Food Allergy: What You Need to Know: Final Perspective and Clinical Recommendations

What Is Food Allergy?

Food allergy is an immunoglobulin (Ig)E- or non-IgE-mediated immune response to food protein. This column will focus on IgEmediated food allergy represented by immediate hypersensitivity (Gell-Coombs Type I), which can include anaphylaxis and can be life-threatening. Non-IgE-mediated reactions are thought to be cell mediated (allergic eosinophilic esophagitis/gastroenteritis, food protein-induced proctocolitis, food protein-induced enterocolitis syndrome, food protein-induced enteropathy [including celiac disease], and food-induced pulmonary hemosiderosis). Adverse reactions to foods are sometimes confused with food allergies, but these reactions are nonimmunologic. Nonimmunologic food reactions can be metabolic (lactose intolerance), pharmacologic (chemical migraine triggers such as tyramine, aspartame, monosodium glutamate, nitrates/nitrites, alcohol, coffee, and chocolate), or toxic (scombroid poisoning or food poisoning) in origin. Lactose intolerance can be managed with replacement of the enzyme lactase. Symptoms of scombroid poisoning, associated with bacterial histamine build-up in contaminated fish such as tuna or mackerel, can appear similar to an allergic reaction; affected patients respond well to antihistamines. [1] In contrast to food allergy, food poisoning often occurs in clusters and is not reproducible.

The High and Increasing Prevalence of Food Allergy

Demographics. Food allergies affect up to 8% of children and 3%-4% of adults. [2,3] Food allergies account for 29%-50% of all cases of anaphylaxis, [4,5] which in turn cause 150-200 deaths annually[6] (6-7 times more than deaths from insect stings).[7] No gender or racial disparities have been noted in food allergy, except for Hispanic children, who have a lower rate of food allergy than white or black children.[8] Prevalence. Food allergy is growing. From 1997 to 2007, the prevalence of reported food allergy increased 18% in children under the age of 18 years.[8] Peanut allergy has tripled in children under the age of 18 years in a similar time frame, from 0.4% in 1997 to 1.4% in 2008.[9] Peanut allergy now affects 0.6% of the population and is the most common cause of fatal food-induced anaphylaxis.[9,10] Adverse reactions to food additives, such as coloring or preservatives, are rare and estimated to affect be between 0.01% and 0.23% of the general population.[11-13] Virtually any food can cause an allergic reaction. The most common allergens in childhood are cow's milk (2.5%), egg (1.6%), peanut, soy, wheat, tree nuts, fish, and shellfish.[2,14] In adults, the most common allergens are peanut, tree nuts, fish, and shellfish. Associated conditions. About 80% of children outgrow their milk and egg allergies; however, recent studies suggest that children now require more time to outgrow these allergies than in the past. [15-18] Only 20% of peanut-allergic children eventually outgrow this allergy and are able to tolerate peanut in their diets. [19] Children who have a food allergy are more likely to have other atopic conditions such as atopic dermatitis, allergic rhinitis, and asthma compared with children who do not have a food allergy.[8] Most children with atopic dermatitis are sensitized (have a positive skin test or elevated specific IgE) to food or aeroallergens.[20,21] In children with moderate-severe atopic dermatitis, 40% have clinical food allergy, [22,23] most commonly egg.[24] Food allergies have also been found to be a risk factor for life-threatening asthma. [25]
The Pathophysiology of Food Allergy

A Type I immediate hypersensitivity reaction is precipitated by the presentation of antigen (in this case, food peptides), by antigen-presenting cells (APCs) to T cells, which direct B cells to produce IgE. [26] The IgE antibodies then bind to tissue mast cells and basophils, the effector cells in an allergic reaction. Upon re-exposure, the antigen binds to and crosslinks IgE on mast cells and basophils, triggering degranulation and the release of preformed contents, such as histamine, tryptase, and

proteoglycans. Activated mast cells and basophils also produce prostaglandins, leukotrienes, platelet-activating factor, and cytokines. These mediators act directly on tissue and recruit inflammatory cells. Histamine, the primary mediator, induces vascular permeability, mucus production, vasodilation, and airway and intestinal smooth muscle contraction; and affects cardiac function.[27,28] These actions result in the flushing, hives, edema, bronchoconstriction, abdominal cramping, vomiting, hypotension, and dysrhythmias typically seen in acute allergic reactions and anaphylaxis. It is possible to react on first known exposure. Some speculate that exposure in the environment, through breastfeeding, or in utero might be the priming event. [29] Food allergy is viewed as a Th2-mediated condition. [30] Th2 CD4+ T cells produce cytokines interleukin (IL)-4, IL-5, and IL-13 and generate a humoral immune response that is classically used to fight off parasites but also inappropriately causes allergies. In contrast, Th1 CD4+ T cells produce IL-2 and IFN-gamma and generate cell-mediated immune responses.
Proposed Explanations for the Rise in Allergic Disease

Why IgE antibody is inappropriately formed against benign food protein is not fully understood. One well-known hypothesis for the apparent Th2 shift and increase in allergic diseases in westernized countries is the hygiene hypothesis. This hypothesis postulates that because of our improved hygiene and vaccinations, our immune systems are not overburdened with disease or parasites, so instead we develop immunity against benign antigens that we are commonly exposed to, such as food. [31] Other hypotheses for the increase in food allergies involve how we grow and process our food, how and when we introduce foods to infants and toddlers, dietary fat content, reduction in dietary antioxidants, vitamin D insufficiency, and environmental exposures to allergens, such as peanut oil in skin moisturizers, which may favor sensitivity as opposed to tolerance. [32-37]

Clinical Manifestations of Food Allergy

Reactions to food can occur with very small amounts of exposure and develop in minutes or up to 2 hours after ingestion. Symptoms can be cutaneous, gastrointestinal, respiratory, circulatory, neurologic, and/or atypical, such as a metallic taste in the mouth (Table 1). Table 1. Symptoms of an Allergic Reaction Organ System Symptoms

Skin Gastrointestinal Respiratory Upper airway

Pruritus, flushing, urticaria, angioedema Oral pruritus, abdominal pain, cramping, vomiting, diarrhea

Sneezing, nasal congestion, coughing, hoarseness, throat pruritus/tightening, difficulty swallowing Wheezing, shortness of breath, cyanosis, respiratory arrest Early tachycardia, late hypotension, dysrhythmia, bradycardia, cardiac arrest Change of activity level, anxiety, feeling of doom, dizziness, loss of consciousness Metallic taste in mouth, uterine cramping, urinary urgency

Lower airway Cardiovascular Neurologic Other

About 90% of reactions present with cutaneous, 70% with respiratory, 30%-45% with gastrointestinal, and 10%-45% with circulatory symptoms ranging from palpitations to collapse. [4] Severe reactions are predominantly respiratory in children and circulatory in adults.[38,39]
Anaphylaxis

Anaphylaxis, by definition, is a severe multiorgan system allergic reaction that can be fatal. [40] Anaphylaxis can progress rapidly without cutaneous symptoms. Although anaphylaxis is usually uniphasic, biphasic reactions can occur in up to 20% of cases, and protracted reactions have been reported.[41] In a biphasic reaction, symptoms typically recur within 1-4 hours after apparent resolution of the initial event, although recurrence as late as 72 hours after exposure has been reported. Biphasic reactions occur more frequently when the initial administration of epinephrine is delayed and are rare after mild initial reactions. Rarely, protracted anaphylaxis can persist for several days, with multiple recurrences interrupted by asymptomatic periods lasting hours.
[42]

Contrary to a commonly held belief, allergic reactions do not automatically get worse each time. However, previous foodinduced anaphylaxis does put a patient at risk for future anaphylactic reactions. [42] A number of factors influence reaction severity such as the amount of allergen ingested, how the food was prepared (raw vs heated), the amount and type of other food ingested, the presence of acute viral illness, the status of an underlying chronic disease, alcohol consumption, and exercise. [43,44] Risk factors for fatal anaphylaxis include adolescence, a history of asthma, a history of anaphylaxis, delayed or no epinephrine received, cardiopulmonary disease, an upright posture during the reaction (mostly in adults, leading to empty ventricle syndrome), adrenal insufficiency, beta blockade, angiotensin-converting enzyme therapy, and initial misdiagnosis. [44]
Other Reactions

Although contact reactions can occur after touching a food allergen, severe reactions are uncommon unless the antigen is ingested or absorbed through the mucosa.[10] Local pruritus, redness, or urticaria can occur in contact reactions. Isolated respiratory symptoms are uncommon during a food-induced allergic reaction, but wheezing can be part of the larger reaction. [10] Chronic asthma symptoms are unlikely to be caused by food allergy. Inhalation reactions can occur particularly if the food protein is airborne; for example, during the process of roasting nuts, steaming fish/shellfish, or boiling milk. [45,46] The smell of food alone, even a strong smell like peanut butter, is comprised of aromatic chemicals that are not proteins and would not be expected to cause an allergic reaction.[47

Diagnosis of Food Allergy

Clinical history is vital in the diagnosis of food allergy. [10] A double-blind placebo-controlled food challenge is the gold standard in food allergy diagnosis but is used mostly in research. Open oral food challenges are used in the clinical setting, usually when it is believed that the individual is not allergic or has become tolerant. [10] Skin tests and allergen-specific IgE levels have high sensitivity but moderate specificity.
Skin Testing

The positive predictive value (PPV) for skin testing is 50%, whereas the negative predictive value (NPV) is 95%. [10] Because of a high rate of false positives, a positive skin test should be correlated with clinical history, whereas a negative skin test can be used to rule out an IgE-mediated allergy. The larger the diameter of a wheal in a positive skin test, the greater the probability of clinical reactivity; however, the size cannot predict the type or severity of a potential reaction. [48-50] In one study, a median wheal size of 8 mm for milk, egg, or peanut in children younger than 2 years was found to be 95% predictive of food allergy. [51]
Food-Specific IgE Testing

Food-specific IgE testing has similar specificity (~ 50%) but slightly lower sensitivity (> 90%) than skin testing. [10] In vitro testing is useful when skin testing is not possible; for instance, if the patient is taking antihistamines, the patient has dermatographism, a large number of allergens need to be tested, the patient is acutely ill, or the patient has active atopic dermatitis and no skin is free of inflammation. Monitoring food-specific IgE levels over time is also useful, because falling levels could indicate that the patient is outgrowing the allergy. Like the size of skin tests, the concentration of food-specific IgE does not predict the type or severity of reaction, only the probability of clinical reactivity. [48-50]

Using the ImmunoCAP system to measure food-specific IgE levels, studies have established PPV and NPV for common food allergens. These are frequently used to confirm an allergy diagnosis and to assess the risks and benefits of doing an oral food challenge. For example, an IgE level of 14 kU/L for peanut is > 95% predictive of clinical reactivity, and on the basis of this level, it would be unlikely that a patient would pass an oral food challenge. [48] An undetectable IgE level (< 0.35 kU/L) for peanut is still associated with a 20% chance of reactivity. [48] The diagnostic levels of food-specific IgE for common allergens and associated PPVs for clinical reactivity are [15,52-54]:

Egg: In children > 2 years of age, IgE level 7 kU/L (98% PPV); in infants 2 years, IgE level 2 kU/L (95% PPV) Milk: IgE level 15 kU/L (95% PPV)

Peanut:IgE level 14 kU/L (95% PPV) Fish: IgE level 20 kU/L (95% PPV) Tree nuts: IgE level 15 kU/L (95% PPV) Soy: IgE level 30 kU/L (73% PPV) Wheat: IgE level 26 kU/L (74% PPV)

The probability of clinical reactivity on the basis of IgE levels depends on the particular food, and these levels are not comparable between foods. Therefore, the "classes" assigned to food-specific IgE levels by many laboratories are often confusing and may not be useful in predicting reactivity.
Overdiagnosis of Food Allergy

The high rate of false positives combined with the wide commercial availability of food-specific IgE testing (particularly the food allergy panels) has led to overdiagnosis and unnecessarily restrictive diets. [10] Not only could this have a significant effect on quality of life, but it may be detrimental in children if dietary restriction affects nutrition and results in poor growth or development. Food allergies can develop at any time; however, people uncommonly develop allergies to foods that are being regularly ingested. Cases of individuals who developed systemic reactions to food allergens that they previously tolerated after a period of strict avoidance because of atopic dermatitis have been reported. [55-57] On the basis of these observations, it is not recommended that a food be taken out of a patient's diet as a result of a positive or even high IgE level, if the patient is tolerating the food on a regular basis. Evaluation by an allergist is recommended for patients who have atopic dermatitis but the causative food is not evident. Trial elimination diets can also be useful in certain situations but should not be continued if improvement is not seen.
Tests Not Recommended for Food Allergy Diagnosis

The following tests have not been supported by scientific data from controlled studies and are therefore not recommended by the American Academy of Allergy, Asthma, and Immunology to diagnose food allergies [58]:

Applied kinesiology testing and Nambudripad's allergy elimination test; Body chemical analysis;

Cytotoxic testing; ELISA/ACT;

Electrodermal diagnosis;

IgG testing;

Provocation and neutralization; and

Pulse testing.

Some of these tests require ingestion or injection of the suspect allergen, which puts the patient at risk for a reaction. The European Academy of Allergy and Clinical Immunology (EAACI) published a strong statement against IgG and IgG4 testing for diagnosing food allergies.[59] Several studies have presented evidence that food-specific IgG4 simply indicates repeated exposure to specific foods, and that IgG4 in conjunction with regulatory T cells seems to be an indicator of tolerance rather than hypersensitivity.[59,60]

Management of Food Allergy

Currently, no cure for food allergy exists. Management consists of education, prevention, and treatment of acute reactions. The mainstays of treatment of acute food-induced allergic reaction are antihistamines and intramuscular epinephrine. [10]
Treatment of Acute Reactions

Antihistamines can be given if symptoms develop or when a known allergen is ingested and symptoms have not yet developed. Evidence shows that oral cetirizine (0.25 mg/kg, maximum of 10 mg) works as fast as diphenhydramine (1.5 mg/kg, maximum of 50 mg); therefore, either can be used, and cetirizine has the added benefit of longer lasting effects. [61] Epinephrine is used when respiratory or circulatory symptoms are present, or if the reaction is progressing and involves 2 or more organ systems. Epinephrine is appropriate, for example, if a patient has generalized hives and protracted vomiting, even without respiratory or circulatory symptoms. Every patient diagnosed with a food allergy is advised to carry 2 epinephrine self-injectors because the severity of each reaction cannot be predicted, and in some cases, 2 doses might be needed. The dose of epinephrine is 0.01 mg/kg; using prepackaged epinephrine, adults receive 0.3 mg epinephrine per dose, and children under 25 kg (55 lbs) receive 0.15 mg epinephrine per dose. Proper administration technique involves intramuscular injection of epinephrine into the thigh muscle. Studies have shown that injection of epinephrine into the thigh muscle achieves higher peak plasma concentrations than injection into the deltoid muscle, and absorption occurs faster with intramuscular vs subcutaneous administration. [62] Epinephrine can be injected through clothes if necessary; however, injecting directly against the skin avoids unseen buttons, seams, or zippers. Patients are instructed to use their epinephrine when in doubt because a delay could allow the reaction to worsen. Patients are instructed to dial 911 or obtain immediate medical attention if the reaction is severe enough to use epinephrine. Not only might additional medication and monitoring be necessary, but the individual should be observed for 4-6 hours in the emergency department for a possible biphasic reaction. Other components to emergency management include high-flow oxygen, inhaled beta-2 agonists for bronchospasm, and steroids. [10] Steroids (prednisone 1 mg/kg, maximum 50 mg; or methylprednisone 1-2 mg/kg) are not intended for acute management because their onset of action is slow; however, these agents could prevent biphasic or protracted reactions. [4] Dosing should be intravenous every 6 hours for severe reactions, whereas a single oral dose might suffice for milder reactions. [40] In cases involving hypotension, H2-blockers (which not only improve cutaneous symptoms but also counteract vasodilation), fluid resuscitation, and a supine position could be useful. [10] Higher doses and intravenous administration of antihistamines can be given in a monitored setting. In refractory hypotension, vasopressors can be used. If a patient is taking beta-blockers, the effect of epinephrine could be diminished, and administration of glucagon might be necessary to reverse this blockade.
Avoidance of Exposure

Patients who have food allergies (and their caretakers) must be aware of the risks for hidden allergens or cross-contact at every meal, and frequently special provisions must be made for these individuals. Food allergies have a profound effect on quality of life,[63] and support groups and food allergy organizations (such as the Food Allergy and Anaphylaxis Network, or FAAN) might be useful. School, camp, restaurants, entertainment events, birthday parties, air travel, and vacationing can be stressful situations for food-allergic individuals. General nutritional health should be assessed periodically, and patients should be monitored for psychological issues such as anxiety and depression as well as food phobias and eating disorders. [64,65]

Conditions Associated With Food Allergy

Oral Allergy Syndrome

Oral allergy syndrome (OAS) is caused by proteins in fresh fruits, vegetables, and nuts that are homologous with proteins in pollen.[66] Up to 50%-75% of individuals who suffer from pollen allergies are estimated to be affected. [67,68] Classic examples of pollen-food associations include birch with apple, peach with hazelnut, and ragweed with banana and melon. [69] Symptoms are typically limited to oral pruritus and mild angioedema, with occasional rhinitis and facial rash. Because these homologous proteins are heat and acid labile, they are broken down easily by stomach acid and destroyed in cooking; therefore, symptoms are rarely systemic.[70,71] Many patients continue to eat these foods in their fresh states despite the oral discomfort, and most patients report being able to tolerate the same foods when cooked or processed. One study showed that symptoms of OAS can become systemic in 8.7% of cases, and 1.7% experience anaphylaxis. [72] Treatment of OAS involves avoidance and treatment of symptoms with antihistamines and/or epinephrine if the reaction is systemic or severe.
Food-Dependent Exercise-Induced Anaphylaxis

Food-dependent exercise-induced anaphylaxis (FDEIA) is a rare condition in which symptoms develop if food (or a specific food) is eaten within 2 hours prior to exercising.[73] The most common food implicated in FDEIA is wheat, but celery, shellfish, tomatoes, grapes, chicken, dairy products, and mushrooms have also been reported, and theoretically any food can be associated with FDEIA. [10,74] These same foods are otherwise tolerated in the diet when exercise is not involved. Factors that can be associated with triggering FDEIA include menstrual cycle, amount of food ingested, alcohol, aspirin or NSAIDs, and weather.[10] The immune mechanism for FDEIA is poorly understood, but proposed theories include altered splanchnic blood flow, stress-increased proinflammatory mediators, autonomic dysregulation, and increased intestinal permeability leading to absorption of larger peptides. [75-80] Management of FDEIA involves avoidance of trigger foods prior to exercise, not exercising alone, wearing a medic alert bracelet, and carrying self-injectable epinephrine in case of anaphylaxis. [10]

Prognosis for Food Allergy

In the past, it was anticipated that avoidance might increase the chances of outgrowing the food allergy and possibly contribute to the development of tolerance.[81,82] The American Academy of Pediatrics' 2000 dietary guidelines recommended that children avoid highly allergenic foods in infancy and early childhood. [83] This has not been shown to be beneficial; in fact, the incidence of food allergy has continued to rise despite these guidelines, which were revised in 2008. [8,84] One study in Jewish children noted a higher prevalence of peanut allergy in those born in the United Kingdom compared with those born and raised in Israel, where infants ingest peanut at an early age.[85] This suggests that some early oral exposure of allergen might be protective, but the timing, amount, and form of exposure necessary are not yet known.

State of the Science: Research in Food Allergy

Subcutaneous immunotherapy (SCIT) has been used successfully for other allergic diseases, such as seasonal allergies, venom allergy, and asthma; however, unacceptable rates of systemic reactions have put SCIT trials for food allergy on hold. [86,87] Results have been favorable in oral immunotherapy (OIT) clinical trials for food allergy, in which patients have tolerated increased amounts of egg, milk or peanut with fewer and more minor side effects. [88-91] When OIT was discontinued, however, clinical reactivity returned in a subset of patients, indicating desensitization, and not permanent tolerance, occurred. [88,92] Food processing alters protein structure and affects allergenicity. [93] For example, heating or incorporating egg or milk into a wheat matrix can reduce allergenicity by destroying or blocking IgE-recognized peptides. Extensively heated protein represents

an alternative and possibly safer method to OIT. In 2 recent studies, 70% of egg- and cow's milk-allergic children were able to tolerate extensively heated egg or milk.[14,94] Decreasing skin test wheal size and increasing egg- or milk-specific IgG4 were seen with continued incorporation of extensively heated egg or milk in the diet, findings that are often seen as allergies resolve. Both OIT and introducing extensively heated egg and milk, however, remain investigational and are not currently the standard of care. Sublingual immunotherapy, oral immunotherapy given in conjunction with omalizumab, recombinant vaccines, and Chinese herbal medicine are other methods that are currently in clinical trials. [95] Food allergy clinical trials may be viewed at ClinicalTrials.gov. Research in peptide immunotherapy, adjuvant-associated protein immunotherapy, and plasmid DNA immunotherapy are still in the laboratory at this time. [95]

Final Perspective and Clinical Recommendations

Food allergies are on the rise in westernized countries for reasons that we do not completely understand. The rise in food allergies parallels the increase in other atopic diseases. No cure currently exists for food allergy. Management consists of education, avoidance of allergens, and appropriate response to acute reactions. The most common food allergies in childhood are milk, egg, and peanut. Most children outgrow their milk and egg allergies, whereas peanut allergy is more likely to be lifelong. The most common food allergies in adulthood are peanut, tree nuts, fish, and shellfish. Although peanut is the allergen most often associated with severe or fatal reactions, any food has the potential to cause anaphylaxis. Patient history is the most important diagnostic tool in the evaluation of food allergies. Skin testing and specific IgE testing provide additional information and can be used to monitor the status of food allergies over time or determine if an oral food challenge is appropriate. An oral food challenge is the gold standard for diagnosis of food allergy; however, this test is typically only used when the diagnosis is in question or if it is believed that the food allergy has been outgrown. Food-allergic individuals and their caretakers must be aware of hidden allergens and cross-contact at every meal and be prepared to treat if an allergen is accidentally ingested. The amount of food required to trigger a reaction or the severity of a reaction cannot be predicted. Intramuscular epinephrine and antihistamines are the mainstays of treating acute allergic reactions. Research into curative or mitigating food allergy therapies is ongoing.
Recommendations for Practitioners

1.

Delaying of potentially allergenic foods until 1, 2, or 3 years of age has not been shown to prevent food allergies. In 2008, the American Academy of Pediatrics amended their earlier position and no longer recommends avoidance of such foods as a preventive measure. 2. Food allergic patients, especially those with a new diagnosis, should be seen by an allergist for complete work-up, education, and management. Children can outgrow their food allergies, and yearly monitoring is warranted. Specific food IgE levels can be measured after careful history-taking identifies potential allergens. The focus should be on foods ingested within 2 hours leading up to an acute reaction or foods that appear to consistently exacerbate eczema. Specific food IgE testing panels are not recommended because of the occurrence of false positives and the potential for foods that an individual has been tolerating to be unnecessarily removed from their diet. Removing a previously tolerated food from a patient's diet solely on the basis of an elevated specific IgE can put the patient at risk for developing an actual clinical allergy to that food. An undetectable specific food IgE level is not a guarantee that an individual is not allergic. If the history is suggestive, skin testing should be performed (and possibly an oral food challenge as well) before the food is ingested again. 7. Specific food IgE levels help to predict the likelihood of reactivity but not the type or severity of reaction. The significance of the levels varies among foods, so they are not comparable.

3.

4.

5.

6.

8.

Food allergic individuals should carry 2 self-injectable epinephrine devices and antihistamine at all times in case of emergency. Self-injectable epinephrine devices should be renewed once a year. Epinephrine given for an allergic reaction is most effective when administered intramuscularly into the thigh muscle.

9.

10. Biphasic reactions can occur in up to 20% of anaphylactic cases, and monitoring patients for 4-6 hours after a food allergy reaction is recommended. 11. Corticosteroids are not useful in the acute management of an allergic reaction because of slow onset, but they might prevent biphasic or protracted reactions. 12. Adolescents and patients with a history of asthma are at higher risk for fatal anaphylaxis and require additional education. Delay of epinephrine is also a risk factor for fatal anaphylaxis. 13. Food allergies have a profound effect on quality of life, and support groups and Websites of food allergy organizations (such as the Food Allergy and Anaphylaxis Network, or FAAN) can be useful Patients who have generated IgE antibodies to egg are at risk for anaphylaxis if they receive vaccines that contain contaminating egg proteins. Per national vaccine guidelines, patients with egg allergy: Can receive measles, mumps, rubella, and varicella vaccinations Should not receive the yellow fever vaccine (unless allergy and vaccine testing are done first)

Should not receive the rabies vaccine (unless allergy and vaccine testing are done first)

May be able to receive the influenza vaccine, depending on severity of reaction to eggs and the content of egg protein in the vaccine product With respect to the influenza vaccine, the guidelines state that:

"insufficient evidence exists to recommend administering influenza vaccine, either inactivated or live-attenuated, to patients with a history of severe reactions to egg proteins. Severe reactions include a history of hives, angioedema, allergic asthma, or systemic anaphylaxis to egg proteins (or chicken proteins). Less severe or local manifestations of allergy to egg or feathers are not contraindications. However, the expert panel notes that egg allergy is relatively common among the very patients who would highly benefit from influenza vaccination. Such patients include children and young adults (from 6 months to 18 years old for seasonal influenza, and from 6 months to 24 years old for H1N1 influenza) and all patients with asthma. It should be noted that live-attenuated vaccine is not licensed for use in patients with asthma." The guidelines recommend against administering influenza vaccines to children with a history of hives, angioedema, egg allergy plus allergic asthma, or systemic anaphylaxis to egg proteins, unless either (1) the vaccine contains < 1.2 g/mL of ovalbumin; or (2) an evaluation for allergy to the vaccine is done first (if the vaccine's ovalbumin content is > 1.2 g/mL, or is unknown).

Treatment of Seasonal Allergic Conjunctivitis With Ophthalmic Corticosteroids

Abstract and Introduction

Abstract

Purpose of review Corticosteroids are an effective short-term treatment option for seasonal allergic conjunctivitis (SAC). Their use has been limited due to their side effects and has led to the development of modified 'soft', 'smart' ophthalmic corticosteroid formulations that retain their anti-inflammatory mechanism of action with an improved safety profile. Recent findings Similar to the development of the prodrug concept for the nose and lung that led to the development of ciclesonide, a chloromethyl-ester group substitution at the carbon-20 (C-20) position of the traditional corticosteroid has led to the development of a family of potential ophthalmic corticosteroids including loteprednol etabonate that has demonstrated similar efficacy to the C-20 ketone corticosteroids in the treatment of the signs and symptoms of ocular allergies, but less likely to induce elevations in intraocular pressure (IOP) or the formation of cataracts. The C-20 ester corticosteroid, loteprednol etabonate has been designed to be rapidly converted to an inactive, nontoxic metabolite, thus minimizing adverse effects, and loteprednol etabonate (0.2%) is currently the only ophthalmic corticosteroid specifically developed for and approved by the Food and Drug Administration for treatment of SAC. Summary The development of modified or soft, smart corticosteroids such as

etabonate provides an avenue for expanding the treatment of the inflammation associated with signs and
symptoms in patients with chronic forms or severe acute exacerbations of allergic conjunctivitis. Modified corticosteroids are an effective and well tolerated option for the short-term treatment of the inflammation and signs and symptoms associated with SAC.
Introduction

loteprednol

About 1540% of the global population is affected by allergic conjunctivitis in response to seasonal allergens such as pollens, animal dander, and other environmental antigens.[13] Seasonal allergic

conjunctivitis (SAC) is associated with different severities of symptoms such as redness, periocular itching (pruritus), tearing (epiphora), burning, stinging, photophobia and swollen or dry eyes. [1,2] The redness and itching of the eyes are the pathognomonic symptoms associated with allergic conjunctivitis. Depending on severity of these symptoms, patients with ocular allergies experience
[2,4]

discomfort that may affect their quality of life significantly by reducing their productivity and restricting their daily activities like reading or spending time outdoors.[1] A study[5] conducted in the UK found that patients with SAC had a 2.3-h reduction in productive time every week during allergy season. Another study [1] conducted in the USA found that 17% of patients with ocular allergy symptoms were unable to perform simple daily tasks. In fact, the estimated annual cost for each patient with SAC in Spain was approximately equivalent to 470 US dollars.[6] Following the first exposure of a genetically predisposed individual to a novel allergen, the impact of allergenic pollen, for example, which lands on the conjunctiva leads to the activation of a cascade of immune responses involving T-lymphocytes, neutrophils, macrophages and toll-like receptors (TLRs) that are responsible for presentation of symptoms in SAC patients. [7,8] Tcell activation leads to production of cytokines that regulate immunoglobulin E (IgE) synthesis and eosinophil proliferation. [7] Activated T-cells also interact with B-lymphocytes in the local lymph nodes, resulting in release of additional cytokines. [8] B-cell activation leads to secretion of allergen-specific IgE-class immunoglobulins that bind to high-affinity IgE receptors on mast cells and basophils, thereby activating the immune cells to initiate an allergic response when re-exposed to the same allergenic pollen. [79] Histamine is the primary mediator involved in ocular allergic response, but other proinflammatory mediators, such as prostaglandins and leukotrienes synthesized by mast cells, can also cause the late-phase allergic response implicated in symptoms of SAC.[1012] Although activation of the H1 and H2 histamine receptors in the conjunctiva are primarily responsible for the majority of the ocular allergic reaction in the early phase, [11,13,14] other proinflammatory mediators, such as prostaglandins and leukotrienes synthesized by mast cells, are the primary mediators of the persistent late-phase allergic response and its associated symptoms of SAC.[1012] Nonspecific induction of matrix metalloproteinases (MMPs) are divided into four groups according to substrate specificity collagenases, gelatinases, stromelysins, and the membrane-type MMPs and are mainly synthesized by connective tissue cells, granulocytes, and monocyte macrophages that are also involved in many critical physiological and pathologic processes, including inflammation in the conjunctival tissue. [12]

Treatment of Seasonal Allergic Conjunctivitis

The current treatment options for SAC include nonpharmacologic management by avoiding the offending allergen and using cold compresses to reduce the associated heat and swelling initially. If adequate relief of symptoms is not achieved, pharmacologic therapies by either systemic or topical treatment options are used (Table 1).
[16]

[15]

The primary treatment options include ocular surface-lubricating agents such as saline solution or artificial tears to help remove the allergens from the ocular surface and minimize exposure.[16] Some artificial tears provide relief by lubrication of the ocular surface, and adding wetting and/or viscosity agents to saline solution.[17] Ointments or time-released tear replacements, used at night, are a longer-lasting alternative for lubricating the ocular surface.[16,18] These agents do not treat the underlying cause of allergic response or inflammation, so their use is limited to mild SAC.[19] Topical decongestants, antihistamines, mast cell stabilizers, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids are among available pharmacologic treatments for SAC.[2,15,16,1820] Most of these
are associated with limitations and side effects when used alone or in combination with each other (Table 1). Topical decongestants can reduce symptoms of SAC through vasoconstriction via -adrenoreceptor stimulation [16] but do not reduce allergic response since they do not antagonize mediators of inflammation [15,18,21] and prolonged use of topical decongestants leads to rebound hyperemia or conjunctivitis medicamentosa. [22,23] Antihistamines block only the histamine-induced symptoms of SAC[13] but may also have some general anti-inflammatory effects [20] that can potentially lead to development of sensitivity or aggravation of allergic response.[21] When an antigen binds the IgE and cross-links it, the degranulation of mast cells leads to vasodilation, vascular permeability and bronchial constriction. Mast cell stabilizers are therefore most effective when used prophylactically to prevent the onset of allergic conjunctivitis. [13,24] Although mast cell stabilizers are generally well tolerated, there have been reports of transient burning or stinging upon application. [2,15] Due to their complementary mechanisms of action, antihistamines and decongestants are often used in combination in a single product, [18,22] although this combination therapy has associated side effects and a shorter duration than either agent alone. [20] The most commonly prescribed multiple-action combination agents work through their antihistamine and intrinsic mast cell-stabilizing activities and potentially through additional, although minor, anti-inflammatory effects. [17,18] These combination agents are generally well tolerated and can be used for a longer time with minimal side effects. [18,25] Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX) that catalyze the formation of prostaglandins and thromboxane from arachidonic acid. One ocular NSAID, ketorolac, is currently approved for SAC treatment for the control of pruritus, [17,24,25] but it may cause associated stinging and burning. [13,17,24]

Keterolac 0.4% had greater anti-inflammatory effects than diclofenac and loteprednol etabonate 0.5% in an animal model of inflammation (P <
0.001).[26] Corticosteroids have been the cornerstone of treatment for various allergic disorders including asthma, atopic dermatitis, and allergic rhinitis. Topical corticosteroids have also been reported to be the most effective in the treatment of severe and chronic forms of ocular allergy,[27] providing effective relief of a broad range of symptoms of ocular inflammation. [2,1517,19,20,22,24,25] Corticosteroids exert rapid anti-inflammatory effects within 6 h of application via interactions with glucocorticoid receptors. [28] The corticosteroidglucocorticoid receptors combination enters the nucleus in which it controls synthesis of several proteins, including one that inhibits the enzyme phospholipase A2 which regulates arachidonic acid, a key late-phase mediator of inflammation. However, systemic corticosteroids have been associated with multiple systemic side effects [e.g. osteoporosis, cataracts, growth failure, hypothalamic-pituitary-adrenal (HPA) axis suppression] that have reduced their use. Topically applied corticosteroids were introduced as safer options with improved therapeutic margins. The efficacy and safety of topically applied corticosteroids depend on pharmacokinetic and pharmacodynamic properties (e.g. systemic and topical bioavailability, deposition, receptor binding, residence time, and clearance). Manipulation of these properties has led to newer topical agents with progressively improved therapeutic margins. However, prolonged use of some of these topical agents at high doses can still be associated with certain local and serious adverse events such as cataract formation and glaucoma. Specifically, ophthalmic steroids may be associated with serious side effects, including increase in intraocular pressure (IOP), glaucoma, cataracts, delayed wound healing, susceptibility to infection, systemic suppression of the HPA axis and increased cardiovascular risks. [2935] Most of the ophthalmic corticosteroids have a ketone group that is located at the C-20 position (Fig. 1), [25] which has been implicated with formation of cataracts. [33] Ketone corticosteroid protein adducts form in ocular lenses and correlate with the development of cataracts, indicating the possibility that corticosteroidprotein adduct formation may play a role in cataract formation with long-term glucocorticoid therapy.[34,35] The formation of Schiff base intermediates between the C-20 ketone position of ketone corticosteroids and the lens protein results in subsequent oxidation of the lens material and eventual

development of stable cataract-forming corticosteroid-protein adducts. [33,34] The marked opacification that developed in the lenses with the ketone corticosteroid prednisolone were absent with nonketone corticosteroids. [34] Topically administered corticosteroids have reduced systemic adverse events,[3639] but ocular side effects may still exist.[31] As a result, guidelines recommend that their use be limited to more severe cases of SAC only. [15,16,19,20,24,25]

Figure 1. Chemical structures of prednisolone acetate, ciclesonide and loteprednol etabonate, and their metabolites The change of the ketone from an ester at carbon-20 position has led to the development of loteprednol etabonate. Ciclesonide is an inactive parent compound activated by esterases to an active metabolite, desciclesonide and the esterification of des-CIC at the carbon-21 position leads to reversible lipid conjugates of des-CIC that represent a pool of active drug available for sustained long-term activity.

(Enlarge Image)

Advancing the search for the 'perfect corticosteroid' with optimized pharmacokinetic and pharmacodynamic profiles has been the thrust of research of the past 40 years for all forms of allergic disorders. [29,30,37,38] That has led to the discovery of the soft corticosteroids. Soft corticosteroids are topical corticosteroids with a low rate of side effects in relation to their anti-inflammatory potency.[36] The soft drug retrometabolic drug design approach has been utilized as a means of delivering these potent antiinflammatory agents close to their site of action while reducing the degree of systemic exposure and thus limiting or eliminating the associated systemic and local side effects. [40] In addition, the search for a once-daily formulation to enhance patient compliance is also important in the 'search for the perfect corticosteroids'. Whereas many soft corticosteroids have failed to progress to the clinical realm, there are two that have come to be used in allergic disorders with various degrees of success. Loteprednol etabonate, (0.2%), a soft steroid that is converted to an inactive metabolite is the only Food and Drug Administration (FDA) ophthalmic agent developed and approved for SAC and is also being examined in clinical trials for its effects on airway inflammation. Ciclesonide, a prodrug corticosteroid, is activated by esterases to an active metabolite, desciclesonide (des-CIC). The esterification of des-CIC at the carbon-21 position leads to reversible lipid conjugates of des-CIC that represent a pool of active drug available for sustained long-term activity. Ciclesonide has demonstrated efficacy without side effects in a once-daily formulation for the treatment of asthma and allergic rhinitis. [41] These drugs represent a significant step forward in the topical treatment of allergic inflammatory diseases. [33,41] Ciclesonide is a prodrug that is enzymatically hydrolyzed at the C-21 to a pharmacologically active metabolite, C21-desisobutyryl-ciclesonide (des-ciclesonide or RM1) following application to the bronchial or nasal mucosa. Des-ciclesonide has anti-inflammatory activity with affinity for the glucocorticoid receptor that is 120 times higher than the parent compound.[33,41]

New Corticosteroids in the Treatment of Seasonal Allergic Conjunctivitis

Several classes of corticosteroids that are ester-based soft or smart corticosteroids have been studied (Table 2).[36,42,43] The various potential ester corticosteroid candidates have resulted in one that has been clinically developed and approved for the treatment of allergic conjunctivitis, loteprednol etabonate (Fig. 1). Loteprednol etabonate is an ester corticosteroid structurally similar to prednisolone, but was designed with a 17-chloromethyl ester at the C-20 position in order to be hydrolyzed to an inactive carboxylic acid moiety.[40,43] Loteprednol etabonate is a 1-cortienic acid etabonate derivative of the prednisolone metabolite 1cortienic acid. This structural modification ensures that loteprednol etabonate undergoes predictable hydrolysis to an inactive metabolite and has limited systemic absorption. [32,42] As a result, loteprednol etabonate is a 'soft' or 'smart' corticosteroid which is active in the ocular tissues in which it is needed and becomes inactive shortly thereafter. [33,44] Similar to ketone corticosteroids, loteprednol etabonate exerts its anti-inflammatory effects by binding to the glucocorticoid receptor. With loteprednol etabonate it is now possible to treat ocular allergic conditions with reduced side effect of elevated IOP (Table 3).[33,34,4548,49,50,5153] Loteprednol etabonate is a safer alternative to C-20 ketone corticosteroids as it was first developed using a retrometabolic drug design by substituting the ketone at the C-20 position of prednisolone acetate with an ester group (Fig. 1), [33] making loteprednol etabonate less cataractogenic than ketone corticosteroids. [34,38] Loteprednol etabonate is the only C-20 ester ophthalmic corticosteroid developed specifically for and approved by the US FDA for the treatment of SAC. Similar to ketone corticosteroids, loteprednol etabonate acts via glucocorticoid receptors and interactions with immune cells to produce anti-

inflammatory effects.[43,54] Loteprednol etabonate provides effective reductions in signs and symptoms of several other types of ocular, inflammatory conditions such as giant papillary conjunctivitis (GPC), [5557] anterior uveitis[54,58] and postoperative inflammation following cataract surgery.[59,60] Thus, the safety and efficacy of loteprednol etabonate have been evaluated in several clinical trials for control of ocular inflammation. Well tolerated and effective prophylaxis of the signs and symptoms of SAC was demonstrated in a randomized, double-masked, placebo-controlled study[61] by loteprednol etabonate 0.5% ophthalmic solution. Loteprednol etabonate provided lasting relief in a conjunctival provocation test (CPT) study[62] of ocular allergy, with remarkable improvement in redness after 8 h, even though the itching was not significantly improved at that point. At days 14 and 28 of dosing, all concentrations of loteprednol etabonate resulted in marked improvement of both redness and itching. [62] Overall all loteprednol etabonate concentrations were well tolerated, and no IOP elevations greater than 4 mmHg were observed. Loteprednol etabonate (0.5%) administered prophylactically for 6 weeks prior to the onset of the allergy season in patients with SAC was evaluated for efficacy and safety ( n = 293).[61] The composite and individual scores for itching and bulbar conjunctival injection during peak pollen counts were significantly better for loteprednol etabonate (P 0.001) relative to placebo.[61] None of the loteprednol etabonate-treated patients experienced an IOP increase greater than 10 mmHg, whereas two placebo-treated patients did. [61] In another study, efficacy of lower concentration loteprednol etabonate (0.2%) in patients with signs and symptoms of SAC was evaluated in two similar studies (n = 133 and n = 135, respectively).[63,64] In both studies, loteprednol etabonate had a greater effect on bulbar conjunctival injection and itching than placebo (P < 0.001 and P = 0.008). In addition, the safety profiles of the two treatment groups were similar, with no patient experiencing elevated IOP in the first study, [63,64] and only one patient in each treatment group experiencing an IOP elevation greater than 10 mmHg in the second study. [63,64] A conjunctival allergen challenge (CAC) study evaluated the efficacy of loteprednol etabonate 0.2%, the antihistamine/mast cell stabilizer olopatadine hydrochloride 0.1%, and placebo in the relief of ocular itching and redness following allergen challenge. [65] Results showed clinically and statistically significant ( P 0.05) improvements in relief of itching and prevention of redness with olopatadine compared with loteprednol etabonate 0.2% and placebo during the early phase of the allergic response, up to 30 min following allergen challenge.[65] This may suggest that corticosteroids do not provide an advantage in the acute phase (within 30 min) of the allergic response. In a more recent 35-day study comparing loteprednol etabonate 0.2% to olopatadine hydrochloride 0.1% for the treatment of allergic conjunctivitis in 60 patients, loteprednol etabonate was found more efficacious than olopatadine in reducing the ocular surface disease index (OSDI). [66,67,68] Other parameters assessed included visual acuity, biomicroscopy, fluorescein corneal staining, applanation IOP and tear production with Schirmer's test. Loteprednol etabonate was chosen as the preferred medication for the treatment of SAC by more patients than olopatadine ( P < 0.05).[66] The CAC study only examined the early-phase reaction and not the late phase, in which corticosteroids show greatest efficacy, [65] so such differences in results were not unexpected. Compared with ketone corticosteroids, the C-20 ester corticosteroids such as loteprednol etabonate show a markedly improved safety profile[69] and therefore offer advantages for the treatment of SAC (Table 3).[25] As mentioned before, since a ketone in the C-20 position has been implicated in cataract development, loteprednol etabonate is expected to be less cataractogenic than ketone corticosteroids.[25,33,69] Additionally, loteprednol etabonate has less of a tendency to elevate IOP, [49,50,58] even in corticosteroid responders[51] or with long-term use likely due to its rapid metabolism to inactive metabolites. [70] However, long-term use of any topcial steroid in the nose or eye has not been studied prospectively. With the projected climate change over the next 2550 years and its impact on increasing pollen count, ocular allergies are expected to increase. As a result, SAC may be chronic and persistent in some patients and may require therapies over a prolonged period of time.[18,52,71] The long-term safety of loteprednol etabonate 0.2% for the treatment of SAC or perennial allergic conjunctivitis (PAC) was examined in a retrospective review of 159 patients who used loteprednol etabonate at least once a day for more than a year.[52] There were no recorded corticosteroid-induced adverse events such as posterior subcapsular opacification detected via slit-lamp examinations and no incidences of corticosteroid-induced elevation of IOP that exceeded 4 mmHg. [52] Although not clinically significant, a statistically significant ( P = 0.017) increase in IOP by an average of 1.89 mmHg was detected in a cohort of patients whose last visit occurred at 30 months. [52] There was no record of new lenticular opacity or significant worsening of previously existing cataract. [52] Overall, the study showed that loteprednol etabonate 0.2% has an excellent safety profile for long-term treatment of SAC or PAC, but routine monitoring of IOP and slit-lamp examinations were recommended as the studies were limited to 1 year. [52] Multiyear studies have not been performed with ophthalmic steroids.

Allergic conjunctivitis is often linked to allergic rhinitis and requires cotreatment. The major symptoms of conjunctivitis such as burning and itching eyes and lacrimation are the same as for allergic rhinitis. Ciclesonide is a corticosteroid in development for allergic rhinitis that has been shown to be well tolerated and effective in seasonal allergic rhinitis and perennial allergic rhinitis (PAR) trials of up to 6 weeks in duration and has been shown to be well tolerated and effective for the long-term treatment of PAR, with no evidence of tachyphylaxis.[72] The combined administration of ciclesonide and at least one antihistamine for the treatment of allergic rhinitis with allergic conjunctivitis has been successful. [73]

Conclusion
Designed based on the 'inactive metabolite' concept, the C-20 ester corticosteroid loteprednol etabonate can be used as a well tolerated ophthalmic anti-inflammatory drug. By design, the metabolism of loteprednol etabonate follows a predicted biotransformation pathway, thus unwanted systemic and local side effects are avoided. The C-20 ester-based corticosteroids such as loteprednol etabonate can block the allergic response via specific and nonspecific anti-inflammatory effects, including binding to glucocorticoid receptors and interactions with immune cells, similar to ketone corticosteroids. [54] Compared with ketone corticosteroids, however, the C-20 esters are less likely to induce elevations in IOP [49,50,51,52,58,74] or cause cataract. The removal of the ketone group at the C-20 position of the molecule is expected to reduce the cataractogenic effects of the corticosteroid drug. Safety studies showed no worsening of lens opacity with long-term use of loteprednol etabonate 0.2%. [52,69] Due to an excellent efficacy and safety profile, C-20 esters such as loteprednol etabonate are effective short-term treatment options for SAC. In fact, the 0.2% dose of loteprednol etabonate has all the anti-inflammatory advantages of a corticosteroid, but almost no corticosteroidinduced side effects.[52,63,64] Currently, loteprednol etabonate is the only C-20 ester topical ophthalmic corticosteroid that was developed specifically for and approved for the treatment of SAC [22,25] and should be included in the treatment algorithm of patients with acute severe exacerbations of SAC or for the chronic persistent forms. However, long-term use of the soft ophthalmic steroid has not been studied for more than a year and if used should be monitored in concert with an ophthalmologist. Other similar therapies under clinical investigation involving the subspecialty of allergy and immunology and ophthalmology will assist in the improvement of care for patients with ocular allergy (given below) and would further promote the development of treatment options thus improving the therapeutic outcomes for all patients with SAC.

Allergy and ophthalmology consultation (for persistent moderateto-severe clinical allergic ocular complaints; at the patient's request, in accordance with physician's treatment plan): To an ophthalmologist Any patient using ocular steroids for more than 2 weeks should be monitored for increased IOP, persistent ocular complaint, presence of ciliary blush suggesting uveitis The patient should then be considered for treatment with topical or systemic corticosteroids To an allergists/clinical immunologist Patient should be evaluated for presence of systemic atopy (eczema, rhinitis, sinusitis, asthma) Patient should be considered for systemic immunomodulation (immunotherapy) Subsequently the patient should undergo systemic assessment of an autoimmune process

Conjunctivitis
Abstract and Introduction
Introduction

Conjunctivitis, or inflammation of the conjunctiva, is commonly referred to as "pink eye" or "red eye." [1,2] Although the actual incidence is unknown, the condition is one of the most frequent causes of patient self-referral. [3] The conjunctiva is a thin tissue extending from the limbus of the eye to the eyelid margin. The three parts of the conjunctiva are the bulbar conjunctiva (covering the anterior portion of the sclera), the palpebral, or tarsal, conjunctiva (lining the inner surface of the eyelid), and the conjunctival sac (space bounded by the bulbar and tarsal conjunctivae). The conjunctiva contains mast cells (MCs) and other inflammatory cells.[4] Conjunctivitis may be caused by one or more of several factors. Allergens, irritants, mechanical abrasions, bacteria, and viruses all can cause inflammation of the conjunctiva; for appropriate treatment, it is important that the etiologic agent be identified. [1,5] Most cases of conjunctivitis are self-limited, and the condition rarely causes permanent vision loss or structural damage. [3] This article will discuss three common classes of conjunctivitis: allergic, viral, and bacterial.

Allergic Conjunctivitis

About 40% of the general population experiences allergic conjunctivitis (AC), and 80% of these patients have concurrent allergic rhinitis. AC is associated with type 1 hypersensitivity reactions, and there are generally four types: seasonal and perennial AC (SAC, PAC), vernal conjunctivitis, atopic conjunctivitis, and giant papillary conjunctivitis (GPC).
[4,6] [3,7]

SAC and PAC

SAC, which is recurrent, is caused by exposure to ragweed, pollen, or other seasonal allergens.[2,4] Patients with PAC exhibit symptoms year
round, and the most common triggers are mold spores, animal dander, dust mites, and feathers. SAC tends to be worse in
[4]

SAC and PAC constitute the majority of AC cases, with SAC comprising more than half. [4,7]

warm, dry weather and to lessen with rain and cool temperatures. SAC and PAC usually have bilateral involvement (the severity of each eye may differ) and result
[4]

in little to no sequelae.[3,4]

Signs and symptoms include watery discharge, chemosis (edema of the conjunctiva), conjunctival injection (dilation of the conjunctival vessels), hyperemia, pruritus, eyelid edema, and ropy mucous discharge. The patient may also experience photophobia. "Allergic shiners" (dark circles under the eyes) may be present. Commonly, the patient has concurrent signs and symptoms of asthma and/or rhinitis.[4,7] The absence of itching rules out AC.
[24,8] [4,7] [4] [7]

Nonpharmacologic measures include saline irrigation, cold compresses, avoiding allergens, avoiding eye rubbing, and using preservative-free artificial tear solution.[3,79] The patient should be instructed to keep the artificial tear solution in the refrigerator, because the
Treatment involves palliative measures and medication therapy. use of cold product causes vasoconstriction. Artificial tears have a dual function: They flush and dilute allergens, and also form a barrier to prevent allergens from coming in contact with the conjunctiva. [9] SAC patients should stay indoors with the windows closed when the pollen count is high; they should not cut grass on windy days and when the pollen count is high. Pets should be kept out of the bedroom, and the bathroom should be kept clean and dry to inhibit mold growth. [9] There are several pharmacologic agents for the treatment of AC. For mild SAC or PAC, topical OTC anti-histaminevasoconstrictor combination agents may be used; however, second-generation topical H 1-receptor antagonists are more effective. With persistent or recurrent conditions, an MC stabilizer may be used. A topical low-potency corticosteroid may be used for 1 to 2 weeks if symptoms remain uncontrolled with use of an antihistamine and an MC stabilizer. [3] Corticosteroid use increases the risk of the development of cataracts or glaucoma. Patients using corticosteroids should be closely monitored. [7] There is an FDAapproved topical formulation of ketorolac for pruritus. An oral antihistamine may be used in conjunction with topical agents. [3] Table 1 lists the agents used to treat AC.[3,4]

Antihistamines: Antihistamines block the H1 receptor. Systemic use may only partially relieve allergic symptoms.
Topical antihistamine/decongestant combination ophthalmic solution is more efficacious for relieving ocular symptoms. [6] Second-generation oral antihistamines (e.g., cetirizine) cause less sedation. The antihistamine is effective for acute onset and reduces pruritus, while the decongestant reduces chemosis, eyelid edema, and redness via vasoconstriction. [9]

MC Stabilizers: MC stabilizers prevent the degranulation of MCs. They are unsuitable for an acute reaction because they have no effect on the histamine that has already been released. [9] They may be used for prophylaxis and maintenance of mildto-moderate symptoms.[4,9] MC stabilizers also provide relief of nasal symptoms because of drainage from the nasal passages into the lacrimal duct.[4] Ketorolac Tromethamine: Topical ketorolac is a nonsteroidal anti-inflammatory drug used for relief of
pruritus.[4] Appropriate for the acute phase of AC, ketorolac does not mask ocular infections or cause increased intraocular pressure and cataract formation.[9] Ketorolac may sting or burn when initially instilled, but this may be alleviated by refrigerating the solution before use.[4,9]

Corticosteroids: Corticosteroids are reserved only for severe symptoms, as they can cause increased intraocular pressure, cataract formation, and corneal infection. [4] Suitable for the acute and late phases, corticosteroids are used for hyperacute onset, for severe symptoms, or when the condition is refractory to other medications. Pulse dosing of a topical solution may be employed, followed by maintenance with an MC stabilizer. [9] Corticosteroids should not be used for longer than 1 to 2 weeks, and the patient should be medically monitored, preferably by an ophthalmologist. Patients should never be given unlimited refills. [4]
Two commonly used topical ophthalmologic corticosteroid solutions are fluorometholone

and

loteprednol. Fluorometholone is highly effective in AC. It penetrates the cornea, but is inactivated in the anterior chamber; therefore, it is less likely to cause increased intraocular pressure and cataract formation. [4] Likewise, loteprednol is less likely to increase intraocular pressure or cause cataracts; it primarily targets the late phase of the inflammatory process. [4,9] It is a safe agent to use when MC stabilizers are inadequate. [4] Vernal Conjunctivitis: Vernal conjunctivitis is a serious condition that may result in vision loss. The mechanism is more complex than merely a type 1 hypersensitivity reaction, and it involves other immune mediators also. [10] This chronic disease most commonly affects males under 20 years of age, with onset usually occurring in childhood. Vernal conjunctivitis is characterized by acute exacerbations in the spring and summer.[3] Exacerbations gradually decrease over time, with most patients outgrowing the disorder by age 30 years.[2,3] The average duration of vernal conjunctivitis is 4 years.[2] One-third of patients have multiple atopic conditions, such as asthma or eczema.[10]
[2,3]

The bulbar and/or tarsal conjunctivae are involved in vernal conjunctivitis, which presents bilaterally. Clinical signs and symptoms include eyelid thickening, ptosis (upper-eyelid paralysis resulting in drooping), conjunctival scarring, corneal neovascularization, ulceration, conjunctival thinning, infection, vision loss, limbal Trantas' dots (small white dots of degenerating eosinophils and epithelial cell debris), watery and mucous discharge, and keratoconus (conical protrusion of the cornea). [2,3,10] The patient may experience foreign-body sensation, pain, and photophobia in the case of corneal involvement. [10]

Palliative measures may be employed. Nonspecific triggers such as sun, wind, and salt water should be avoided. Pharmacologic treatment includes systemic and/or topical antihistamines. Often, a course of pulse dosing of a topical steroid is needed. Severe cases require the addition of an MC stabilizer to the topical steroid. Topical cyclosporine may be substituted for the steroid unless there is corneal involvement. In patients aged 2 years and older, pimecrolimus cream or topical tacrolimus ointment may be applied to the eyelid skin. The patient should take care not to get the medication on the conjunctiva, cornea, or tear film.
[9] [3,7,9] [3]

Atopic Conjunctivitis

Atopic conjunctivitis is quite similar to vernal conjunctivitis. The typical patient is male and aged 30 to 50 years.[7] Atopic conjunctivitis is a chronic condition with a childhood onset; the patient typically has atopic dermatitis or eczema during childhood and develops ocular symptoms later in life. [2,3,7] Like vernal conjunctivitis, this condition presents bilaterally with a similar clinical picture. [3,7,9]

Mild cases usually respond to palliative measures plus antiallergy medications. Acute cases, no matter how mild, require pulse topical steroid dosing. Moderate-to-severe cases require prophylactic antibiotics and topical steroids. As with vernal conjunctivitis, pimecrolimus cream or tacrolimus ointment may be used. Topical cyclosporine may be used instead of a topical steroid (except in the case of corneal involvement). Severe cases that are unresponsive to topical therapy may require systemic immunosuppression.
[9] [3,9] [3,7] [3

GPC
GPC is not a true allergic condition; it is chronic inflammation caused by irritation of the tarsal conjunctiva. [7,9] Typical causes include contact lens wear (most common), exposed sutures, and ocular prosthesis. [2,3] GPC has been associated with the use of hard, soft, and rigid gas permeable contacts.[2] The two components of GPC are mechanical irritation and immune hypersensitivity reaction mediated by MCs, eosinophils, and T lymphocytes. [9] GPC may present unilaterally or bilaterally, depending on the causative agent. There may be itching, tearing, burning, mucous discharge, giant papillae on the superior tarsal conjunctiva, and conjunctival injection. [9] Severe cases may result in eyelid swelling and ptosis.[3] Corneal erosion and superficial punctate keratitis may also occur. [9] When GPC is associated with contact lens use, there may be increased lens movement with blurry vision upon blinking. [2,9] Treatment consists primarily of modifying the causative agent. [3,9] For contact lenses, one strategy is to switch from conventional to daily-wear or disposable lenses or from extended overnight-wear to daily-wear lenses. [9] Other measures include more frequent lens replacement, decreased lens-wearing time, and use of enzymatic treatments and preservative-free lens care systems. For moderate-to-severe GPC, contact lens use should be discontinued for several weeks to months. [3] If pharmacologic therapy is

indicated, antihistamines and MC stabilizers may be used. Severe cases may require an MC stabilizer and a topical steroid (loteprednol).[3,9] Nedocromil is appropriate for long-term maintenance. [9]

Viral Conjunctivitis
This is the most common form of conjunctivitis.[11] It is far more common than bacterial conjunctivitis. [5] The three main viral types are adenovirus, herpes simplex virus (HSV), and herpes zoster (HZ) (varicella-zoster virus). [3]
Adenoviral Conjunctivitis

This is the most common type of viral conjunctivitis. [8] It is self-limited, and improvement usually occurs within 5 to 14 days; however, contagion is possible for up to 14 days after the appearance of symptoms. [3,12] Adenoviral conjunctivitis is highly contagious and is spread through direct contact with contaminated hands, medical equipment, pool water, or personal items. [12] Patients must take appropriate measures to reduce the risk of spread. [3] Adenoviral conjunctivitis may present unilaterally or bilaterally with an acute onset (often sequentially bilateral). [3] Frequently, the patient suffers from a concomitant upper respiratory infection. Symptoms include red, itchy eyes with a watery or mucous discharge.[13] Severe cases may involve conjunctival scarring, symblepharon (adhesion of eyelids to the eyeball), and subepithelial corneal infiltrates.[3,12] Because it is difficult to differentiate adenoviral conjunctivitis from bacterial conjunctivitis, antibiotics are frequently prescribed. [5,12] There may also be an opportunistic bacterial infection warranting antibiotic use. [5] No antiviral solutions are effective against adenoviruses.[1,3] Artificial tears, topical antihistamines, and cold compresses may alleviate symptoms. [3,12] Topical corticosteroids may be beneficial, but the patient must be monitored closely. [3] If symptoms do not resolve on their own or if there is corneal involvement, the patient should be referred to an ophthalmologist. [12]
HSV Conjunctivitis

HSV occurs in neonates of infected mothers 1 to 2 weeks after birth; it also may occur in sexual partners of infected individuals. [11] Triggers include stress, trauma, infection with another virus, and ultraviolet exposure. [3] HSV is the most common cause of blindness from corneal disease in the U.S.[2,11] The disease presents unilaterally with bulbar conjunctival injection, watery discharge, epithelial keratitis of the cornea or conjunctiva, stromal keratitis, neovascularization, scarring, thinning, perforation, uveitis, trabeculitis, and vesicular rash or ulceration of the eyelids. [3] HSV usually does not require treatment. Symptoms resolve within 4 to 7 days, unless there are complications. To prevent corneal infection, oral or topical antivirals should be used. Trifluridine 1% solution 5 to 8 times daily or oral acyclovir 200 mg to 400 mg 5 times daily may be used; oral valacyclovir 500 mg 2 to 3 times daily or famciclovir 250 mg twice daily are effective also. Vidarabine 3% ointment is another topical antiviral. [1] Use of topical antivirals for longer than 2 weeks may result in toxicity. Topical steroids are contraindicated.[3]
HZ Conjunctivitis

Patients with chickenpox (or people exposed to it) may develop HZ conjunctivitis. The condition is usually selflimited, with symptom resolution within a few days.[3] HZ may present unilaterally or bilaterally. Symptoms include bulbar conjunctival injection and watery discharge. Punctate keratitis may result in primary infection. Limbal vesicles may form, especially with primary disease. Vesicle formation may result in necrosis and scarring on the eyelid margins, conjunctiva, and corneal stroma. [3] Topical antibiotics are sometimes used to prevent secondary bacterial infections. There are no effective topical antivirals, but immunocompromised patients may be given acyclovir 800 mg 5 times daily for 7 days, valacyclovir 1,000 mg every 8 hours for 7 days, or famciclovir 500 mg 3 times daily for 7 days. [3]

Bacterial Conjunctivitis

Bacterial conjunctivitis often presents similarly to the viral form. The best way to distinguish between them is by the discharge. Bacterial infection causes a more mucopurulent discharge, and when the patient awakens in the morning, the eyes are often "glued" shut.[8,12,13] For neonates, prevention strategies include prophylactic use of erythromycin 0.5% or tetracycline 1%. [3] There are three classifications of bacterial conjunctivitis: hyperacute, acute, and chronic. [12] Hyperacute infection is often caused by Neisseria gonorrhoeae in sexually active adults.[12] There are many pathogens that can cause an acute infection, whereas Chlamydia trachomatis most often causes the chronic condition.[13]
Gonococcal Conjunctivitis

Gonococcal conjunctivitis can occur in adults and neonates. Symptoms in neonates typically occur before those of chlamydial conjunctivitis (17 days after birth), but may be delayed if prophylactic antibiotics have been used. [3] Often associated with systemic disease, the condition progresses quickly to a severe purulent infection that may result in eye pain, corneal infection, scarring and/or perforation, septicemia with arthritis, and meningitis, and can lead to blindness. [3,11,12] Immediate referral to an ophthalmologist is warranted.[12] One or both eyes may be affected.[3] Often, patients have systemic disease (sometimes without symptoms); therefore, systemic and topical antibiotics are indicated. [3,13]
Nongonococcal Conjunctivitis

Nongonococcal conjunctivitis, an acute infection, is the most common form of bacterial conjunctivitis seen in primary care. There are many natural defenses against conjunctival infection, but sometimes bacteria overcome them. [2] Staphylococcus aureus is a common pathogen in adults, whereas Streptococcus pneumoniae and Haemophilus influenzae are more common in children. [12] Moraxella lacunata may also cause infection.[1,2] In infants and children, bacterial otitis media, pharyngitis, or sinusitis may lead to bacterial conjunctivitis, which without treatment may progress to severe infection. [3] Direct contact with contaminated hands is the most common means of transmission.[12] Infection is often mild and self-limited in adults, but may progress to complications in children. One or both eyes may be affected, with the most common symptoms being bulbar conjunctival injection and mucopurulent discharge. Rarely will mild infection progress to corneal infection and preseptal cellulitis (infection of the eyelid and periorbital tissues). [3] When symptoms persist beyond 4 weeks (often with frequent relapses), the condition is considered chronic and the patient must be referred to an ophthalmologist.[2,12] S aureus is often the causative agent.[2] Treatment is empirical, with a topical broad-spectrum antibiotic for 5 to 7 days. [1,3] Table 2 lists topical antibiotics used for nongonococcal conjunctivitis.[9,12]
Chlamydial Conjunctivitis

Chlamydial conjunctivitis can affect adults and neonates. [3,11] The most common cause of infectious neonatal conjunctivitis, chlamydial conjunctivitis is transmitted from the mother's genital tract. [11] Half of infants are infected at other sites, such as the nasopharynx, genital tract, or lungs.[3] In neonates, symptoms appear 5 to 19 days after birth (or earlier, if the placenta ruptures). Untreated, the condition can persist for 3 to 12 months. [3] One or both eyes may be affected. Neonatal symptoms include eyelid edema, bulbar conjunctival injection, discharge (purulent or mucopurulent), and lack of follicles. Adults exhibit bulbar conjunctival injection, mucopurulent discharge, corneal pannus (vascularization), punctate epithelial keratitis, preauricular lymphadenopathy, and bulbar conjunctival follicles. [3] Since infection is usually systemic, treatment includes both systemic and topical antibiotics. [3,13] Erythromycin ophthalmic ointment, along with a single 1-g dose of azithromycin or doxycycline 100 mg twice daily for 14 days, is efficacious. [12]

Conclusion

Conjunctivitis is quite common, and the pharmacist will see many afflicted patients throughout his or her career. The pharmacist is often the first health care professional the patient seeks out, and can be a valuable resource. Questions about contact lens use, recent upper respiratory infections, exposure to others with conjunctivitis, and use of new eye cosmetics may shed light on the etiology of the condition; however, all conjunctivitis patients should be referred to a physician for treatment.[4,11] The pharmacist can facilitate the selection of preservative-free artificial tear solutions, OTC topical anti-histamine-decongestant products, contact lens cleaning solutions, and oral OTC antihistamines. The pharmacist also can counsel the patient on palliative measures, refrigerating topical solutions, and modifying contact lens use during treatment.

A Comprehensive Management Guide for Atopic Dermatitis

Abstract and Introduction

Abstract

Atopic dermatitis is a chronic relapsing, pruritic, inflammatory skin disease. The latest in the detection of disease and its triggers, prognosis, treatment, prevention, and patient education is reviewed.
Introduction

Atopic dermatitis (AD) is a chronic relapsing, pruritic, inflammatory skin disease. It is associated with personal or family history

of other atopic diseases, including asthma and allergic rhinitis, and females are more frequently affected (Wuthrich, 1999). Sixty to 65% of patients with AD develop their disease before age
1, and by age 5, 85% to 90% of patients have developed signs of their disease (The Lewin Group, Inc., 2005; Rudikoff & Lebwohl, 1998). The etiology of AD appears to be the result of interactions between genetics, environment, skin barrier defects, and the immune system. Over the last few decades, the prevalence of atopic dermatitis, asthma, and allergic rhinitis have been rising in industrialized countries (Spergel & Paller, 2003). It is hypothesized to be the result of a Western lifestyle and environment including smaller family size, migration to urban areas, increased use of antibiotics, decreased incidence of early childhood infections, and high socioeconomic status (von Mutius, 1999). Currently, the lifetime prevalence of AD is estimated to be between 10% to

20% in children and 1% to 3% in adults (Leung & Bieber, 2003).

The economic burden of AD is substantial with nearly $2.6 billion spent yearly on the disease in the United States. It is the fourth most expensive skin disease with prescription drugs and over-the-counter products composing a large portion of these costs. This disease also has a severe impact on the quality of life of the patient and the family unit (The Lewin Group, Inc., 2005).

Intrinsic Versus Extrinsic Atopic Dermatitis

As mentioned previously, the immune system plays a critical role in the development of atopic dermatitis. Over the past few decades, researchers and clinicians have discovered that there are two forms of AD: intrinsic (nonallergic) and extrinsic

(allergic).

Although the two forms are clinically indistinguishable based on the findings of the physical examination,

there are numerous differences in other aspects (see Table 1 ).

Extrinsic AD composes 70% to

85% of atopic dermatitis, while intrinsic atopic dermatitis makes up the remaining 15% to 30%. Extrinsic AD is associated with high serum IgE levels, exhibits allergen-specific IgE to aeroallergens and foods, positive skin prick reactions, and has a cytokine profile of high IL-4 and IL-13 levels (Bardana, 2004). IL-4, IL-5, and IL-13 cytokines play
a role in the Th2 response which is seen in the early stages of AD. Chronic atopic dermatitis lesions principally have a Th1 response with the cytokines IL-12 and interferon-playing a dominant role (Schmid-Grendelmeier, Simon, Simon, Akdis, & Wuthrich, 2001). Patients with intrinsic AD, by contrast, have normal IgE levels, negative skin prick reactions, low IL-4 and IL13 levels, and they do not have allergen-specific IgE to aeroallergens and foods (Bardana, 2004). The onset of extrinsic AD typically is in early childhood while patients with intrinsic AD have a later onset. Finally, patients with intrinsic AD are characterized by an absence of other atopic disease, asthma, and allergic rhinitis (Schmid-Grendel meier et al., 2001).

Detection

There are three phases of atopic dermatitis: the infantile stage, the childhood phase, and the adult phase. Pruritus and dry skin are at the hallmark of all stages and the pruritus is frequently worse at night (Leung & Bieber, 2003). The infantile stage includes children up to 2 years of age, and is characterized by pruritic, erythematous papules, patches, and vesicles on the cheeks and extensor surfaces of the extremities. Lesions may have a weeping and exudative appearance (Rudikoff & Lebwohl, 1998; Leung & Bieber, 2003). There may be additional involvement of the scalp, forehead, chin, and trunk; but the diaper area is not involved in the majority of cases (Spergel & Paller, 2003). The next phase is known as the childhood phase and affects children age 2 years to puberty. As a result of chronic rubbing and scratching, the skin lesions become less weeping and exudative and more lichenified (thickened) and excoriated. The distribution of the lesions changes from the extensor surfaces to the flexor surfaces, particularly the antecubital and popliteal fossae (see Figure 1). The neck, periorbital, perioral, hands, feet (see Figure 2), wrists, and ankles may also be affected (Rudikoff & Lebwohl, 1998; Spergel & Paller, 2003). Black children sometimes show a follicular pattern of disease that can lead to post-inflammatory hypo or hyperpigmentation (Rudikoff & Lebwohl, 1998). Lastly, the adult phase begins at puberty and may follow a continuous course from infantile to childhood to adult stages or may be a form of recurrence from other stages. Affliction of the flexural folds is also seen in the adult stage along with lesions on the face,

hands, upper arms, back, wrists, and the dorsa of the hands, fingers, feet, and toes (Spergel & Paller, 2003). A chronic course of hand or foot eczema may be the only manifestation of adult atopic dermatitis (Leung et al., 2004). Large lichenified plaques and scaling, erythematous papules and plaques, and prurigo papules are featured in the adult phase (Leung, 2003; Spergel & Paller, 2003).
Figure 1. In the childhood phase, distribution of the lesions changes from the extensor surfaces to the flexor surfaces, particularly the antecubital and popliteal fossae.
(Enlarge Image)

Figure 2. The neck, periorbital, perioral, hands, feet, wrists, and ankles may also be affected.

(Enlarge Image)

In 1980, Hanifin and Rajka proposed criteria for the diagnosis of AD (see Table 2 ). With these criteria, the patient must exhibit three of the major and three of the minor criteria. The major criteria include pruritus, typical

morphology and distribution (facial and extensor involvement in infants and children or flexural lichenification or linearity in adults), chronic or chronically relapsing dermatitis, or personal or family history of atopy (allergic rhinitis, asthma, atopic dermatitis). The minor
criteria are further explained in Table 2 (Abramovits, Goldstein, & Stevenson, 2003; Correale, Walker, Murphy, & Craig, 1999; Hanifin & Rajka, 1980; Rudikoff & Lebwohl, 1998; Williams, 2005).

Course and Prognosis

Atopic dermatitis is a chronic and relapsing disease and persists for an average of 4.4 years in children and 18.2 years in adults (The Lewin Group, Inc., 2005). While most forms of childhood disease improve with puberty, up to 40% of cases do not and recurrences in adulthood are common. Factors associated with a more persistent course include early onset, severe disease at an early age, being the oldest or only child, respiratory disease, family history, and very high serum IgE levels (Williams, 2005; Wuthrich, 1999). Atopic dermatitis is associated with other atopic diathesis

and many patients suffering from atopic dermatitis will go on to develop other atopic diseases in what as known as the atopic march (Spergel & Paller, 2003). It is estimated that 30% to 60% of patients with AD will develop asthma and 35% to 66% will develop allergic rhinitis (The
Lewin Group, Inc., 2005; Williams, 2005; Wuthrich, 1999).

Identifying Triggers
When taking a history from a patient with atopic dermatitis, it is crucial to ask about possible triggers of his or her disease.

Common triggers in AD include aeroallergens, climate, emotional stress, hormones, food, irritants, and microbes (see Table 3 ), but not every patient will
react to every trigger that is listed (Bardana, 2004; Darsow et al., 2005; Leung & Bieber, 2003; Werfel & Kapp, 1999).

As mentioned earlier, patients with intrinsic AD are not exacerbated by aeroallergens and foods, but patients with extrinsic AD can produce antigen-specific IgE to various foods and aeroallergens. This production of IgE not only plays a role in triggering atopic dermatitis, but also the primary development and pathogenesis of AD. In atopic dermatitis, the most frequent aeroallergens are animal danders, cockroach, dust mites, human dander, molds, and pollens (Schmid-Grendelmeier et al., 2001). Cow milk, eggs, fish, peanuts, soy, tree nuts, and wheat are the most common foods allergies that can serve as triggers in atopic dermatitis (Rudikoff & Lebwohl, 1998). Between 20% to 40% of young children and infants with AD have clinically relevant food allergies that worsen his or her disease (Leung & Bieber, 2003; Rudikoff & Lebwohl, 1998). However, aeroallergens are more critical in exacerbating the disease process in adults and older children. If patients are suspected of having allergies to foods or aeroallergens, skin prick tests or RadioAllergoSorbent Tests (RASTs) can be done (Leung et al., 2004). A RAST measures antigen-specific IgE in a patient's blood. A negative test rules out a certain food or aeroallergen playing a role in the disease process. A positive skin test, especially in regards to foods, does not always correlate well with a patient's symptoms (Leung et al., 2004). It has been suggested that if a patient has three or more positive skin prick tests to foods, that they undergo a doubleblind, placebo-controlled food challenge to verify the results (Burks et al., 1998). The double-blind, placebo-controlled food challenge is considered the gold standard at diagnosing food allergies, but should be avoided in patients with life-threatening symptoms or a history of anaphylaxis. It allows for identification of food allergies so that they can be avoided in the future and proves what foods do not play a role in the patient disease process (Niggemann, 2004). Studies show that symptoms often improve after the contributory food has been eliminated from the diet. Extensive elimination diets are not helpful in managing patients with AD and may lead to nutritional deficiencies; therefore, they are not encouraged (Leung & Bieber, 2003). Physicians should consider performing atopy patch tests (APTs) if the results of a skin prick test or RAST is positive for an aeroallergen (Darsow et al., 2005). Certain climates may serve as triggers for patients with AD. The Winter is often troublesome as the associated decreased humidity allows the skin to dry out easier through increased transepidermal water loss (Abramovits et al., 2003). Sweating as a result of heat or exercise may act as an irritant in some patients causing burning in their eczematous lesions (Leung et al., 2004).

Emotional stress has been well documented to trigger and maintain lesions (Werfel & Kapp, 1999). Atopic dermatitis has a significant affect on quality of life secondary to stigmatization of
the condition, psychological stress, lack of sleep secondary to pruritus and pain, and effects on social and financial well-being (The Lewin Group, Inc., 2005). Emotional stress can increase pruritus, scratching, and trigger the immune system (Leung et al., 2004). Children may experience a negative affect on their academic and social development as a result of AD-related stresses (The Lewin Group, Inc., 2005). Referral to a psychiatrist or therapist is beneficial

for patients in which emotional stress plays a strong role in aggravating their disease. Relaxation therapies, behavioral modification strategies, and biofeedback have all been used to reduce exacerbations in AD precipitated by scratching (Leung et al., 2004). In women, hormones may act as a trigger for AD. Patients have had exacerbations during menstruation, the first and second trimesters of pregnancy, the peripartum period, and menopause. Further studies are needed to investigate how these hormonal changes induce flares (Bardana, 2004; Werfel & Kapp, 1999).
The skin of patients with atopic dermatitis is very sensitive and vulnerable to irritants. Irritants play a provocative role in AD, but are not involved in the primary pathogenesis of the disease (Bardana, 2004). Hot water, soaps, cigarette smoke exposure, enzyme rich laundry detergents, household disinfectants (bleach and ammonia), solvents (alcohol, gasoline, and kerosene), clothing made with synthetic fibers (rayon and polyester) or wool, and juice from fresh fruits (tomatoes, citrus, and strawberries) are the most common irritants in AD (Abramovits et al., 2003; Bardana, 2004; Leung et al., 2004; Wuthrich, 1999).

A variety of microorganisms including bacteria, viruses, fungi, and yeast aggravate atopic dermatitis. Staphylococcus aureus is well known to play a role in the pathogenesis, maintenance, and

exacerbation of atopic dermatitis. S. aureus can secrete toxins that act as superantigens to stimulate the proliferation of T cells and other cells of the immune system and thus worsen atopic dermatitis
(Abramovits, 2005; Bardana, 2004). Over 90% of AD skin lesions are colonized with S. aureus as opposed to only a 5% rate of colonization in normal skin of healthy controls (Abramovits, 2005). IgE-specific antibodies against S. aureus superantigens have been found in the serum of patients with AD (Bardana, 2004). Most experts recommend using antibiotics against S. aureus if there is an active infection or the individual is heavily colonized with S. aureus. However, antibiotics are not recommended to treat common colonization due to the concern over antibiotic resistance (Darsow et al., 2005; Leung et al., 2004). If the patient has developed a secondary infection with S. aureus his/her skin lesions undergo impetiginization and the lesions become weeping and crusted (classically the honey-colored crust). Superficial pustules and periauricular fissures may also be present (Lubbe, 2003). b-hemolytic streptococcus infections occur at an increased rate in AD and may also play a role as a trigger in atopic dermatitis (Darsow et al., 2005; Lubbe, 2003). Children with AD who develop streptococcal infections present with beefycolored erythema, crusts, pustules, fever, and adenopathy. It is recommended that these cases also be treated with antibiotics (Lubbe, 2003).

Atopic dermatitis carries a higher incidence of recurrent cutaneous viral infections as a consequence to local impaired T-cell function (Abramovits, 2005). These viral infections have
the potential to disseminate because of the epidermal barrier damage in AD and become life-threatening in patients with atopic dermatitis (Leung et al., 2004; Lubbe, 2003). Eczema herpeticum is a disseminated form which can occur in patients with AD and must be treated with antiviral medications (Leung et al., 2004). In young adults with AD, eczema herpeticum may be a recurrent infection (Lubbe, 2003). Widespread punched out erosions, vesicles, infected skin lesions that do not respond to antibiotics, fever, and lymphadenopathy are typical findings seen in eczema herpeticum (Darsow et al., 2005; Leung et al., 2004). Another cutaneous viral infection,

of herpes simplex

molluscum contagiosum, has the potential to become extensively distributed in patients with AD and is known as eczema molluscatum. Eczema molluscatum is characterized by tens to hundreds of small,
umbilicated, skin-colored papules (Leung et al., 2004). These lesions can be spread by auto-inoculation from scratching. A variety of treatment options are available for eczema molluscatum including destruction via cryotherapy,

carbon dioxide vaporization, electrodessication and curettage, or topical treatment with imiquimod 5% cream (Aldara) (a medication that enhances the immune response by increasing the release of cytokines) (Darsow et al., 2005). Eczema vaccinatum, a widespread skin infection in patients with atopic dermatitis, follows smallpox vaccination, has a clinical presentation similar to eczema herpeticum, and is extremely life threatening (Leung
et al., 2004).

Finally, dermatophytes and yeasts can complicate and exacerbate a course of AD. The dermatophytes most commonly involved are Malassezia furfur (which affects the scalp and seborrheic areas), Trichophyton, and Epidermophyton, while the yeasts involved include Candida and Pityrosporum ovale (the yeast form of Malassezia furfur). Patients have clinical improvement of their atopic dermatitis following antifungal therapy aimed against their concomitant dermatophyte or yeast infection (Lubbe, 2003).
Topical Therapy
Therapy for atopic dermatitis is multi-faceted and encompasses restoring the skin barrier function, using anti-inflammatory medications (topical or systemic), identifying and eliminating triggers, and secondary prevention . The skin

barrier in AD is faulty with a decrease in the amount of and an abnormal ratio between skin lipids (most notably ceramide), which leads to increased transepidermal water loss (Chamlin et al., 2001; Darsow et al., 2005). Genetic mutations of the epidermal barrier protein filaggrin are a predisposing factor for AD (Palmer et al., 2006; Weidinger et al., 2006). Emollients are regarded as a standard of care in preventing and treating AD. When used as a moisturizing regimen in conjunction with steroids, emollients enhance the anti-inflammatory affect of topical steroids resulting in a steroid-sparing phenomenon (Hanifin et al., 2004; Hanifin et al., 1998). It is recommended that emollients be applied at least twice

daily and immediately after bathing (Darsow et al., 2005).

Since their development over 50 years ago, topical corticosteroids have served as the first line of therapy for AD and this recommendation remains in the most up-to-date position of the European Academy of Dermatology and Venereology (Darsow et al., 2005). Topical steroids are anti-inflammatory medications and are classified according to their vasoconstrictor assays, with the most potent topical steroids in Class 1 and the least potent in Class 7 (see Table 4 ). Longer duration of therapy and more potent topical steroids have a higher potential for adverse effects. The amount of absorption of a topical steroid is influenced by the surface area of the skin, thickness of the skin (epidermis), the type of vehicle, drug concentration, and the presence of absence of occlusive dressings. Class 1 to 5 topical steroids should be avoided in areas of thinner skin, including the eyelids, face, mucous membranes, genitalia, and intertriginous areas, as these areas have increased likelihood of transepidermal corticosteroid absorption (Leung et al., 2004). In contrast, potent topical steroids may be needed on the palms and soles as the epidermis in these areas is much thicker (Brazzini & Pimpinelli, 2002). Children have a low body volume to skin surface area ratio, which allows for a greater absorption of corticosteroids leading to a higher potential for adverse affects. As a result, higher-potency steroids should be avoided in children (Paller et al., 2005). Local adverse effects of topical steroids include striae, skin atrophy, telangiectasias, perioral dermatitis, erythema, acne, glaucoma, and cataracts. Potential systemic adverse effects include growth suppression, suppression of the hypothalamic-pituitary-adrenal axis, and osteoporosis, and are most likely to occur with the use of high-potency steroids (Brazzini & Pimpinelli, 2002; Paller et al., 2005). Benefits of topical steroids include a low-cost, wide variety of preparations, and proven clinical effectiveness (Leung et al., 2004). Topical steroids are available in a wide variety of vehicles including creams, lotions, ointments, solutions, gels, and foams. In general, ointments are more potent than creams because of superior ability to hydrate the stratum corneum (the top layer of the epidermis) which enhances absorption (Brazzini & Pimpinelli, 2002; Leung et al., 2004). Selection of a vehicle can also be based on the body area to which the medications will be applied. For example, ointments on hairy areas of the body can be messy, so foams and lotions are preferred. Sometimes in severe disease, occlusive dressings may be employed. Occlusive dressings have the advantage of increasing the penetration of a steroid and making therapy more effective, but they also increase the risk of side effects; therefore, they should not be used for prolonged periods of time (Brazzini & Pimpinelli, 2002). The choice of a topical steroid should be tailored to each patient based on the potency, vehicle, lesion location, patient age, season, environment, socioeconomic class, prior medication(s), the presence or absence of infection, and patient preferences. Currently, it is recommended that the least-potent topical steroid be used (along with a good skin care regimen) to achieve the maximum benefit; then tapered, discontinued, or changed to less-potent topical steroid (Paller et al., 2005). Optimally, topical steroids should be used for only a few weeks in a continuous fashion and then used intermittently (for example, twice a week) (Hanifin et al., 2004; Paller et al., 2005). It is preferable for low-potency steroids to be used in maintenance therapy and mid to high-potency steroids to be used to treat flares (Leung et al., 2004). Pruritus can serve as a marker in evaluating a treatment response, and tapering of the steroid should not be attempted until pruritus has disappeared. Tapering of the topical steroid should be done gradually to avoid a flare (Darsow et al., 2005). Multiple large reviews have shown that once-a-day application of an appropriately selected topical steroid is as effective as twice-daily application (Green, Colquitt, Kirby, & Davidson, 2005; Hanifin et al., 2004). In children with mild-to-moderate AD, the use of intermittent, short cycles of potent steroids is safe and equivalent in effectiveness to the long-term use of weaker topical steroids (Hanifin et al., 2004). In recent years, topical calcineurin inhibitors have become available for treating atopic dermatitis. These medications also have anti-inflammatory affects, but do not contain steroids. The two medications offered are pimecrolimus and tacrolimus, and both are approved to treat patients over age 2 (Darsow et al., 2005). Both medications decrease the extent, severity, and symptoms of AD (Hanifin et al., 2004). Pimecrolimus (Elidil) is effective in treating mild-to-moderate forms of AD and is available in a 1% cream. Tacrolimus (Protopic) is used in treating moderate-to-severe AD and is available in 0.03% and 0.1% ointments (Hanifin et al., 2004). The 0.1% tacrolimus ointment is indicated for patients older than 16 years of

inhibitors are applied twice a day and can be used along with topical corticosteroids. Some clinicians may choose to initiate
treatment of atopic dermatitis with topical corticosteroids and make a transition to topical calcineurin inhibitors when the extent of the inflammation is reduced. Others have layered these products together by applying the steroid first, applying the topical calcineurin inhibitor 30 minutes later, and decreasing the potency of the steroid or eliminate it all together once clinical improvement is seen (Paller et al., 2005). Studies have shown that tacrolimus 0.1% is either equal to or more efficacious than a Class 5 corticosteroid in treating AD, and tacrolimus 0.03% is more efficacious than a low-potency steroid, but not as efficacious as a mid-potency topical steroid (Beck, 2005). Studies comparing tacrolimus and pimecrolimus demonstrated that 0.1% tacrolimus is more efficacious than pimecrolimus; 0.03% tacrolimus has equal efficacy to 1% pimecrolimus in mild disease; and 0.03% tacrolimus is better than 1% pimecrolimus in decreasing the itch associated with AD (Paller et al., 2005). Tacrolimus has a faster onset of action as compared to pimecrolimus, with improvement in symptoms during the first week of therapy (Paller, 2004). Both of these medications were proven safe and effective (up to 1 year in all and 4 years in tacrolimus 0.1%) in numerous trials (Chapman et al., 2005; Darsow et al., 2005; Hanifin et al., 2005; Koo et al., 2005; Leung et al., 2004; Paller, 2004; Paller et al., 2005). These medications do not have the side effect profile of topical steroids, and therefore can be used in areas where the epidermis is thinner such as the eyelids, face, mucous membranes, genitalia, and intertriginous areas, without the risk of skin atrophy and striae. The most frequent side effect is burning at the application site (which may be more frequent in tacrolimus); however, this symptom often improves with time and usage (Abramovits, 2005; Darsow et al., 2005). Other local side effects include itching and erythema (Chapman et al., 2005). In noncomparative trials, the incidence of cutaneous viral infections such as herpes simplex, eczema herpeticum, molluscum, varicella zoster, and warts is slightly increased in patients treated with topical calcineurin inhibitors (Hanifin et al., 2005; Koo et al., 2005). Additional side effects include flu-like symptoms, allergic reactions, asthma, cough, fever, otitis media, and headache (Hanifin et al., 2005; Koo et al., 2005). In March of 2005, the U.S. Food and Drug Administration (FDA) issued a Public Health Advisory concerning a potential increased risk of cancer associated with topical tacrolimus and pimecrolimus. The advisory was based on animal studies and a small number of case reports of skin cancer and lymphoma in adults and children treated with topical calcineurin inhibitors. The FDA made recommendations on the use of topical calcineurin inhibitors to health care providers, patients, and caregivers, as follows (see Table 5 ). Pimecrolimus and tacrolimus should be used only as second-line agents for

age (Paller, 2004). All topical calcineurin

short-term and intermittent treatment of atopic dermatitis in patients unresponsive to, or intolerant, of other treatments. Avoid the use of pimecrolimus and tacrolimus in children younger than 2 years of age. The effect of pimecrolimus and tacrolimus on the developing immune system in infants and children is
not known. In clinical studies, infants and children younger than 2 years old treated with pimecrolimus had a higher rate of upper-respiratory infections than did those treated with placebo cream. Use pimecrolimus and tacrolimus only for short periods of time, not continuously. The long-term safety of pimecrolimus and tacrolimus are unknown. Children and adults with weakened or compromised immune system should not use pimecrolimus and tacrolimus. Use the minimal amount of pimecrolimus and tacrolimus needed to control the patient symptoms. In animals, increasing the dose resulted in higher rates of cancer. The FDA will be requiring a black box warning to be placed on these medications and the development of a medication guide for tacrolimus and pimecrolimus (FDA, 2005). The American Academy of Dermatology (AAD) issued a statement in response to the FDA that it was disappointed that the FDA took this action, despite the lack of data proving proper topical use of pimecrolimus and tacrolimus is dangerous to people (AAD, 2005). The chance of systemic exposure of these medications has been studied in various trials and shown to be minimal and transient and not associated with an increase in adverse effects (Beck, 2005). Prospective clinical studies of topical calcineurin inhibitors have not shown an increase risk of lymphoma, lymphoproliferative disease, or skin cancers (Beck, 2005). Taking into consideration that systemically administered (oral) calcineurin inhibitors, cyclosporine, and tacrolimus have demonstrated an increased risk of lymphoproliferative diseases and skin cancers in transplant patients (Beck, 2005; Darsow et al., 2005; FDA, 2005), additional long-term studies of 10 years or more will be needed to determine the safety profile of topically administered calcineurin inhibitors (FDA, 2005).

Other topical treatments for AD include coal tar, doxepin, and topical sodium cromoglicate (Hanifin et al., 2004; Stainer et al., 2005; Williams, 2005). Coal tar and coal tar derivatives have been used for decades to treat AD and have efficacy similar to a Class 7 steroid (Williams, 2005). These medications exhibit antipruritic and anti-inflammatory effects and should only be used in chronic lesions of atopic dermatitis (Leung & Bieber, 2003). Coal tar can be used as monotherapy or in combination with topical steroids. Photosensitivity and folliculitis may result from coal tar (Leung & Bieber, 2003), but the major drawback is the odor and dark color which stains clothes (Correale et al., 1999). These cosmetic disadvantages generally lead to issues with compliance (Hanifin et al., 2004). Doxepin is a topical antihistamine that is able to decrease the pruritus associated with AD within 48 hours (Williams, 2005). Concerns over its potential for cutaneous sensitization and the side effect of sedation may limit its use (Leung et al., 2004). Studies in the past regarding the effectiveness of topical cromoglicate in treating AD are inconsistent. Cromoglicate acts to prevent or reduce the release of inflammatory and chemotaxic mediators from mast cells. A recent randomized trial demonstrated that the application of cromoglicate lotion (in addition to a treatment plan of topical steroids and emollients) can improve symptoms and severity of skin lesions and decrease steroid use in children with AD as compared to the lotion vehicle. Erythema and burning at the site of application are the most common side effects of topically applied cromoglicate (Stainer et al., 2005).

Systemic Therapy
Various forms of systemic therapy have been studied for treating atopic dermatitis including oral antihistamines, oral steroids, systemic immunomodulators, phototherapy, and antimicrobials (Darsow et al., 2005; Hanifin et al., 2004). Sedating and nonsedating oral antihistamines are not effective at relieving pruritus in the majority of patients. However, oral antihistamines may provide some benefit to patients who have poor sleep (secondary to pruritus, dermatographism, or allergic rhinitis), dermatographism, urticaria, or allergic rhinitis (Hanifin et al., 2004). Systemic steroids may be employed temporarily to treat severe AD; however, concerns over side effects and a rebound affect that may occur after discontinuation limits their use (Abramovits, 2005). In severe, recalcitrant AD,

immunomodulators may be used, but it is important that the patient be followed

closely to detect any side effects and these medications should not be used long-term (Paller et al., 2005 ).

Cyclosporine is an immunosuppressant that works quickly (within 2 weeks) and can treat recalcitrant AD effectively
(Abramovits, 2005; Darsow et al., 2005). Adverse effects include renal toxicity, hypertension, nausea, and abdominal pain (Leung et al., 2004; Rudikoff & Lebwohl, 1998). In most cases, this medication should only be used for short periods of time and patients may relapse quickly after the medication is discontinued (Abramovits, 2005). Azathioprine, an anti-inflammatory and antiproliferative medication, has also been used in treating refractory AD. Azathioprine is a slow-acting medication (4 to 6 weeks) (Leung et al., 2004) and has the potential for inducing bone marrow suppression, hepatotoxicity, hypersensitivity reactions, pancreatitis, squamous cell carcinoma of the skin, and non-Hodgkins lymphoma (Abramovits, 2005). Patients who may undergo therapy with azathioprine should have a thiopurine-methyltransferase (TPMT) level monitored, as low levels of TPMT are associated with increase bone marrow suppression and therapy with azathioprine should be avoided in the cases. The adult and pediatric dose of cyclosporine is 3 to 5 mg/kg/day while the adult and pediatric dosage of azathioprine is 2.5 mg/kg/day (Darsow et al., 2005). Myclophenolate mofetil is another immunosuppressant that may be beneficial in treating AD. The adult dosage of myclophenolate mofetil is 2 g/day (Darsow et al., 2005). There is a risk of bone marrow suppression and patients should be treated for only short periods of time (Leung et al., 2004). Data concerning the use of IVIG (intravenous immunoglobin) in treating AD are inconsistent (Hanifin et al., 2004), and clinical trials evaluating the use of methotrexate and biological therapies in AD are lacking (Abramovits, 2005). Another option for the treatment of recalcitrant atopic dermatitis is ultraviolet ( UV) light therapy. Phototherapy has an anti-inflammatory effect on the cells of the immune system (Paller et al., 2005). Types of UV therapy that have been used successfully in treating AD include psoralen plus UVA (PUVA), the combination of broadband UVB/UVA, broadband UVA, broad-band UVB, narrowband UVB (311 nm), and UVA-1 (340-400 nm) (Hanifin et al., 2004; Leung et al., 2004; Paller et al., 2005). PUVA therapy should only be used in patients with severe, widespread, recalcitrant AD (Leung & Bieber, 2003). Topical steroids may be used concomitantly with PUVA therapy and patients may be able to decrease topical steroid use during PUVA therapy (Hanifin et al., 2004, Leung et al., 2004). Combination broadband UVB/UVA therapy, narrowband UVB therapy, and UVA-1 are all superior to broadband UVB therapy alone (Hanifin et al., 2004; Leung et al.,

2004). Adverse effects of ultraviolet light therapy include stinging, burning, premature skin aging, pigmentation, and the increased likelihood of squamous cell carcinoma and melanoma (Abramovits, 2005; Paller et al., 2005; Williams, 2005). Relapses, usually within 3 months, are common after therapy is discontinued (Abramovits, 2005). Finally, as mentioned previously, microbes including bacteria, viruses, fungi, and yeast can all exacerbate atopic dermatitis. Antibiotic treatment is recommended for patients with an active infection or heavy colonization of S. aureus (Darsow et al., 2005; Hanifin et al., 2004). Systemic antibiotics are preferred and first-generation cephalosporins are often prescribed due to the growing number of cases of macrolide-resistant S. aureus. Cultures can be very beneficial for guiding therapy, as the prevalence of methicillin-resistant Staphylococcus aureus is increasing (Paller, 2004). Furthermore, some studies have shown that topical steroids and topical calcineurin inhibitors can decrease S. aureus counts in AD lesions (Leung et al., 2004). Topical antiseptics have limited usefulness in treating AD (Hanifin et al., 2004). Antiviral treatment, often with acyclovir, is critical in patients with eczema herpeticum as this infection can be life threatening in patients with AD. Eczema molluscatum lesions will resolve on their own with time, but treatment decreases further spreading by autoinoculation and accelerates resolution of lesions (Darsow et al., 2005).

Prevention
It is imperative to distinguish between the kinds of prevention of atopic dermatitis: primary prevention and secondary prevention. Primary prevention involves an intervention that prevents a disease from occurring in individuals at risk of a disease; secondary prevention decreases the likelihood of a disease reoccurring. In the case of primary prevention of AD, there is no conclusive evidence that exclusive breastfeeding, infant avoidance of aeroallergens, early introduction of solid foods, or mother avoidance of aeroallergens or certain foods will prevent the development of AD. Evidence does show that treatment with probiotics,

particularly Lactobacillus, during pregnancy or infancy may delay the onset of AD in infants and children; however, more studies are needed (Hanifin et al.,
2004). Secondary prevention of atopic dermatitis involves avoiding and/or reducing the identifiable triggers in AD and maintaining a good skin care regimen. The prevention program must be tailored to each patient. Elimination of foods should be based on the results of a double-blind, placebo-controlled food challenge (Niggemann, 2004). Patients whose disease is exacerbated by dust mites can employ several measures to decrease household dust mite burden

including adequate household ventilation, mattress covers, pillow covers, avoiding wall-to-wall carpeting, removing dust with a damp sponge, vacuuming floors and upholstery at least once a week, washing linens in hot water every 7 to 10 days, and decreasing indoor humidity levels with air conditioning (Darsow et al., 2005; Leung et al., 2004). In the Winter, patients should be advised to increase emollient use.
Avoiding irritants is a large portion of secondary prevention of atopic dermatitis. If a patient's disease is worsened by sweating, he/she may need a progressive adaptation to exercise (Darsow et al., 2005). Other options include water sports, such as swimming, but patients must shower and moisturize immediately after getting out of the swimming pool. Household temperature and humidity are also important to patients whose disease is worsened by sweating (Leung et al., 2004). Clothing

made of synthetic fibers and wool should be avoided and fabrics such as cotton used instead. Loose-fitting clothing is preferable to tight clothing (Darsow et al., 2005; Leung et al., 2004). Liquid laundry detergents should be substituted for powder detergents and a second rinse cycle can be added, as residual laundry detergent can be irritating. Patients sensitive to enzyme-rich detergents should use nonenzymatic detergents. Mild soaps with a neutral pH and minimal defatting capabilities should be used for

bathing in all patients with AD (for example Dove, Cetaphil, Basis, Aveeno, and Neutrogena (Leung et al., 2004). Patients should bathe in warm water once a day for 5 to 10 minutes, pat dry, and immediately apply emollients (Bardana, 2004; Correale et al., 1999). Finally, nails should be trimmed to decrease abrasions to skin (Correale et al., 1999).
Patient Education
Patient and family education is an integral part of managing atopic dermatitis. It is important to answer the questions of patients and their caregivers completely. Education should include information on causes and triggers of atopic dermatitis; prognosis, treatment, prevention; and address the patient quality of life. Nursing education of patients with atopic dermatitis increases patient compliance, increases in the appropriate usage of topical corticosteroids, and is vital to overall clinical improvement (Hanifin et al., 2004). Table 6 provides an Internet re source guide for patients and their families.
CE Information

The print version of the article was originally certified for CME credit. For accreditation details contact the publisher, Anthony J. Jannetti, Inc., East Holly Avenue Box 56, Pitman, New Jersey 08071-0056

Background
Although allergic rhinitis (AR) is a common disease, the impact on daily life cannot be underestimated. Some patients find allergic rhinitis to be just as debilitating and intrusive as severe asthma. Employees with untreated allergies are reportedly 10% less productive than coworkers without allergies, whereas those using allergy medications to treat allergic rhinitis were only 3% less productive.[1] This suggests that effective medications may reduce the overall cost of decreased productivity. Allergic rhinitis is caused by an immunoglobulin E (IgE)mediated reaction to various allergens in the nasal mucosa. The most common allergens include dust mites, pet danders, cockroaches, molds, and pollens. For example, tree pollen allergen binds to IgE antibodies that are attached to a mast cell via Fce receptor. When 2 IgE molecules bind to the same tree pollen allergen, they cause the mast cell to fire off (degranurate), leading to release of various inflammatory mediators that cause the symptoms we feel as allergic rhinitis, including sneezing; nasal congestion; stuffiness; rhinorrhea (runny nose); cough; itching of the nose, eyes, and throat; sinus pressure; headache; and epistaxis (bloody nose). The allergens present in the outdoor environment vary with the time of year and location. Knowing what allergens are in the environment at a specific time of year helps in diagnosing and treating allergic rhinitis and helps in excluding allergy as a cause of the patient's symptoms. For example, a patient who presents with nasal congestion in November in Boston, Massachusetts cannot have allergic rhinitis attributed to tree pollen allergy, which is prevalent in spring. Allergen exposure likely causes both upper and lower airway inflammation, meaning that both the nose and the lungs may be involved. Many experts believe that a patient's airway needs to be evaluated as a total entity, not as individual parts. Studies have shown that most patients with asthma also have allergic rhinitis. Guidelines regarding the impact of allergic rhinitis on asthma have been established.[2] Allergic reactions of the upper airway can trigger lower airway

symptoms and vice versa. One study showed that patients with untreated allergic rhinitis and asthma have an almost 2-fold greater risk of having an emergency department visit and almost a 3-fold greater risk of being hospitalized for an asthma exacerbation, respectively.[3] Similarly there are studies that reveal treatment of one disease entity improves the other. The graphs below detail the significant impact of nasal allergies.

Impact of nasal allergies.

How

patient feel when they have allergy symptoms. and affect on work performance.

Nasal symptoms

Pathophysiology
Understanding the function of the nose is important in order to understand allergic rhinitis. The purpose of the nose is to filter, humidify, and regulate the temperature of inspired air. This is accomplished on a large surface area spread over 3 turbinates in each nostril. A triad of physical elements (ie, a thin layer of mucus, cilia, and vibrissae [hairs] that trap particles in the air) accomplishes temperature regulation. The amount of blood flow to each nostril regulates the size of the turbinates and affects airflow resistance. The nature of the filtered particles can affect the nose. Irritants (eg, cigarette smoke, cold air) cause short-term rhinitis; however, allergens cause a cascade of events that can lead to more significant inflammatory reactions. In short, rhinitis results from a local defense mechanism in the nasal airways that attempts to prevent irritants and allergens from entering the lungs. Allergic reactions require exposure and then sensitization to allergens. To be sensitized, the patient must be exposed to allergens for a period of time. Sensitization to highly allergenic indoor allergens can occur in children younger than 2 years. Sensitization to outdoor allergens usually occurs when a child is older than 3-5 years, and the average age at presentation is 9-10 years. The allergic reaction begins with the cross-linking of the allergen to 2 adjacent IgE molecules that are bound to high-affinity Fc receptors on the surface of a mast cell. This crosslinking causes mast cells to degranulate, releasing various mediators. The best-known mediators

are histamine, prostaglandin D2, tryptase, heparin, and platelet-activating factor, as well as leukotrienes and other cytokines. These substances produce 2 types of reactions: immediate and late-phase. The immediate reactions in the nasal mucosa induce acute allergy symptoms (eg, nasal itch, clear nasal discharge, sneezing, congestion). The late-phase reaction occurs hours later, secondary to the recruitment of inflammatory cells into the tissue by the action of mediators (termed chemokines) released by the mast cell. Recruited cells are predominated by eosinophils and basophils, which, in turn, release their inflammatory mediators, leading to continuation of the cascade. In very sensitive individuals, this allergen-induced nasal inflammation causes priming of the nasal mucosa. Primed nasal mucosa becomes hyperresponsive, at which point even nonspecific triggers or small amounts of the antigen can cause significant symptoms.

Epidemiology
Frequency
United States Prevalence in the United States is 10-20%.[4] One survey demonstrated rates as high as 38.2% when patients were asked if they experienced fewer than 7 days of symptoms. When allergic rhinitis was defined as symptoms lasting more than 31 days, prevalence dropped to 17%. International In temperate areas of Europe and Asia, frequency is similar to that in the United States.

Mortality/Morbidity
Mortality is not associated with allergic rhinitis, but significant morbidity occurs. Morbidity is manifested in several ways. Annually, an estimated 824,000 school days are missed, and an estimated 4,230,000 days of reduced quality-of-life functions are reported.[5] Comorbidity of other atopic diseases (asthma, atopic dermatitis) or upper airway inflammation (sinusitis, otitis media) is significant in allergic rhinitis. Individuals with allergic rhinitis have a higher frequency of these conditions than individuals without allergic rhinitis. Quality-of-life surveys have revealed that patients with significant allergic rhinitis found symptoms to be just as debilitating as symptoms in patients with moderate-to-severe asthma. Patients with allergic rhinitis felt they were equally impaired and unable to participate in the activities of normal living similar to those with the moderate-to-severe asthma. They felt that chronic congestion, sneezing, the need to wipe the nose, and a decrease in restful sleep compromised levels of their daily activity. The financial cost of allergic rhinitis is difficult to estimate. Self-treating patients are estimated to spend an average of 56 dollars per year. The direct cost of prescription medication exceeds 6 billion dollars per year worldwide, and lost productivity is estimated at 1.5 billion dollars per year.

Race

Allergic rhinitis has no race predilection; however, individuals from nonwhite backgrounds seek out medical attention less often than whites.

Sex
Allergic rhinitis has no sex predilection.

Age
Allergic rhinitis usually presents in early childhood. Allergic rhinitis caused by sensitization to outdoor allergens can occur in children older than 2 years; however, sensitization in children aged 4-6 years is more common. Clinically significant sensitization to indoor allergens may occur in children younger than 2 years. This is typically associated with significant exposures to indoor allergens (eg, molds, furry animals, cockroaches, dust mites). Some children may be sensitized to outdoor allergens at this young age if they have significant exposure. Incidence continues to increase until the fourth decade of life, when symptoms begin to fade; however, individuals can develop symptoms at any age. Allergic rhinitislike symptoms (runny nose, blocked nose, or sneezing apart from a cold) may begin as early as age 18 months. In a report from the Pollution and Asthma Risk: an Infant Study (PARIS), 9.1% of the 1859 toddlers in the study cohort reported allergic rhinitislike symptoms at age 18 months.[6]

History
The history of the patient with allergic rhinitis (AR) may be straightforward or may include a complex set of symptoms. The diagnosis is easy to make in a patient with a new pet or with symptoms that have distinct seasonal variation. Alternatively, younger patients may present with varying signs or symptoms, the family may not appreciate the nasal stuffiness but may note the chronic nasal congestion. In older children, symptoms may have been present for years and, therefore, appear to be less severe because the child has accommodated them. Physicians should try to identify seasonal variations, provocative elements in the environment, and the timing of events that lead to symptoms. Few patients present soon after the onset of allergic rhinitis symptoms. Usually, allergic rhinitis symptoms have been present for years and have been slowly worsening during each allergy season. This is especially true for patients with pet allergies. The symptoms appear slowly, over years. They can worsen in the spring and fall and be confused with pollen allergy. This occurs for pets usually shed more in the warmer weather and then in the fall when more time is spent indoors with worsening symptoms. Also, many families believe that the fact that the pet was present before the onset of the child's symptoms exclude the possibility of allergy to the family pet, but this is not true. The family often believe that the family pet is hypoallergenic. No cats or dogs are truly hypoallergenic. Unless a new exposure to large amounts of allergens is reported (eg, pet, feather pillow), a patient who describes a sudden onset of nasal allergy symptoms is not experiencing allergic symptoms. Sudden onset of nasal symptoms is often associated with acute sinusitis or acute bacterial sinusitis superimposed on chronic sinusitis. In children younger than 5 years,

differentiating allergy symptoms from recurrent upper respiratory viral infection is even more difficult, especially in those who attend daycare and experience frequent rhinitis symptoms.

Nature of symptoms o Symptoms of rhinitis consist of rhinorrhea, nasal congestion, postnasal drainage, repetitive sneezing, and itching of the palate, nose, or eyes. Snoring, frequent sore throats, constant clearing of the throat, cough, itchy eyes, and headaches are symptoms often associated with rhinitis.
o

When obtaining the history, ascertain the following:

Determine which symptoms are reported by the patient or parent. Determine whether the patient has rhinorrhea, sniffling, nasal itching, sneezing, cough, congestion, or nasal discharge. Determine the color of the nasal discharge. Determine whether any associated ocular or respiratory symptoms are present. Ask about snoring, which may worsen in pollen season.

Timing of symptoms
o

Identify whether symptoms are present or worsen during certain seasons, such as the spring or fall. In addition, try to identify whether symptoms are worse in specific places, such as home, work, or school, or when the patient is around animals. Determine when symptoms occur and whether they occur primarily at night, in school, outdoors, or at a relative's or friend's home. Determine whether symptoms occur only at a certain time of the year or throughout the year. Remember that symptoms in the fall and spring may still indicate a pet allergy. Determine whether symptoms ever improve and, if so, what actions help alleviate symptoms. Most patients have tried over-the-counter antihistamine medication. If these medications help, allergic rhinitis should be suspected; however, a negative response does not eliminate the possibility of allergic rhinitis. Ask if the patient's symptoms improve when they are away from certain locations. For example, a child who has less symptoms at college or camp may have an allergy to the family pet, feather pillows, or dust mites in their bedding. Determine whether symptoms improve when the patient is taking antibiotics. Most patients receive antibiotics for various reasons unrelated to nasal symptoms. If symptoms respond to antibiotic therapy, the clinical diagnosis may be sinusitis, which may have been either primary sinusitis or secondary sinusitis caused by allergic rhinitis.

Duration of symptoms
o o

Determine whether symptoms last for weeks, months, or hours. Most pollen seasons are at least 6 weeks long in more moderate climates. In the south and far north, the season can be longer or shorter, respectively. Symptoms that last less than 2 weeks rarely indicate allergic rhinitis unless concomitant exposure occurs. In winter in the northern regions, virtually all pollens are absent; therefore, any allergic rhinitislike symptoms are the result of indoor allergen exposure or are associated with nonallergic causes. Although patients are usually exposed to the same allergens throughout the year, allergic rhinitis symptoms triggered by indoor allergens can worsen in winter secondary to longer hours spent indoors during the cold months. This may also be associated with closed windows and doors in winter, resulting in increased recirculation of indoor allergens. An example of winter-only exposure is a person who is allergic to dust mites who uses a down comforter only during the winter (dust mites are highly infested in a down comforter.)

Family history
o o

Children with parents who have allergies or asthma are more likely to be affected. If a child has one parent with allergies, chances are 30% that a child will have allergic rhinitis. This increases to 50-70% if both parents have allergies or atopic asthma.

Related medical history

o

Patients with a history of infantile eczema (atopic dermatitis) have a 70% chance of having allergic rhinitis, asthma, or both. Patients with a history of asthma also have higher incidence of allergic rhinitis.

Social and environmental history

o

The patient's environment is very important. Ask about the presence of a pet or beddings (eg, pillow, bedspread, comforter [especially containing feathers]) and other home items likely infested by dust mites (eg, carpeted floor, stuffed animals, dusty closet, nonleather furniture) as well as the timing of initial exposure. Many times, exposure to dust, feathers, or pets coincides with the onset of symptoms, making diagnosis and treatment easier. However, patients could become sensitized to indoor allergens by exposure in places other than the home where they spend a fair numbers of hours (eg, schools, daycare center, baby sitters' and relatives' homes).

Questions must be raised regarding any environment in which the patient spends more than a few hours per week. This includes baby-sitters' and relatives' homes, daycare facilities, and schools (classroom pets). For children younger than 3 years, ask about the child's bed. Cribs or toddler beds that use crib mattresses do not have dust mites because of the plastic covers, but standard bedding (bed mattress) can harbor dust mites.

Physical
A full examination should always be performed to detect other diseases, such as asthma, eczema, and cystic fibrosis, which occur in connection with allergic rhinitis. Evaluation involves the head, eyes, ears, nose, and throat. Upon inspection, the following signs can be noted:

Head
o

Allergic shiners (dark, puffy, lower eyelids) may be present (see image below).

Photo demonstrates allergic shiners. Note the periorbital edema and bluish discoloration seen in allergic rhinitis and sinusitis.
o o

Morgan-Dennie lines (lines under the lower eyelid) may be observed. Transverse crease at the lower third of the nose secondary to the allergic salute, which is the upward rubbing of the nose, is commonly seen in parents as well.

Eyes
o

Marked erythema of palpebral conjunctivae and papillary hypertrophy of tarsal conjunctivae are observed. Chemosis of the conjunctivae may be present. Patients usually have a watery discharge. Cataracts have occurred from severe rubbing secondary to itching.

Ears
o

Tympanic membranes should be examined for the presence of chronic infection or middle ear effusion. The role of allergic rhinitis in chronic otitis media is not clear, but decreased numbers of infections have been noted in children with allergic rhinitis once therapy was instituted.

Nose
o

Nasal examination is often helpful in the diagnosis.

o o

Turbinates are enlarged and have a pale-bluish mucosa due to edema. Discharge is usually clear but can be white. The discharge is rarely yellow or green. If colored discharge is observed, a diagnosis of viral infection or sinusitis should be considered. Dried blood is commonly observed secondary to trauma from rubbing the nose. Polyps are rarely observed in children. If polyps are noted or suspected, perform rhinoscopy. If polyps are detected, a workup for cystic fibrosis is mandatory in children. Also consider the diagnosis of aspirin sensitivity in adults.

o o

Throat
o

Inspection of the dentition can be informative. Discoloration of frontal incisors and a high arched palate are associated with chronic mouth breathing. Malocclusion is commonly associated with chronic mouth breathing. Cobblestoning in the posterior pharynx is also a sign of follicular hypertrophy of mucosal lymphoid tissue secondary to chronic nasal congestion and postnasal drainage. Note the size of tonsillar tissue, which may provide a clue to the size of the adenoids; large adenoids can mimic the signs and symptoms of allergic rhinitis. Chronic nasal congestion due to adenoid hypertrophy is frequently seen in young children with recurrent otitis media and sinusitis.

Causes

Perennial symptoms are usually caused by indoor allergens, including the following: o Dust mites
o o o o o

Cat dander Dog dander Indoor molds Cockroaches Feathers: In most occasions, feather pillows and comforters are highly allergenic, secondary to dust mite infestation. Nonfeathered bedding usually has less dust mite infestation but does have progressively more dust mites over time; dust mites lay eggs every 3 weeks and accumulate where human dander accumulates. Thus nonwashable beddings (eg, pillows, bed mattress) should be encased by dust miteproof encasings. Other furry animals

Seasonal symptoms are usually caused by airborne pollen and outdoor molds, including the following:
o o o o

Tree pollen Grass pollen Outdoor mold spores Weed pollen: Flowers do not cause allergic rhinitis because they do not use windborne pollination.

Differentials

Adenoidal hyperplasia Agammaglobulinemia Aspergillosis Cystic Fibrosis Gastroesophageal Reflux Nasal Polyps Sinusitis

Laboratory Studies
No studies are needed in allergic rhinitis (AR) if the patient has a straightforward history. When the history is confusing, various studies are helpful, including the following:

Nasal smear: Eosinophils usually indicate allergy. Neutrophils are more indicative of an infectious process, such as sinusitis. CBC count with differential: A CBC count may reveal an increased number of eosinophils. An eosinophil count within the reference range does not exclude allergic rhinitis; however, an elevated eosinophil count is suggestive of the diagnosis. Immunoglobulin E (IgE): Serum IgE values are not routinely recommended to evaluate atopy. An IgE value within the reference range does not exclude allergic rhinitis; however, an elevated IgE value is suggestive of the diagnosis. Allergen-specific IgE testing, also known as radioallergosorbent test (RAST), can be helpful if a specific allergen is suspected. Screening of a large number of allergens can cause confusion because of the possibility of false positives. This is especially true for IgE food allergy testing. Skin prick testing: This test is highly sensitive and specific for aeroallergens.

Imaging Studies

Imaging studies are not needed unless sinusitis is suspected, in which case, a limited CT scan of the sinuses (without contrast) is indicated. RAST for common allergens can be used to identify the patient's triggers. These might include dust mites, cat dander, dog dander, grass pollens, tree pollens, weed pollens, and molds. Foods rarely cause allergic rhinitis, and tests for food allergies are not indicated in patients with allergic rhinitis. RAST testing for allergens, such as dust mites, cat dander, and dog dander, is almost as sensitive and specific as allergen skin testing.

Procedures

Skin testing to identify the triggering agent o Skin testing has high sensitivity and specificity and is the preferred method of quick allergen identification for aeroallergens.
o

Skin testing is helpful if the allergens can be eliminated from the patient's environment or if the patient can avoid them. Skin testing is extremely helpful when patients are unresponsive to standard therapy or are unwilling to acknowledge the trigger, which is especially true if the family pet is a possible trigger. Skin testing is required if the patient is interested in allergen immunotherapy.

Rhinoscopy: This is helpful in direct examination of the upper airway in identifying whether the etiology of rhinitis is obstructive or infectious and for evaluation of nasal polyposis.

Medical Care
Treatment of allergic rhinitis (AR) can be divided into 3 categories: avoidance of allergens or environmental controls, medications, and allergen-specific immunotherapy (allergy shots).

Use of environmental controls is not adequately explored in most patients. For many patients, the removal of the trigger can have a dramatic effect. Difficulty arises when the trigger needs to be identified and eliminated. Eliminating the trigger may be simple if removal of a feather pillow or blanket is involved; however, it can be very difficult if a family pet needs to be removed. Although avoiding outdoor pollens is impossible, the patient can reduce exposure to pollens to attenuate symptoms. Identification and elimination is easiest for dust mite allergens.
o

Feathered bedding should be removed and replaced with a fiber-filled product encased by dust miteproof encasings. Such encasings can be purchased at the local stores or via mail orders. These encasings should be zip-locked and cover all surface areas.

A bed pad that is placed on top is not helpful and may be another source of dust mite infestation. Less expensive plastic encasings may leak allergens through needle holes or between zipper teeth; therefore, more expensive dust miteproof covers are preferable. The pillow must be covered; this is even more crucial than covering the bed mattress itself because the pillow is where the patient's head usually spends most of the night. Box springs usually do not need to be covered. Care should be taken to be sure the encasings are dust miteproof. Some products may claim to be an allergy cover but may not provide the proper protection for dust mite. Also hypoallergenic bedding usually refers to the fact that the bedding is not made of feathers and does not necessarily mean that it is dust miteproof.

Pollen is more difficult to avoid because daily activities must be altered to do so.
o

The patient is best advised to remain indoors with air-conditioning during the period of the highest pollen counts of the day. Commonly, remaining indoors is not possible because of activities, and many schools are not air-conditioned. An easy intervention is to keep the windows closed, which is easily accomplished in air-conditioned homes and must be done throughout the year. Windows tend to be opened most frequently during fall and spring in moderate climates, but these seasons are the worst possible times for open windows for patients with pollen allergy. If windows must be open, open them during the day and close them at night. Many pollen counts are highest during the night, especially for molds and trees. Another intervention is to obtain a window filter or filter fan, which allows air, but not pollen, to enter the room. Advise patients to wash head to toe and to change clothing upon coming in from the outdoors during high pollen season. Avoid hanging cloths outdoors to dry.

The most difficult trigger to avoid is the family pet. Ideally, the pet should be removed from the home, but removal is the option, not the rule. Some helpful manipulations include removing the pet from the patient's bedroom and play area, using air cleaners in these areas and, occasionally, frequently sponge-bathing the pet (once per week). Even when these interventions are performed, many patients continue to experience symptoms. Other therapies are necessary in these patients; however, some patients choose to live with the source of offending allergens. See Medication for a discussion of medications and allergen-specific immunotherapy (ie, allergy shots). A recent study concluded that specific immunotherapy can be recommended for treatment because it is effective in reducing symptoms.[7] No routine surgical care is needed.

Some patients may be seen by ear, nose, and throat (ENT) specialists, and turbinectomies may be performed to provide some relief. This is an extreme measure and is reserved for patients in whom all other therapies have failed. Rarely, in adults, if nasal polyps do not respond to topical nasal steroids, surgical removal may be necessary, although the polyps often grow back Primary care physicians can attend to most patients. Patients in whom diagnosis or treatment is more difficult may require consultation with a specialist. This usually starts with an allergist, who performs a complete allergy evaluation, including diagnostic tests. Therapy is instituted, which is a combination of environmental manipulations, medications and, in some patients, allergen-specific immunotherapy. If medical therapies do not produce an adequate result, referral to an ENT specialist should be indicated for possible surgical intervention.

Dietary restrictions do not help because allergic rhinitis is not triggered by foods.

No limitations are placed on activity. For some pollens, patients with allergic rhinitis benefit from avoiding the outdoors during peak pollen periods of the day. This time varies according to pollens and location. Geographic location and distance from the source have an impact. Patients who are miles away from the source have different peak pollen times than patients near the source.

Medication Summary
Many groups of medications are used for allergic rhinitis (AR), including antihistamines, corticosteroids, decongestants, saline, sodium cromolyn, and antileukotrienes. These can be further subdivided into intranasal and oral therapies. Intranasal administration has the advantage of directly affecting the site of action, and, in general, intranasal medications have fewer adverse effects and no systemic effects. The main advantage of oral therapy is ease of use. Some patients resist using intranasal medications. Allergen-specific immunotherapy is an alternative form of therapy that has several advantages. Most importantly, it is the only form of therapy that can cure allergy symptoms. Allergenspecific immunotherapy must be customized to the patient's individual allergies and involves weekly injections of increasing concentrations of an allergen until the maintenance dose is reached and a monthly injection of the maintenance dose for several years. The process usually does not produce clinical results in the first 6 months but results are seen afterwards. The recommended course is usually 4-5 years. Allergen-specific immunotherapy has been demonstrated to be more cost effective and improves the patient's quality of life more efficiently than standard allergy medications. Sublingual immunotherapy is also available in some parts of the United States as well as other countries of the world.[8] In this form of therapy, small amounts of the allergen are placed under the tongue on a daily basis. The 2 main advantages are that no injections are necessary and that it can be administered at home. The efficacy rate is about 20-30% in countries outside of the

United States. Currently, it is not approved by the US Food and Drug Administration (FDA), and the formulation that is presently used has not been shown to be effective for this use. The formulations that have been tested in other countries are not available in the United States. This form of treatment is controversial. Saline nasal irrigation is effective in approximately 50% of patients with allergic rhinitis. Irrigation assists the body's natural function of rinsing allergens out of nasal passages. Tap water cannot be used because it is hypotonic and causes edema, leading to greater congestion.

Class Summary
Antihistamines are classified in several ways, including sedating and nonsedating, newer and older, and first- and second-generation antihistamines (most widely accepted classification). First-generation antihistamines are primarily over the counter and are included in many combination products for cough, colds, and allergies. These include brompheniramine, chlorpheniramine (Chlor-Trimeton), and diphenhydramine (Benadryl), fexofenadine (Allegra), loratadine (Claritin) and cetirizine (Zyrtec) are now available over-the-counter (OTC) without a prescription. Second-generation antihistamines include desloratadine (Clarinex), and levocetirizine dihydrochloride (XYZAL), which require a prescription. View full drug information

Cetirizine (Zyrtec)
Low-sedating second-generation medication with fewer adverse effects than first-generation medications. Selectively inhibits peripheral histamine H1 receptors. Available as syr (5 mg/5 mL) and 5- or 10-mg tab. View full drug information

Levocetirizine (Xyzal)
Histamine H1-receptor antagonist. Active enantiomer of cetirizine. Peak plasma levels are reached within 1 h, and half-life is about 8 h. Available as a 5-mg breakable (scored) tab. Indicated for seasonal and perennial AR

Pediatric Dosing & Uses

Dosing Forms & Strengths
tablet

5mg

oral solution

0.5mg/mL

Allergic Rhinitis

<6 months: Safety and efficacy not established 6 months to 5 years: 1.25 mg PO qDay (evening) 6-12 years: 2.5 mg PO qDay (evening) >12 years: 5 mg PO qDay (evening)

Chronic Urticaria
<6 months: Safety and efficacy not established 6 months to 5 years: 1.25 mg PO qDay (evening) 6-12 years: 2.5 mg PO qDay (evening) >12 years: 5 mg PO qDay (evening)

Renal Impairment
<12 years: Contraindicated 12 years or older

CrCl: 50-80 mL/min: 2.5 mg PO qDay CrCl: 30-50 mL/min: 2.5 PO qOD CrCl: 10-30 mL/min: 2.5 mg every 3-4 days CrCl: <10 mL/min, hemodialysis: Contraindicated

Loratadine (Claritin)
Nonsedating second-generation antihistamine. Fewer adverse effects than with first-generation medications. Selectively inhibits peripheral histamine H1 receptors. Available as tab, disintegrating tab (Reditab), syr (5 mg/5 mL), or combined with pseudoephedrine in 12- or 24-h preparations. The only one that is presently available without a prescription

Desloratadine (Clarinex)
Nonsedating second-generation antihistamine. Fewer adverse effects than with first-generation antihistamines. Selectively inhibits peripheral histamine H1 receptors. Relieves nasal congestion and systemic effects of seasonal allergies. Long-acting tricyclic histamine antagonist selective for H1-receptor. Major metabolite of loratadine, which, after ingestion, is extensively metabolized to active metabolite 3-hydroxydesloratadine. Available as tabs, syr (0.5 mg/mL), or PO disintegrating Reditabs (2.5 and 5 mg).

Fexofenadine (Allegra)

Nonsedating second-generation medication with fewer adverse effects than first-generation medications. Competes with histamine for H1 receptors in GI tract, blood vessels, and respiratory tract, reducing hypersensitivity reactions. Available OTC in qd and bid preparations. Also OTC available combined with pseudoephedrine.

Intranasal antihistamines
Class Summary
These agents are an alternative to oral antihistamines to treat allergic rhinitis. Currently, azelastine and olopatadine are the only agents available in the United States.

Azelastine (Astelin)
An effective antihistamine delivered via the intranasal route. Mechanism is similar to PO antihistamines. Systemic absorption occurs and may cause sedation, headache, and nasal burning.

Olopatadine intranasal (Patanase)

Intranasal antihistamine indicated for seasonal allergic rhinitis. Available as 6% intranasal solution (delivers 665 mcg/spray).

Intranasal corticosteroids
Class Summary
This class of medications is most effective. Intranasal corticosteroids are potent antiinflammatory agents shown to decrease allergic rhinitis symptoms in more than 90% of patients. Presently, 9 medications are available in this class, and all are essentially equivalent in efficacy, although few head-to-head studies have been performed. Mometasone (Nasonex) and fluticasone furoate (Veramyst) have been demonstrated to have a somewhat faster onset of action; however, after one week, no difference is found between medications. Most can be used on a once-daily basis, and all have a similar safety profile. Nasonex is the only medication that did not show an affect on growth at one year. Veramyst did not show a growth effect in a 2-week study that is designed to evaluate for growth affects. A longer study began in late 2007. View full drug information

Beclomethasone (Beconase AQ)

May decrease number and activity of inflammatory cells, resulting in decreased nasal inflammation. View full drug information

Budesonide inhaled (Rhinocort Aqua)

May decrease number and activity of inflammatory cells, resulting in decreased nasal inflammation. View full drug information

Ciclesonide (Omnaris)
Corticosteroid nasal spray indicated for AR. Prodrug that is enzymatically hydrolyzed to pharmacologic active metabolite C21-desisobutyryl-ciclesonide following intranasal application. Corticosteroids have a wide range of effects on multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (eg, histamines, eicosanoids, leukotrienes, cytokines) involved in allergic inflammation. Each spray delivers 50 mcg. View full drug information

Flunisolide (AeroBid)
May decrease number and activity of inflammatory cells, resulting in decreased nasal inflammation. View full drug information

Fluticasone propionate (Flonase)

May decrease number and activity of inflammatory cells, resulting in decreased nasal inflammation. View full drug information

Fluticasone furoate (Veramyst)

Intranasal corticosteroid. Indicated for seasonal and perennial allergic rhinitis. Relieves nasal symptoms associated with allergic rhinitis. Has also demonstrated improvement in allergic eye symptoms. Contains 27.5 mcg/spray. View full drug information

Mometasone (Nasonex)
May decrease number and activity of inflammatory cells, resulting in decreased nasal inflammation. Demonstrated no mineralocorticoid, androgenic, antiandrogenic, or estrogenic activity in preclinical trials. Decreases rhinovirus-induced up-regulation in respiratory epithelial cells and modulate pretranscriptional mechanisms. Reduces intraepithelial eosinophilia and inflammatory cell infiltration (eg, eosinophils, lymphocytes, monocytes, neutrophils, plasma cells). View full drug information

Triamcinolone inhaled (Nasacort AQ)

May decrease number and activity of inflammatory cells, resulting in decreased nasal inflammation.

Intranasal decongestants
Class Summary
Decongestants are effective for short-term symptom control. They decrease nasal discharge and congestion and are available without a prescription. The 2 medications in this group are oxymetazoline hydrochloride (Afrin) and ipratropium bromide (Atrovent). Oxymetazoline hydrochloride is an addictive medication that is effective in shrinking nasal membranes and is not recommended for long-term use. Use of oxymetazoline hydrochloride for more than 7-10 d is habit forming. Patients can be addicted for years at a time. Addiction is termed rhinitis medicamentosa. Ipratropium bromide can be used for a prolonged period of time. View full drug information

Ipratropium bromide 0.03% or 0.06% (Atrovent)

Anticholinergic used for reducing rhinorrhea in patients with AR or vasomotor rhinitis. An excellent medication for decreasing rhinitis. Nonaddictive and lasts for 12 hours. Does not shrink the nasal mucosa, but inhibits secretion that causes rhinitis. Used alone or in conjunction with other medications. Previous Next Section: Intranasal mast cell stabilizers

Intranasal mast cell stabilizers

Class Summary
These are effective therapy for AR in approximately 70-80% of patients. They produce mast cell stabilization and antiallergic effects by inhibiting mast cell degranulation. They have no direct anti-inflammatory or antihistaminic effects and minimal bronchodilator effects. They are effective for prophylaxis. They also clean out antigens mechanically, similar to saline. These products are now available over the counter. View full drug information

Cromolyn sodium (Nasalcrom)

Used on a daily basis for seasonal or perennial AR. Significant effect may not be seen for 4-7 d. Administer just before exposure in patients with isolated and predictable periods of exposure (eg, animal allergy, occupational allergy). Generally less effective than nasal corticosteroids. Protective effect lasts 4-8 h; thus, frequent dosing is necessary. If desired, may be used with other medicines, including other allergy medicines.

Antileukotrienes
Class Summary
Montelukast has been approved as monotherapy for allergic rhinitis. It has been shown to be most effective in patients in whom significant congestion is a primary complaint. It has also been shown to work as adjunctive therapy with present second-generation antihistamines to provide greater relief of symptoms than antihistamines alone. It is beneficial in patients with symptoms in whom present antihistamines are not adequate. A study has shown a combination with cetirizine is as effective as an intranasal corticosteroid. Antileukotriene can also be added to the treatment plan in patients receiving antihistamines and intranasal therapy. View full drug information

Montelukast (Singulair)
Inhibits airway cysteinyl leukotriene receptors. Because these receptors are found throughout the airway, the medication can mediate the effect in the upper and lower airway.

Further Outpatient Care

Patients with allergic rhinitis (AR) need continuous follow-up care because allergic rhinitis is a chronic disease that waxes and wanes with seasons and age. The fluctuation of symptoms requires adjustment of medications. Patients rarely outgrow allergic rhinitis in childhood. Refer patients in whom allergic rhinitis becomes hard to manage or diagnose to an allergist for complete evaluation and advanced treatment, including institution of allergen-specific immunotherapy

Deterrence/Prevention

The best deterrent is to avoid allergens that trigger symptoms. This means diligent environmental controls and patient compliance with medication use. Primary complications of allergic rhinitis are associated diseases. Sinusitis is a common complication occurring secondary to the inflamed nasal turbinates that block the ostiomeatal complex of the sinuses and other sinus passages. Recurrent or chronic otitis media can also be a secondary complication. It is thought to occur as a result of an inflamed nasal passages that adversely affect the drainage of the auditory tube. Allergic rhinitis can lead to rhinitis medicamentosa when topical nasal decongestants are used in excess. Allergic rhinitis can cause other conditions, such as insomnia, irritability, headache, chronic fatigue, and pharyngitis. These occur secondary to chronic nasal congestion and discharge, mouth breathing, and sleep disturbance

Prognosis

Most patients are able to live normal lives with the symptoms. Only patients who receive allergen-specific immunotherapy are cured of the disease; however, many patients do very well with intermittent symptomatic care. Allergic rhinitis symptoms may recur 2-3 years after discontinuation of allergen immunotherapy. A small percentage of patients improve during the teenage years, but in most, symptoms recur in the early twenties or later. Symptoms begin to wane when patients reach the fifth decade of life.

Patient Education

An abundance of educational material is available from many resources such as medical associations, professional societies (eg, American Academy of Allergy, Asthma, and Immunology, American College of Allergy, Asthma, and Immunology), and pharmaceutical companies. All basically instruct the patient to avoid triggers, use medications, and see a specialist if symptoms persist. Some educational materials are very sophisticated, and several pharmaceutical companies provide extensive web sites to assist patients. For excellent patient education resources visit eMedicine's Allergy Center. Also, see eMedicine's patient education articles Hay Fever, Indoor Allergies, and Allergy Shots.