What are Allergies?

Allergies occur when the immune system responds aggressively to harmless substances (eg, dust or certain foods). Exposure to an allergen can cause a wide range of symptoms, the most severe being an anaphylactic reaction which causes respiratory distress and must be treated immediately.

Allergies may be caused by an overproduction of Th2 cells—immune cells responsible for destroying foreign pathogens—in response to an allergen. Overproduction of Th2 may generate immunoglobin E (IgE) antibodies against harmless foods or other environmental materials. IgE in turn signals allergic mediators like histamine, prostaglandins, and leukotrienes to be released, leading to the symptoms associated with an allergic reaction.

Natural interventions like probiotics and vitamin D may help balance immune responses and improve allergy symptoms.

What are Symptoms of an Allergic Reaction?

• Itchy, stuffy, and/or runny nose
• Postnasal drip
• Facial pressure and pain
• Tingling/swelling around the mouth
• Itchy throat
• Swollen, itchy, red eyes
• Wheezing, coughing, difficulty breathing
• Hives and/or rashes
• Cramps, vomiting, diarrhea
• Anaphylaxis

Note: Anaphylaxis is a medical emergency. People prone to anaphylaxis should always carry self-injecting epinephrine pens in case of emergency.

What are Types of Allergic Disorders?

• Atopic dermatitis (eczema) – a chronic inflammatory skin disorder
• Allergic rhinitis – inflammation of the nasal mucosa in response to allergen exposure
• Asthma – inflammatory disease of airway hyperresponsiveness and airflow obstruction
• Food, drug, or insect allergy – allergic reaction brought on by exposure to a specific allergen (eg, milk, peanuts, penicillin, or bug bite)
• Urticaria (hives)
• Angioedema (swelling under the skin)

How are Allergies Diagnosed?

• Scratch or skin prick test – suspected allergen is put on the skin to see whether an allergic response is generated
• Radioallergosorbent test and enzyme-linked immunosorbent assay – tests where a blood sample is analyzed to measure for specific IgE antibodies
• Differential leukocyte count – measures total number and type of white blood cells; may indicate a person has allergies but cannot provide information about specific allergens
• Elimination-challenge diet – common allergens are slowly eliminated and then reintroduced into the diet to determine allergic triggers

What are Conventional Medical Treatments for Allergies?

• Antihistamines
• Decongestants (eg, pseudoephedrine and phenylephrine)
• Glucocorticosteroids
• Leukotriene antagonists
• Cromolyn sodium
• Beta-agonists (eg, albuterol and epinephrine)
• Immunotherapy (subcutaneous injection or sublingual drops)

What Natural Interventions May Be Beneficial for Allergies?

• Probiotics. The “hygiene hypothesis” of allergies posits that over-sanitization has resulted in a lack of microbial stimulation to the gut immune system and therefore causes an increase in allergies. Clinical trials with strains such as Bifidobacterium longum BB536 and Lactobacillus rhamnosus GG (LGG) have shown benefits for patients with allergies.
• Vitamin D. Vitamin D appears to be involved in immune function and response. Epidemiological studies have linked low vitamin D status with an increased incidence of allergic diseases, and supplemental vitamin D may improve atopic dermatitis symptoms.
• Vitamin E. Research suggests vitamin E may modulate allergies and other diseases. Low maternal intake during pregnancy is linked with breathing problems in children, and supplementation with vitamin E may improve symptoms of seasonal allergies.
• Magnesium. Preclinical studies indicate that magnesium is involved in immune response. Magnesium supplementation has been shown to improve symptoms in asthma patients in several clinical trials.
• Butterbur. Butterbur has long been used in traditional Chinese medicine to alleviate symptoms of asthma. Compounds in the butterbur plant are known to inhibit histamine, leukotrienes, and the priming of mast cells in response to allergens. Petasin, a compound extracted from the plant, is used as a seasonal allergy drug in some countries.
• Rosmarinic acid. Rosmarinic acid, a flavonoid found in various herbs, is reported to have several health benefits. Supplementing in patients with different allergic diseases was shown to improve symptoms.
• Other ingredients that may help those with allergic diseases include vitamin C, fish oil, quercetin, spirulina, and more.

Allergies are a global public health menace.¹ More than 500 million people worldwide suffer from food allergies. More than 300 million, or about 5% of the global population, now suffer from asthma.² Allergic rhinitis, a risk factor for asthma, affects up to 30% of adults and 40% of children.³

Some scientists theorize that a potential cause of allergies in the modern world may be over-sanitation. Excess utilization of antibiotics and less frequent exposure to microbes like bacteria and viruses during childhood may impair development of balanced immunity, causing hyper-reactivity to allergens later in life, a phenomenon known as the "hygiene hypothesis."^4,5

Relieving allergy symptoms in hopes of improving quality of life is the primary goal of treatment. However, patients often report that their conventional medications fail to provide relief.^6,7 Also, corticosteroids and beta-2-agonists, drugs frequently used to treat allergic asthma, are fraught with potentially deadly side effects over the long-term.

Reliable allergy testing methods allow for a more guided treatment approach that includes identification and avoidance of troublesome allergens, as well as targeted immunotherapy with allergy shots, or via sublingual immunotherapy—an effective method underutilized in the United States, but which has been employed in Europe for decades.⁸

When you read this protocol, you will learn what causes allergies, how medical treatment can help relieve allergic reactions, and how allergy testing strategies can empower you to significantly reduce your allergic symptoms by identifying and avoiding the dietary or environmental culprits driving them. You will also read about several natural compounds with immunomodulatory properties that quell allergen-induced inflammatory responses to provide symptom relief.

An allergy occurs when your immune system responds aggressively to a harmless environmental substance.

Common inhaled allergens include tree and flower pollen, animal dander, dust, and mold. Ingested allergens include medications (penicillin, for example) and foods such as eggs, peanuts, wheat, tree nuts, and shellfish. Nickel, copper, and latex can also cause allergies.^9,10

These allergens can affect various parts of the body and elicit symptoms in the nasal passages (such as itchy, stuffy and/or runny nose, postnasal drip, facial pressure and pain); mouth area (tingling sensation, swollen mouth and lips, itchy throat); eyes (swollen, itchy, red eyes); respiratory (wheezing, coughing, difficulty breathing, shortness of breath); skin (hives, rashes, swelling); and gastrointestinal (stomach cramps, vomiting, diarrhea). Symptoms can occur within minutes to days after exposure and can range from mild to severe.

The most severe form of allergic reaction is called anaphylaxis. It is a potentially deadly condition that results in respiratory distress and swelling of the larynx, often followed by vascular collapse or shock.¹⁰ Anaphylaxis should be treated rapidly because death can occur within minutes or hours after the first symptoms appear. Many people prone to anaphylaxis carry self-injecting epinephrine pens in case of emergencies.

The immune system normally functions to protect the body against viruses, bacteria, fungi, and other pathogens by targeting these substances for destruction upon recognition. However, an allergic response arises when your immune system mistakes harmless substances as potential pathogens and attacks them.

A Closer Look at the Immunology of an Allergic Response

According to the Th2 hypothesis of allergy, atopy results from an overproduction of Th2 cytokines in response to allergens. The atopic individual is genetically predisposed such that he is more likely to over-produce Th2 cytokines and muster an insufficient Th1 response; the result of this imbalance is production of antibodies against normally innocuous environmental substances.¹²

The first time an allergen is encountered, the Th2 cytokines interleukin-4 (IL-4) and/or IL-13 alert B cells (components of the immune system responsible for antibody generation) to produce a particular type of antibody called immunoglobulin E (IgE); this process is called "sensitization."

Next, circulating IgE alerts other immune cells (basophils in the blood and mast cells in the skin and mucosal lining) that they should be ready to destroy the antigen in question if they detect it. IgE also triggers the formation of "memory" T cells, which are able to react much more quickly to future recognition of the same antigen.
Upon subsequent exposure to the same antigen, an atopic individual will have a dual response characterized by an immediate, or acute reaction within minutes, and a delayed, or late-phase reaction within the next 4‒8 hours after exposure.¹³

Acute response. During an acute immune reaction, IgE antibodies, upon binding (crosslinking) a previously categorized antigen, provoke release of allergic mediators including histamine, prostaglandins, and leukotrienes from mast cells and basophils; these chemicals are responsible for the classic symptoms we think of in association with "allergy" (eg, itchy skin, runny nose, etc.).

This immediate IgE reaction responds to antihistamines and decongestants.¹²

Late-phase response. After the acute response subsides, late-phase reactions can occur and produce long-term effects. The late-phase reaction manifests when an antigen is presented to a T cell (especially those already "primed" by IgE specific to that antigen) that then releases cytokines (primarily IL-5), which induce degranulation (release of allergic mediators) from another type of immune cell called an eosinophil.

For example, the pathogenesis of allergic rhinitis, atopic dermatitis and asthma, are thought to be influenced more by the late-phase immune reactions. In general, late-phase allergic reactions respond to anti-inflammatory agents such as corticosteroids.

Together, allergic mediators including histamine, leukotrienes and interleukins cause a typical "allergy attack." In the skin, they cause itchy hives, rashes and swelling. In the nasal cavities, these chemicals cause runny nose, tearing, burning or itching eyes, itching in the nose, throat, roof of the mouth and eyes. The release of histamine and other mediators in the lungs cause muscles of the bronchial wall to tighten, become inflamed and produce excessive mucus. This causes the symptoms of asthma—wheezing, difficulty breathing and coughing. In the digestive system, histamine can cause vomiting, diarrhea and stomach cramps.

Epidemiological studies revealed that the prevalence of allergic diseases has increased worldwide over the last few decades.^14-17 Allergic diseases include atopic dermatitis, allergic rhinitis, asthma, food, drug and insect allergy, urticaria (hives) and angioedema (swelling beneath the skin).

Atopy, the genetic predisposition to producing IgE antibody in response to allergens, increases the risk of developing allergic disorders.^18,19 Having one allergic disorder significantly increases the risk of developing other allergic disorders.²⁰ Atopy is the strongest predisposing factor of asthma in children. Epidemiological and experimental studies have shown that atopic disorders typically follow a natural history of manifestation or a progression of clinical signs, beginning with atopic dermatitis in infants and developing to allergic rhinitis and asthma in children.²¹ This progression, called atopic march, may be influenced by shared genetic and environmental risk factors.²²

Atopic Dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disorder that affects at least 15% of children and up to 10% of adults. Studies among children reveal that AD develops very early in life. In fact, around 45% of affected children develop AD in the first six months of life, 60% develop it in the first year, and 85% before age 5. Further, more than half of affected children will continue to have AD beyond 7 years of age, and more than 40% will experience it through adulthood.¹

Atopic dermatitis is often the first manifestation of allergic disease and many patients may develop allergic rhinitis and asthma later in life.²² Eczematous rashes are dry, scaly and itchy, and can become infected if left untreated. In infants and young children, the rashes appear on the face, neck, cheeks and scalp. In older children and adults, eczema may appear on the folds of the forearms, the inner elbows and behind the knees. Factors that make the symptoms worse include temperature, humidity, irritants, infections, food, inhalant and contact allergens and emotional stress.²³ Atopic dermatitis can affect development, personality, and quality of life of patients and their families.
Patients with atopic dermatitis have reduced skin barrier function. When vital skin lipids are lost, moisture escapes from the skin epidermis (top layer of the skin) and the skin becomes dry, causing cracks and microfissures to develop through which allergens and microbes can easily enter.¹ Soaking baths followed by an application of emollient (moisture-retaining lotion or salve) can help retain moisture and give the patient relief.

Topical corticosteroids are the standard treatment for atopic dermatitis. Low-potency corticosteroids help keep the symptoms under control and high-potency corticosteroids are used in severe flare-ups. Because of their potential adverse effects, high-potency corticosteroids should be used over short periods of time and topically only in areas that are lichenified (areas in which the skin has become leathery and thickened).²⁴

Allergic Rhinitis

Allergic rhinitis is an IgE-mediated inflammation of the nasal mucosa in response to outdoor and indoor allergens, the most common of which are pollens, dust mites, molds and insects. Sensitization and subsequent exposure trigger a release of symptoms that include sneezing, runny or stuffy nose, teary eyes and itchy nose, throat or skin.²⁵ The nose becomes primed and hyper-reactive on repeated exposure to the allergen, and over time, the amounts of allergen needed to mount an immune response decreases.¹
Allergic rhinitis is a major respiratory health problem that affects 10‒30% adults and more than 40% of children worldwide. The prevalence of this disease is increasing. Allergic rhinitis negatively affects the patient's quality of life, school/work performance and social interaction, and creates financial burden.¹ Allergic rhinitis is a risk factor for asthma,²⁶ and many patients with it also suffer from atopic dermatitis and conjunctivitis, and co-morbidities that include sinusitis, nasal polyps, upper respiratory infections, sleep disorders and impaired learning in children.²⁷ It can also develop three to seven years later among patients with non-allergic rhinitis.²⁸

Based on frequency and severity of symptoms, allergic rhinitis may be classified into: (1) mild intermittent; (2) mild persistent; (3) moderate/severe intermittent; or (4) moderate/severe persistent.²⁹ Based on type of allergen, rhinitis is classified as perennial or seasonal, although patients can respond to both types of triggers. Symptoms can also last up to four to nine months of the year.²⁵ Risk factors of allergic rhinitis in childhood include a family history of atopy, birth by cesarean section, exposure to cigarette smoke in infancy, endotoxin levels in house dust of inner city homes and pollutants.³⁰

Conventional treatment of allergic rhinitis usually begins with controlling exposure to the allergen(s), followed by use of intranasal corticosteroid sprays and non-sedating antihistamines. A survey of pediatric allergies in the United States²⁵ reported that parents and physicians consider nasal allergy medications as insufficient for relieving immediate and long-term symptoms and often have bothersome side effects. Some of the adverse side effects reported include nasal dryness, nosebleeds and drowsiness from antihistamines.

Asthma

Asthma is a life-long inflammatory disease characterized by airway hyperresponsiveness and airflow obstruction. In people with asthma, the inner lining of the airways become inflamed and the muscles surrounding the airways tighten up. Mucus glands in the airways secrete thick mucus. Together, these changes cause the airway to narrow and leads to difficulty breathing, shortness of breath, cough and wheezing.

Between 60% and 70% of asthma cases in children are allergic or atopic. Children with allergies have a 30% increased risk of developing asthma.¹ Genes play an important role in the susceptibility to develop asthma and several candidate genes have been identified in this regard.³¹ Genes can impact a child's response to medications, and in particular, to beta-adrenergic agonists, glucocorticoids and leukotriene modulators.² Other factors that affect the development and severity of asthma include indoor allergen exposures, outdoor pollens, viral upper respiratory infections, exercise, foods, occupational history of the child and parents, environmental smoke, pollution and exposure to day care.

Inhaled corticosteroids are anti-inflammatory medications for the treatment of persistent asthma. However, clinical control deteriorates within weeks to months once corticosteroid treatment is discontinued. The most effective long-term medications are long-acting inhaled beta-agonists,¹ but they come with potentially serious adverse effects.²

Food Allergy

Food allergy is a global health burden; it is estimated to affect up to 10% of the population.32 In the United States alone, food allergy is responsible for 200 anaphylaxis-related deaths and 2,000 hospitalizations every year.³³

The most common food allergens include cow's milk, eggs, peanuts, tree nuts, seafood, soy and wheat. Symptoms of food allergy, which may occur following ingestion, inhalation or contact, are mediated by IgE and non-IgE reactions. Upon sensitization of an allergen, IgE synthesis increases and elevated numbers of cytokines are produced in the serum and intestinal fluids.³⁸ IgE-mediated reactions occur within minutes to hours of exposure and include symptoms like angioedema (swelling of the inner layers of the skin), nausea and vomiting, swelling of the throat, hives, swelling and itchiness of the mouth area, diarrhea and wheezing. Symptoms of non-IgE-mediated reactions can occur hours to days later and may include constipation, atopic eczema, protein-induced enterocolitis syndrome, allergic proctitis or rectal inflammation and Heiner syndrome (a pulmonary disease).³⁴

The health of the gastrointestinal system plays a pivotal role in food allergies and food sensitivities. The gastrointestinal system acts as a semipermeable barrier, allowing only usable molecules into the bloodstream after food has been broken down. Studies have shown that allergen challenge in sensitized individuals can cause the intestinal walls to become more permeable.^35,36 When the intestinal wall has been weakened by infection or inflammation, the barrier function is compromised, allowing large molecules to pass through the intestinal wall and into the bloodstream.^37,38 Allergic sensitization can occur as the immune system responds to these abnormally large molecules, causing digestive complaints such as upset stomach or diarrhea, or symptoms such as joint pain and headaches.³⁷

Healthy individuals host 100 trillion symbiotic bacteria that include Lactobacillus, Clostridium, Bacteroidetes, Proteobacteria and Bifidobacteria.³⁹ Enteric bacteria modulate intestinal morphology; they also produce short chain fatty acids, vitamins, ferment dietary fiber, and shape mucosal immunity.^40,41 Animal models have shown that enhancing or restoring intestinal commensal bacteria through supplementation (ie, supplemental probiotics)⁴² can induce tolerance and prevent allergy. Evidence also suggests a healthy population of intestinal bacteria can help reduce intestinal permeability.^43,44

Probiotic bacteria include Lactobacilli, Bifidobacteria, and Bacillius coagulans Saccharomyces boulardii is a probiotic yeast.^45-48 Also, prebiotics, such as fructooligosaccharides, may be included to encourage the growth of beneficial bacteria.⁴⁹ Consuming plenty of dietary fiber each day supports intestinal microbiota as well.⁵⁰

Proper diagnosis of allergy begins with a thorough medical history and physical examination. When a relationship between specific allergen(s) and symptoms is suspected, allergy tests can be performed to identify the specific allergenic substance(s) and treat the symptoms.

Scratch or Skin Prick Test

This is the most commonly used allergy test. During this test, small amounts of suspected allergens are introduced on normal skin on the forearm or on the upper back using a small prick or needle. Redness, itching, and a raised wheal (welt) appear within 20 minutes if there is a positive reaction to an antigen. A common side effect is itchiness or hives around the wheal. Because it involves introduction of possible allergens, it does carry some risk, including the rare but serious occurrence of a life-threatening anaphylactic reaction.

Radioallergosorbent Test

This test evaluates the levels of specific IgE antibody and activity in serum. Like the skin test, the radioallergosorbent test (RAST) provides allergen-specific information. The patient provides a blood sample at a clinic or laboratory. Because it is performed in the lab on serum only, there are no risks associated with this test. Common side effects are related to giving blood, such as minor pain or slight bruising.

Enzyme-Linked Immunosorbent Assay

The enzyme-linked immunosorbent assay, or ELISA, is another method used to measure various levels of IgE. It provides an indirect determination of what materials a person may be allergic to. Like RAST, it carries no direct risk to the patient.

Differential Leukocyte Count

The white blood cell count and differential is part of the complete blood count (CBC). The total number and types of white blood cells are measured. They generally include neutrophils, lymphocytes, monocytes, basophils, eosinophils, and bands. Eosinophils are often elevated with allergic reactions.⁵⁶ This test is nonspecific and provides no information about specific allergenic substances.

Elimination-Challenge Diet

The elimination-challenge diet is useful for detecting food allergies, but is very difficult to follow and requires diligence. This diet involves removal of common allergenic foods for at least two weeks; typically wheat, corn, soy, dairy, etc. Overly processed foods, food dyes, and spices may also be eliminated. The patient then remains cognizant of symptoms for several weeks and slowly continues removing select food items until all the symptoms of allergy disappears. The elimination diet is followed by a systematic reintroduction of possible triggers to the diet, one at a time, until symptoms reappear. Symptoms should be closely monitored.⁵⁷

Once an allergen has been identified, conventional therapy relies on avoidance of the allergen whenever possible and a diverse group of pharmaceuticals. The most common pharmaceuticals include the following:

Antihistamines

This group of pharmaceuticals blocks the effect of histamine and reduces the signs and symptoms of asthma and allergy. Oral antihistamines can be used to treat nasal symptoms including congestion, sneezing, itchy or runny nose and itchy, watery eyes. Antihistamines may also control skin flares and itching, and smooth muscle constriction in the lungs which produces wheezing and aggravates asthma. Some antihistamine drugs may cause drowsiness and loss of coordination. Antihistamines are to be avoided in patients with high blood pressure or narrow angle glaucoma.

Decongestants

These drugs cause small arterioles to constrict and decrease fluid and mucous secretion. Decongestants may be oral medications, nasal sprays, or eye drops. Active ingredients include pseudoephedrine, desoxyephedrine, oxymetazoline, and phenylephrine. Over-the-counter decongestants are frequently sold in combination products with antihistamines. Side effects may include increased blood pressure, arrhythmia, heart attack, anxiety, and dizziness.

Glucocorticosteroids

Glucocorticosteroids are anti-inflammatory medications taken orally, topically, inhaled into the lungs, or taken in nasal sprays. Intranasal corticosteroid sprays are used to treat allergic and non-allergic rhinitis with a minimal risk of systemic adverse effects. Relief can be expected after 7‒8 hours of dosing but it may take two weeks before the drug becomes maximally effective. Inhaled corticosteroids are typically used as treatment in persistent moderate to severe asthma. It can reduce symptoms, decrease airway hyperresponsiveness and inflammation and improve lung function. Topical corticosteroids are used to treat eczema. They are an effective first-line treatment, but they can inhibit the repair of skin cells and interfere with recovery in the long term.¹ Side effects can be serious if corticosteroids are taken orally over a long period of time.

Leukotriene Antagonists

Leukotrienes are generated in mast cells and other white blood cells and contribute to the allergic response. Leukotriene antagonists are designed to inhibit leukotriene formation and are used to treat seasonal allergic rhinitis and mild persistent asthma.

Cromolyn Sodium

Cromolyn is used as a nasal spray for rhinitis and inhaled for asthma and bronchospasm. It works by stabilizing mast cell membranes, preventing them from releasing histamine. It can prevent allergic rhinitis if used before symptoms start. However, cromolyn has fallen out of favor as a primary treatment option due to an inconvenient dosing regimen requirement (it must be taken four times daily) and the advent of effective, long-acting medications such as leukotriene receptor antagonists.

Beta-Agonists

These are drugs that selectively activate beta-1- and beta-2-adrenergic receptors, causing smooth muscle relaxation and bronchodilation. There are two kinds of beta-agonists: long-acting B2-agonist (LABA) and short-acting B2-agonist (SABA). In combination with inhaled corticosteroids, LABAs improve symptoms, decrease nighttime asthma and reduce the number of exacerbations.¹ SABAs can rapidly dilate the airways and improve breathing during an asthma attack. SABA should only be used as needed to reduce the risk of adverse side effects. The most common associated with bronchodilators include nervousness, restlessness and trembling. Albuterol and epinephrine are included in this category.

Immunotherapy

Allergen-specific immunotherapy involves a gradual desensitization of the immune response. The patient receives increasing amounts of the specific antigen to induce the immune system to produce protective antibody. Treatment may be continued for three or more years. It is the only treatment that can reduce symptoms related to allergic rhinitis over time although there is a risk of side effects because of allergic reaction to the antigen that is intended to be therapeutic.

In the United States, immunotherapy is most frequently as a subcutaneous injection. However, European physicians have employed another form of immunotherapy for decades—sublingual immunotherapy or "allergy drops."⁸

Sublingual immunotherapy, in which small doses of allergen are delivered in a diluted solution under the tongue, works in the same way injectable immunotherapy does. Several comprehensive reviews have shown that sublingual immunotherapy is effective for reducing symptoms associated with allergic conditions including allergic rhinitis and allergic conjunctivitis.^58,59 Moreover, sublingual immunotherapy appears to be associated with fewer systemic reactions.⁶⁰ Data indicate that sublingual immunotherapy may be an alternative for those at high risk for anaphylactic reactions or those who do not wish to receive an antigen injection.

Probiotics

In order to prevent the development of childhood allergic diseases, an infant's immune system must mature from a Th2- to a Th1-dominated response through microbial contact soon after birth. In comparison with the time before antibiotics and common presence of infectious diseases, along with the widespread use of antimicrobial agents in consumer products like soap, individuals in modern times have reduced contact with microbes. In the theory known as the "hygiene hypothesis," scientists speculate that an antiseptic environment results in a lack of microbial stimulation to the gut immune system and causes an increase in allergic disease.^61,62 In fact, studies have shown that non-allergic children have higher levels of Bifidobacteria and Lactobacilli compared to allergic children.⁶³ The presence of these 'harmless' probiotic bacteria in the intestinal biota seem to correspond with protection against allergy.

As defined by the World Health Organization, probiotics are "live microorganisms which, when administered in adequate amounts as part of food, confer a beneficial health effect by producing gut microflora on the host."⁶⁴

Many randomized trials, clinical and experimental studies and meta-analyses have been conducted on the efficacy of probiotics on the treatment or prevention of allergic diseases.

Randomized controlled trials showed that using probiotics provided significant clinical benefits to children with allergic rhinitis. Heat-killed or live Lactobabillus casei decreased the frequency and severity of nose and eye symptoms and improved the quality of life for children who were sensitized to house dust mites.^65,66 Among preschool children with seasonal allergic rhinitis, L. casei was also found to reduce symptoms and the number of episodes, and lessen the use of relief medications. The effect, however, was not statistically significant for asthma.⁶⁷ Similar positive effects were observed among children with pollen-sensitized allergic rhinitis who were treated with oral Bacillus clausii spores.⁶⁸

Studies that examined the effects of probiotics at the level of the immune system also showed some positive effects. Supplementation with L. gasseri significantly reduced serum IgE specific to Japanese cedar pollen in children with seasonal allergies.⁶⁹

Positive effects were also observed among patients who received Bifidobacterium longum BB536 supplement.⁷⁰ Moreover, BB536 seems to suppress Th-2 cell attraction and activation, suggesting it may be effective in blunting the IgE-mediated allergic response.⁷¹ In a 28-week clinical trial, BB536 favorably modulated intestinal microbiota, lessening the burden of allergens, in subjects with cedar pollen allergies.⁷² In an experimental model, a BB536 DNA oligodeoxynucleotide, shunted the cytokine profile in favor of Th1 and suppressed IgE levels, both markers of and contributors to a lessened allergic response.⁷³

In two randomized controlled trials studying the clinical effects of L. plantarum No. 14 (LP14), eosinophil counts decreased immediately after intake in the group that took LP14, and the percentage of Th1 helper T cells increased after six weeks. LP14 also strongly induced the gene expression of Th1-type cytokines, indicating that probiotics are clinically effective in the management of seasonal allergic disease.⁷⁴

A review of 13 randomized, controlled trials on the effectiveness of probiotics in the treatment or prevention of atopic dermatitis found that, regardless of IgE sensitization, L. rhamnosus GG (LGG) and other probiotics were effective in preventing AD. Probiotics also reduced the severity of AD in half of the trials evaluated, although there was no significant change observed in the inflammatory markers.⁷⁵ One study demonstrated that skin severity scores were significantly lower in group given heat-killed L. paracasei, and the placebo group used nearly double the amount of topical medicine during the study period.⁷⁶ Similar positive results were observed among preschool children with moderate-to-severe AD who were treated with a supplemental probiotics mixture. The absolute counts and percentages of CD lymphocyte subsets in the peripheral blood also decreased in the probiotic group.⁷⁷

On the other hand, a randomized trial showed that prenatal treatment withLGG was not sufficient to prevent eczema among infants in the first year of life.⁷⁸

In terms of preventing allergies, a meta-analysis of six studies reported significant benefits in infants at high risk of allergy who used probiotic supplements containing L. rhamnosus. A recent study⁷⁹ demonstrated that infants with suspected cow's milk allergy who were given partially hydrolyzed infant food supplemented with LGG had a higher probability of acquiring tolerance to cow's milk protein at six and 12 months compared with infants who were not given LGG supplementation. In addition, skin patch test responses were negative in all infants who acquired tolerance.

Clinical improvements have been reported among patients with allergic rhinitis and IgE-sensitized atopic eczema, but studies on the efficacy of probiotics in the management of asthma remain inconsistent. Possible reasons include differences in study designs, types of probiotics used and duration of probiotic supplementation, which limits the comparability of results.⁸⁰

A specialized dried yeast fermentate from S. cerevisiae (Epicor) has been shown to reduce seasonal allergies in two small studies. In one study, 25 healthy participants consumed Epicor or a placebo daily for five weeks during allergy season. The placebo group experienced increased seasonal allergy frequency, but the Epicor group did not. Interestingly, allergic symptoms returned within 1–2 weeks after the participants stopped taking Epicor.⁸¹ In a larger study, daily doses of 500 mg of Epicor or placebo were compared in 96 healthy subjects with a history of seasonal allergies. Subjects in the Epicor group had less severe nasal congestion and runny nose, and used less allergy medication than those taking placebo.⁸²

Allergies are mediated in part by an immune-signaling protein called immunoglobulin E (IgE). If the immune system produces too much IgE in response to a stimulus, an allergic reaction can ensue. A strain of Lactobacillus acidophilus called L-92 was shown in a preclinical screening study to reduce production of IgE in mice challenged with a pro-allergenic substance.⁸³ Based on these intriguing results, three clinical trials of L. acidophilus L-92 were carried out. First, L-92 was administered to subjects over two allergy seasons. Dosages were 50 billion colony forming units (CFUs) twice daily for six weeks during the first season and 20 billion CFUs once weekly during the second season. Twenty-three people participated during season one, and 20 did so during season two. During the first season, L-92 reduced eye-related distress related to allergies by 31%. During the second, a statistically significant reduction in overall allergy-related distress among the subjects receiving L-92 was observed.⁸⁴ In the second study, 49 participants with allergic rhinitis took either 30 billion CFUs of L-92 or placebo daily for eight weeks. Nasal mucosal swelling decreased by 24% at week eight in the L-92 group. Also, nasal symptom scores decreased 19% in the L-92 group compared with placebo at week eight.⁸⁵ In the third and slightly larger study, 80 subjects who had a cedar pollen allergy and were exposed to cedar pollen at baseline took L-92 or placebo for eight weeks before re-exposure to cedar pollen. L-92 led to a significant reduction in nasal and eye allergy symptoms compared with placebo upon re-exposure.⁸⁶

Vitamin D

In recent years, there has been an increased interest in the role that vitamin D plays in the immune system and, in particular, allergic diseases. It is known that vitamin D receptors are found in multiple tissues and cells in the human body, including mononuclear cells, T lymphocytes and dendritic cells, which are important in the recognition of antigens. Vitamin D also has multiple cytokine-modulating effects and can decrease proliferation of both Th1 and Th2 cells, and lower the production of interleukins and interferons.⁸⁷ This vitamin has also been shown to have a role in airway remodeling, which may be important in understanding and treating asthma.⁸⁸ Molecular studies also provide evidence that vitamin D can modulate inflammatory responses, enhance antimicrobial peptide activity and promote the integrity of the permeability barrier of the skin.⁸⁷

Epidemiological studies revealed that Vitamin D deficiency is associated with an increased incidence of asthma and allergy symptoms,^89-91 higher IgE responses to food and environmental allergens in children and adults⁹² and severity of atopic dermatitis.⁹³ Similarly, children with well-controlled asthma were found to have higher levels of vitamin D⁹⁴ and adults with chronic urticaria (hives) have lower vitamin D levels than controls.⁹⁵ A randomized controlled trial involving 45 atopic dermatitis patients provided evidence for the beneficial effect of vitamin D and E supplementation on clinical manifestations. Symptom scores significantly improved in the treatment groups for vitamin D and vitamin E was associated with more favorable symptom scores.⁹⁶

On the role of vitamin D in preventing asthma and atopic diseases, studies demonstrated that a woman's high intake of vitamin D during pregnancy lowers the risk of her child developing wheezing⁹⁷ or rhinitis at age 5.⁹⁸ This correlation was found in different populations, regardless of the amount of vitamin D intake. A prospective follow-up study showed conflicting results.

A recent longitudinal study demonstrated vitamin D as a predictor of asthma or atopy in later years. The study, involving 689 children from a cohort unselected for asthma or atopy who were examined at age 6 and again at age 14, showed that among male children, inadequate levels of vitamin D is a risk factor for developing atopy, bronchial hyperresponsiveness and asthma. More importantly, vitamin D levels at age 6 were predictive of atopy/asthma-associated phenotypes at age 14 years.⁹⁹

Although many epidemiological studies over the past decade have clearly identified a link between vitamin D levels and asthma and/or atopic diseases, such studies have limitations and cannot establish causality. A clinical trial examining whether maternal supplementation with 4,000 IU of vitamin D daily can reduce the incidence of asthma in their offspring during the first three years of life is currently underway. This trial will provide stronger evidence regarding the role of vitamin D in preventing allergies.¹⁰⁰

Vitamin E

Vitamin E is a fat-soluble vitamin that acts as a free-radical scavenger. It protects cell membranes and prevents damage to membrane-associated enzymes. Research suggests that vitamin E inhibits the activation of neutrophils—cells that contribute to respiratory inflammation in asthmatics.¹⁰¹ Studies also indicate that vitamin E can influence and halt the proliferation of mast cells in culture,^102,103 suggesting a role for vitamin E in modulating allergies, atherosclerosis, cancer and other diseases in which mast cells play a role.

Several studies provide evidence on the relationship between vitamin E intake and asthma or allergic diseases. A Japanese prospective study reported that low maternal vitamin E intake during pregnancy was associated with increased likelihood of wheezing in children younger than 2 years of age.¹⁰⁴ A Scottish birth cohort study reported that low alpha-tocopherol intake during the first trimester of pregnancy was associated with an increased risk of wheezing and asthma in 5-year old children.¹⁰⁵ A case-control study reported that childhood asthma is associated with low dietary vitamin E intake,¹⁰⁶ and a 10-year prospective study of adult-onset asthma also reported similar findings.¹⁰⁷ In a clinical study of atopic dermatitis, patients randomly selected to orally receive 400 IU of vitamin E daily for eight months reported remarkable improvement in facial erythema (redness) and lichenification (scaling and thickening of the skin). Eczematous lesions were also reportedly healed as a result of decreased itch sensation.¹⁰⁸

Animal models have shown that supplementation with high dose vitamin E reduced proliferation of splenic lymphocytes, the production of IL-4, IL-5 and total serum IgE levels. Sneezing and nasal allergic response were also suppressed in the treatment group.¹⁰⁹ In a randomized controlled trial, patients with seasonal allergic rhinitis who received vitamin E supplementation during hay fever season experienced improvement in their symptoms.¹¹⁰

Vitamin C

Vitamin C (ascorbic acid) increases the function of many immune cells, including T cells, phagocytes (which destroy pathogenic organisms), and others. As an antioxidant, ascorbic acid can protect cells from reactive oxygen species known to cause tissue damage and disease. Vitamin C has antihistamine properties¹¹¹ that can help relieve allergy symptoms, but the evidence is still controversial.

Early studies demonstrated that 2 grams of vitamin C improve pulmonary function one hour after ingestion, compared with a placebo¹¹² and another study found a 5-fold increase in bronchial hyperreactivity among those with the lowest intake of vitamin C.¹¹³

An animal model showed that high dose vitamin C supplementation significantly decreased inflammation in the lungs.¹¹⁴

Magnesium

Magnesium is utilized by every cell in the body and participates in energy metabolism and protein synthesis. Magnesium participates in at least 350 enzymatic processes within the body. Evidence from animal models indicates that magnesium plays a role in immune response, and that deficiency leads to increased inflammation.¹¹⁵

Results from randomized clinical trials showed that children and adults who were hospitalized for severe, acute asthma benefited from using intravenous (IV) magnesium sulfate.^116-119 One of these studies used a higher dose of magnesium sulfate (40 mg/kg) and observed a faster and more prolonged improvement in pulmonary function.¹¹⁹ But, one randomized study found no evidence that IV magnesium sulfate can treat moderate-to-severe asthma.¹²⁰

A randomized study found that taking 200‒290 mg of magnesium for 16 weeks significantly reduced the use of bronchodilators in children with mild to moderate asthma.¹²¹ Similar beneficial effects of 12-week magnesium supplementation were found in a small study involving children with moderate persistent asthma treated with inhaled fluticasone.¹²² More recently, long-term treatment with oral magnesium (170 mg twice a day for 6.5 months) in adults with mild-to-moderate asthma showed improvement in objective measures of bronchial reactivity and in subjective measures of asthma control and quality of life.¹²³

Fish Oil and Fatty Acids

Fish oils contain the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). EPA and DHA exert anti-inflammatory and antithrombotic (anti-clotting) effects¹²⁴ because omega-3 fatty acids compete with arachidonic acid, which is converted into pro-inflammatory eicosanoids.^125-127 Studies suggest fish oils reduce the production of inflammatory cytokines such as interleukin-1, IL-2, and tumor necrosis factor, which are all involved in the allergic response. Additionally, lower levels of omega-3 fatty acids in the blood are associated with delayed-type hypersensitivity skin reactions in elderly malnourished subjects.¹²⁸

In one study, an ointment containing DHA and EPA produced satisfactory results in 64 patients with refractory dermatitis.¹²⁹ A systematic review of maternal supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFA) found evidence that they reduced the prevalence of childhood asthma, but supplementation during lactation did not prevent asthma or food allergy.¹³⁰ Intake of n-6 PUFA among 1,002 pregnant Japanese females showed a tendency towards lesser allergic rhinitis in the children.¹³¹

Life Extension suggests that the omega-6 to omega-3 ratio should be kept below 4:1 for optimal health. More information on testing and optimizing your omega-6 to omega-3 ratio can be found in the Life Extension Magazine® article entitled "Optimize Your Omega-3 Status."

Butterbur

The perennial shrub Butterbur (Petasites hybridus) is known to inhibit plasma histamine, leukotrienes, and the priming of mast cells in response to allergens.^132,133 Traditional Chinese Medicine has used Butterbur to treat asthma, migraine stress and gastric ulcer.¹³⁴ Petasin, a pharmacological compound extracted from the plant, has been commercialized as Ze 339 and approved in Switzerland as an anti-allergic drug to treat seasonal allergic rhinitis.

A randomized controlled study found Ze 339 effective in improving asthma scores compared with placebo.¹³⁵ Other studies found the effect of Ze 339 comparable to cetirizine¹³⁶ and fexofenadine (antihistamine drugs).^137,138 A systematic review of six randomized controlled trials found that butterbur extract is effective as a non-sedative antihistamine for intermittent allergic rhinitis as well.¹³⁹ Ze 339 reduced allergic airway inflammation in the lungs of asthmatic animals and inhibited the production of Th2 cytokines, interleukins and RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted), which facilitates infiltration of white blood cells during the inflammatory response.¹⁴⁰

Extracts from the Japanese butterbur (Petasites japonicus), which contains a profile of active compounds similar to Petasites hybridus, inhibited eosinophil infiltration and reduced mucus secretion in an animal model of asthma. In cell culture studies, the extract inhibited the release of interleukins triggered by house dust mites,¹⁴¹ suggesting butterbur can suppress the pathogenesis of airway inflammation.

Quercetin

Quercetin, one of the most common flavonoids found in a variety of foods such as red wine, green tea, and apples, has been studied for its ability to reduce the symptoms of allergies. It has been shown to inhibit leukotrienes, mast cells, and the release of histamine,¹⁴² which makes it a good candidate for anti-allergy therapy. Evidence also demonstrated that quercetin blunts the inflammatory response of immune cells upon antigen recognition.¹⁴³

In an animal model of peanut allergy, quercetin completely stopped peanut-induced anaphylactic reactions after challenge. Histamine levels in quercetin-treated rats were significantly lower than the positive control group.¹⁴⁴ In guinea pigs sensitized with ovalbumin, a relatively low dose of quercetin reduced the hyperactivity of airways and caused significant bronchodilation.¹⁴⁵ Quercetin microemulsion treatment exhibited anti-inflammatory properties in a similarly designed murine model.¹⁴⁶

Patients with nasal allergies treated with nasal spray containing quercetin and Artemisia abrotanum L. experienced rapid and significant relief of nasal symptoms that was comparable to antihistamine preparations.¹⁴⁷ In two independent randomized controlled studies among patients with pollen allergies, taking 100 mg of a quercetin-related compound for eight weeks, significantly reduced nasal symptoms compared to placebo group.^148,149

Hesperidin Methyl Chalcone

Chemically similar to quercetin, the flavonoid hesperidin has been studied in a variety of contexts in both experimental models and in human clinical trials.¹⁵⁰ Its chalcone form was specifically studied in 99 atopic individuals in 1949. At daily doses ranging from 100–600 mg, hesperidin methyl chalcone provided complete relief of allergic symptoms in 35% of study participants; another 34% of the subjects achieved partial symptom relief.¹⁵¹ More recently, hesperidin methyl chalcone has emerged as an effective treatment for chronic venous disorders.¹⁵² Today, innovative doctors frequently suggest hesperidin methyl chalcone to patients with allergic symptoms and report clinical effectiveness.

Rosmarinic Acid

Rosmarinic acid is a flavonoid found in various herbs such as basil, sage, mint, rosemary and Perilla frutescens. It is reported to have antioxidant, anti-inflammatory, anti-microbial, and anti-tumor effects.^153,154 Rosmarinic acid can also inhibit pro-inflammatory cytokines and chemokines and stabilize mast cells.^155,156 In animal models, cell cultures, and human studies, rosmarinic acid has shown potential as a natural therapeutic agent for asthma and allergic diseases.

Researchers demonstrated that daily treatment with rosmarinic acid from perilla leaf extract given orally to mice prevented allergic asthma caused by dust mite allergen. The investigators concluded that oral administration of perilla-derived rosmarinic acid may treat allergic asthma effectively by attenuating the production of cytokines and allergy-specific antibodies.¹⁵⁷ In another study, volatile rosemary extract significantly suppressed cytokines, eosinophils and neutrophils in mice models of allergic asthma induced by house dust mites.¹⁵⁸ Similarly, rosmarinic acid effectively suppressed cytokines, chemokines and IgE levels in murine models of atopic dermatitis.¹⁵⁴ It was also able to alleviate symptoms related to allergic rhinitis and allergic rhinoconjunctivitis in allergen-sensitized animal models.¹⁵⁹

Oral supplementation with rosmarinic acid in patients with allergic rhinoconjunctivitis significantly relieved symptoms and inhibited eosinophils in nasal lavage fluid.¹⁵⁵ Another study demonstrated that perilla leaf extract enriched with rosmarinic acid is effective among humans suffering from seasonal allergic symptoms.¹⁵⁶ In this study, rosmarinic acid inhibited the eye-related symptoms associated with seasonal allergies. In a randomized study on atopic dermatitis, patients given topical rosmarinic emulsions applied to the elbows twice daily for eight weeks reported improvement in skin dryness and redness and general symptomatic relief.¹⁶⁰

Stinging Nettle

Urtica dioica acquired the common name 'stinging nettle' because the leaves, flowers, seeds and root contain different chemicals such as histamine, formic acid, acetic acid and other irritants that cause mildly painful stings, itchiness or numbness on contact.¹⁶¹

Historically, stinging nettle has been used to treat allergic rhinitis, but very few clinical studies have been conducted. In an open trial of 69 patients with allergic rhinitis, 58% of subjects who took 600 mg freeze-dried nettle leaf reported a relief in symptoms of rhinoconjunctivitis, and 48% found it more effective than over-the-counter medications.¹⁶² Long-term use of the stinging nettle extract, IDS 30, was shown to have anti-inflammatory effects and to be effective in preventing chronic colitis in animal models.¹⁶³

Data from bioassay experiments revealed that bioactive constituents in nettle extract inhibit histamine receptors, inhibit enzymes involved in releasing cytokines and chemokines that cause allergy symptoms, and reduce the production of allergy-specific prostaglandins. For the first time, these results provided a mechanistic understanding of the role of nettle extracts in reducing allergy and other inflammatory responses.¹⁶⁴

Spirulina

The term "spirulina" refers to the dried biomass of a species of cyanobacterium called Arthrospira platensis. It is widely consumed by humans as a dietary supplement and even used as a food source for some aquatic species and poultry.

Spirulina is a source of a variety micronutrients and phytonutrients; it is also, by weight, a good source of non-animal protein. Studies have shown that spirulina exerts a number of favorable biologic effects in both humans and animals when it is consumed as a food or a supplement.¹⁶⁵ Additionally, the United States Pharmacopeial Convention (USP) recently assigned a safety rating of "Class A" to spirulina, meaning that data support a high level of confidence regarding the safety of spirulina when used as a dietary supplement.¹⁶⁶

Several trials have examined the role of spirulina in modulating the biology of allergic response. Administered at 2,000 mg per day, spirulina was shown by Mao et al¹⁶⁷ to shift the T-cell profile away from Th2 in allergic rhinitis patients by inhibiting IL-4 signaling. Upon analyzing their results, the scientists stated "this… human feeding study …demonstrates the protective effects of Spirulina towards allergic rhinitis."

In a similarly designed clinical trial, Cingi and colleagues corroborated Mao's findings by showing that "spirulina consumption significantly improved the symptoms and physical findings [in allergic rhinitis patients] compared with placebo including nasal discharge, sneezing, nasal congestion and itching."¹⁶⁸

To better explore the mechanisms by which spirulina blunts allergic reactions,¹⁶⁹ studied its biological effects in a murine model of allergic rhinitis. They found that spirulina lowered IgE levels and, correspondingly, attenuated degranulation of nasal mast cells, resulting in suppressed histamine levels in serum. Very similar findings were reported by Remirez et al¹⁷⁰ as well.

Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) and its metabolites are naturally present in humans and exert an array of actions throughout human physiology. DHEA has been studied in numerous contexts, and it is from these studies that the realization that DHEA possess considerable immunomodulatory action has arisen.

With respect to its immunological properties, DHEA has been shown to promote balance between Th1 and Th2 cytokines and combat inflammatory responses.^171,172 Accordingly, researchers have carried these findings forward and examined the impact of DHEA on allergic reactions in clinical trials.

In once trial, immune cells were taken from subjects with asthma and cultured with or without DHEA. When DHEA was included, those immune cells produced less inflammatory cytokines and other allergic mediators, leading the investigators to conclude that "DHEA may be a useful therapy for asthma."¹⁷³ Another group¹⁷⁴ showed that nebulized (inhaled) DHEA-sulfate (DHEA-s; a major metabolite of DHEA) improved symptoms in patients with asthma.

Several lines of evidence support an anti-inflammatory role of DHEA in atopic individuals,¹⁷² but levels of DHEA decline with advancing age. Supplementation with DHEA can restore blood levels of DHEA-s to youthful ranges. Individuals interested in reading more about DHEA should consult Life Extension's "Male Hormone Restoration" and "Female Hormone Restoration" protocols.