisms for this association. These include nasal congestion induced by food allergy, direct middle ear mucosal damage by food immune complexes, and other hypersensitivity response. One study demonstrated elevated serum IgG response, but a lack of IgE response, to foods in oti-tis-prone children compared with controls. More definitive studies are needed in this area. Nevertheless, current results encourage consideration of a food elimination diet in select patients before surgical intervention.

Patients with allergic rhinitis, one of several inflammatory disorders of the upper respiratory tract, often suffer from impaired sleep. A recent survey of allergic rhinitis patients revealed that 68% of respondents with perennial allergic rhinitis and 48% with seasonal allergic rhinitis reported that their condition causes significant sleep disturbances. One of the major symptoms of the disorder, nasal congestion, in addition to such underlying disease processes as the release of inflammatory mediators, can cause the sleep impairment associated with allergic rhinitis.

The symptoms of allergic rhinitis include rhinorrhea, sneezing, pruritus of the eyes, nose, and throat, and nasal congestion. Nasal congestion stands as one of the most prominent and bothersome symptoms of the disorder, especially because it is linked to sleep-related problems associated with allergic rhinitis, such as sleep-disordered breathing, sleep apnea, and snoring.

The prevalence of inflammatory disorders of the upper respiratory tract make the sleep impairment associated with many of these disorders a common problem. Allergic rhinitis alone reportedly affects approximately 25% of the world’s population, and its prevalence has continued to climb. It has been estimated that the disorder affects 20 to 40 million people in the United States, which includes approximately 40% of the nation’s children. In Europe, the prevalence of allergic rhinitis is estimated as 23%.

Those who suffer from allergic rhinitis often cannot escape the socioeconomic burdens associated with living with the disorder. In 2000, patients spent over $6 billion on prescription medications for allergic rhinitis. Along with this overwhelming cost of treatment, patients must face the secondary cost of poor productivity, which stems from the negative impact of the disorder’s symptoms on patients’ lives, as well as the use of inappropriate therapies. The detrimental effect of allergic rhinitis on patients’ quality of life has been demonstrated by generic health-related quality of life questionnaires, such as the Medical Outcomes Study Short Form Health Survey (SF-36), and disease-specific measures, such as the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). This adverse impact on patients may result from the sleep impairment associated with the disorder. Although studies have shown that treatments for allergic rhinitis, particularly those that improve symptoms of nasal congestion, can improve patients’ sleep and quality of life, further research is needed to elaborate this limited existing data. This chapter explores the sleep impairment associated with allergic rhinitis and the adverse effects of disturbed sleep on patients’ quality of life. This chapter also examines how these effects are impacted by therapies that target the disorder’s underlying problems influencing sleep.

Evidence for sleep impairment in allergic rhinitis

Allergic rhinitis and other inflammatory disorders of the upper respiratory tract are generally associated with sleep impairment, daytime somnolence, and fatigue. Of the multiple symptoms of allergic rhinitis, nasal congestion, in particular, detrimentally affects sleep. The Allergic Rhinitis and its Impact on Asthma guidelines (Table Allergic rhinitis severity guidelines for the classification of allergic rhinitis.) serve to classify allergic rhinitis severity and provide a measure for this degree of sleep impairment. The sleep disturbances allergic rhinitis patients suffer from include microarousals and sleep-disordered breathing, which includes snoring to obstructive sleep apnea and/or hypopnea. Chronic excessive daytime sleepiness or fatigue has been demonstrated as more likely disturbances in patients with frequent nighttime symptoms than in those with rare or no such symptoms. Further examples illustrating that sleep impairment stands as a major concern for allergic rhinitis patients include a study showing that allergic rhinitis leads to snoring in children, and another study demonstrating that concomitant allergic rhinitis independently relates to difficulty sleeping and daytime sleepiness in bronchial asthma patients.

Table. Allergic rhinitis severity guidelines for the classification of allergic rhinitis.

Mechanisms of sleep impairment

Sleep impairment and quality of life

The Effects of Sleep Impairment

Patients with allergic rhinitis often must face adverse consequences of sleep disturbances, such as impaired cognitive function and decreased productivity and performance in the workplace. In children with allergic rhinitis, learning ability and school performance are afflicted.

Table. List of mediators contributing to daytime somnolence and fatigue (allergic rhinitis vs. severe sleep apnea).

Although symptoms of the disorder may lead to these consequences, the sleep impairment caused by allergic rhinitis is the likely cause of aggravation. Sleep-disordered breathing and sleep impairment have been known to correlate with decreased quality of life in the general population. Specifically, experimentally induced sleep fragmentation in healthy subjects leads to impaired mental flexibility and attention, increased daytime fatigue, and impaired mood. Children and adolescents with allergic rhinitis also suffer from impaired sleep, which results in problems doing schoolwork and poor school performance, compared to controls.

A survey across five European countries using patients suffering from allergic rhinitis or urticaria showed that a considerable proportion of respondents reported snoring or poor sleep and not feeling rested in the morning. Of these respondents, 29% to 79%, and 28% to 56%, respectively, depending on the country, considered these problems either disruptive or extremely disruptive. Results from an Internet survey of 1322 individuals with rhinitis showed that both perennial and seasonal rhinitis interfered with sleep (68% and 51% of respondents, respectively) and daily routine (58% and 48%, respectively). Additionally, the sleep impairment suffered by allergic rhinitis patients has been linked to reduced psychological well-being, daytime fatigue, difficulty concentrating, and impaired psychomotor performance.

Measuring sleep impairment and impact on quality of life

Effects of therapy

Conclusion

The quality of life in patients with allergic rhinitis is detrimentally impacted by the sleep impairment associated with the disorder. One of the key causes leading to sleep disruptions and sleep-disordered breathing is nasal congestion, one of the most common and bothersome symptoms of allergic rhinitis. Recent research has led to the use of therapeutic agents that specifically target the nasal congestion associated with sleep impairment.

Intranasal corticosteroids stand as effective treatment that significantly reduces nasal congestion in allergic rhinitis. Clinical trials using this treatment suggest that this reduction in nasal congestion correlates with decreased sleep impairment, reduced daytime somnolence, and improved quality of life.

Further research is necessary to conclude definitively that intranasal corticosteroids hold the ability to improve sleep and quality of life in patients with allergic rhinitis. These studies should use sleep-related measures as primary endpoints and assess sleep parameters both subjectively and objectively, thus serving to identify the most effective therapies for alleviating the detrimental effects of sleep impairment associated with allergic rhinitis.

Evidence-based medicine

The hypothesis is that sleep and the consequences of poor sleep has been supported primarily by subjective assessments in studies where sleep-related outcomes stood as secondary endpoints. No controlled study has shown definitively that the reduction of nasal congestion, as measured by an objective instrument, correlates with improvement in daytime somnolence and fatigue or objective sleep measures. Despite this deficiency, a direct correlation between subjective improvement of congestion and sleep has been demonstrated. However, placebo-controlled, double-blinded, large randomized clinical trials that subjectively and objectively assess the outcomes of intranasal corticosteroid use on allergic rhinitis with impaired sleep, productivity, and daytime somnolence are needed.

Nasal Congestion

Nasal congestion, which results when the cavernous tissues of the nasal turbinates swell following dilation of the capacitance vessels, is a common and bothersome symptom that affects numerous allergic rhinitis patients. Its mechanism involves the reduction in the internal nasal diameter and the increase in airway resistance to nasal airflow, and the symptom can also cause nasal obstruction. Subjective clinical assessments of nasal congestion severity exist, as well as objective measures of nasal airflow, such as peak nasal inspiratory flow, assessments of airway resistance and conductance (rhinomanometry), and acoustic rhinometry, which assesses the volume and area of the nasal cavity by analyzing reflected sound waves.

The symptom of nasal congestion worsens at night and first thing in the morning, peaking at 6 AM, presumptively due to the posture change when an individual first lies down and to the normal decrease in serum cortisol levels overnight. The lower cortisol levels lead to greater nocturnal airway obstruction and may partially explain the large-amplitude circadian variation. These changes and others noted in Table Changes in early morning that may account for the circadian variation seen in allergic rhinitis may serve to explain why patients with inflammatory nasal conditions and nasal congestion often suffer from sleep impairment and daytime fatigue.

Results from an Internet survey of 2355 individuals with allergic rhinitis or the parents of children with allergic rhinitis further reinforced the complaints of those suffering from the disorder. Eighty-five percent of the respondents or their children reported experiencing nasal congestion, and 40% of all respondents, the greatest proportion of participants who rated the severity of various symptoms, considered their nasal congestion severe.

Approximately 50% of the respondents reported that nasal congestion was their most bothersome symptom and that it woke them during the night and made it difficult to fall asleep. Twenty percent of adult respondents claimed that their bed partner’s sleep was adversely affected by their nasal congestion, and the degree of sleep impairment correlated with the severity of their congestion. Moreover, the survey revealed that nasal congestion negatively impacted the individuals’ or their children‘s emotions and ability to perform daily activities, all of which may result from the detrimental effects of nasal congestion on sleep.

Table. Changes in early morning that may account for the circadian variation seen in allergic rhinitis.

Studies on treatments for the nasal congestion associated with allergic rhinitis, such as one by Craig et al. on treatment with topical nasal corticosteroids, propose that the poor sleep and daytime somnolence characteristic of the disorder is predominantly attributed to the symptom of nasal congestion. Increased sleep apnea and transient arousals even occur when subjecting healthy individuals to nasal occlusion with a nose clip. Previous studies that objectively assessed the sleep patterns of allergic rhinitis patients demonstrated that their symptoms of nasal congestion led to increased microarousals and episodes of apnea at night. Subjective instruments, such as Juniper’s Nocturnal Rhinoconjunctivitis Quality of Life Questionnaire (NRQLQ), correlate with the objective findings noted on polysomnography Allergic rhinoconjunctivitis patients who complained of impaired sleep due to nighttime symptoms found nasal and sinus congestion to be among their most bothersome and troublesome symptoms.

A population-based study on the role of acute and chronic nasal congestion in sleep-disordered breathing, which used 4927 subjects with a history of nasal congestion and impaired sleep, showed that patients with frequent nocturnal rhinitis symptoms, compared to those with rare or no symptoms, were more likely to complain of habitual snoring, chronic nonrestorative sleep, and excessive daytime fatigue. Additionally, the study illustrated that subjects with allergic rhinitis — associated nasal congestion were 1.8 times more likely to suffer from moderate-to-severe sleep-disordered breathing, compared to subjects with allergic rhinitis and no reported nasal congestion. Rhinitis and other forms of nasal obstruction must be considered and treated in patients with primary sleep-associated breathing disorders as an adjunct to surgical and nonsurgical treatment. Topical nasal steroids may enhance compliance and effectiveness of continuous positive airway pressure especially, but not limited, to those patients with allergic rhinitis.

Immune Response Mediators

Histamine and cytokines are examples of inflammatory mediators released in the process of an allergic reaction, and such mediators may directly influence the central nervous system and result in the disturbed sleep daytime somnolence characteristic of allergic rhinitis. Histamine helps regulate the sleep-wake cycle and arousal; the higher levels of the cytokines interleukin (IL)-1(3, IL-4, and IL-10 seen in patients with allergies, compared with healthy individuals, correlate with increased latency to rapid eye movement sleep, decreased time in rapid eye movement sleep, and decreased latency to sleep onset. It is postulated that any such disruptions in rapid eye movement sleep may cause daytime fatigue, difficulty concentrating, and poor performance in allergic rhinitis patients. Inflammatory cells and mediators exhibit evident circadian variation, with its highest levels in the early morning hours, thus possibly explaining why the peak of allergic rhinitis symptoms frequently occurs upon waking and why nighttime sleep is detrimentally affected in the disorder. In addition, TNF, IL-1 and IL-6 are cytokines increased in allergic rhinitis and may cause fatigue and other nonspecific generalized symptoms typical of a flulike condition.

Studies on allergic rhinitis that objectively assess sleep by using polysomnography are small in number. One such study observed 25 patients with seasonal allergic rhinitis and 25 healthy volunteers, all of whom underwent two consecutive nights of polysomnography before and during the pollen season, and results showed statistically significant differences between the two groups in sleep parameters, which included increases in the apnea index (number of apneas per hour), hypopnea index (number of hypopneas per hour), apnea-hypopnea index, snoring time, amount of rapid eye movement sleep, and sleep latency. However, parameter values fell within normal limits, preventing the changes from showing clinical relevance. Statistical significance was also reported in daytime sleepiness, which was subjectively measured using the Epworth Sleepiness Scale, in seasonal allergic rhinitis patients compared to healthy subjects. These results thus point toward a weak correlation between subjective and objective measures of sleep impairment.

Table. Disease-specific quality of life questionnaires and general measures of sleep quality.