How to Cure Atopic and Allergic Disorders

Atopic and allergic disorders
Type I hypersensitivity reactions underlie all atopic and many allergic disorders.
The terms atopy and allergy are often used interchangeably but are different.
Atopy is an exaggerated lgE-mediated immune response
All atopic disorders are type I hypersensitivity disorders.
Allergy is any exaggerated immune response to a foreign antigen regardless of mechanism.

Thus all atopic disorders are considered allergic but many allergic disorders like hypersensitivity pneumonits are not allergic.
Allergic disorders are the most common disorders among people.

Atopic disorders most commonly affect the nose, eyes, skin and lungs. These disorders include Atopic dermatitis,contact dermatitis,urticaria and angioedema which might be primarily disorders or symptoms of systemic disorders ,latex allergy ,allergic lung disorders(asthma, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis) and allergic reactions to venomous stings.

Etiology
Complex genetics environmental and site specific factors contribute to the development of allergies.
A role for genetic factors I suggested by familial inheritance of disease association between atopy and specific HLA loci,and polymorphism of genes for the high-affinity lgE receptor beta chain,IL-4 and CD14.

Environmental factors interact with genetic factors to maintain helper type 2T cell immune responses, which activate eosinophils and lgE production and are pro allergic.

Normally early childhood exposure to bacterial and viral infections and endotoxins (lipopolysaccharide) shifts native 2T cell responses to helper 1T cell responses,which suppress 2T cells and induce tolerance to foreign antigens.

The mechanism may be mediated by Toll-like receptor -4 and occur through development of population of regulatory T (CD4 + CD25+) cells that suppress 2T cell responses.

But trends in developed countries toward smaller families with fewer children, cleaner indoor environments and early use of vaccinations and antibiotics may deprive children of these exposures and inhibit 2H cell suppression, such behavioral changes may explain the increased prevalence of some allergic disorders.

Other factors thought to contribute to allergy development include chronic allergen exposure and sensitization, diet and physical activity.

Site specific factors include adhesion molecules in bronchial epithelium and in skin and molecules in the GI tract that direct 2H cells to target tissues.

By definition, an allergen induces lgE mediated and 2H cell immune responses.

Allergic triggers are almost always low molecular weight proteins, many of which can be constituted as airborne particles.

Allergens most commonly responsible for acute and chronic allergic reactions include house dust, mite feces, and animal dander, pollens (tree, grass and weed) and molds.

Pathophysiology
When allergen binds to lgE, histamine is released from intracellular granules of mast cells, which are widely distributed but most concentrated in skin, lungs and GI mucosa, histamine reinforces immune cell activation and is the primary mediator of clinical atopy.

Physical disruption of of tissue and various chemicals eg (tissue, irritants, opioids, surface active agents) can trigger histamine release directly, independent of IgE .

Histamine causes local vasodilation (producing erythema), increased capillary permeability and edema (producing a wheal), surrounding arteriolar vasodilation mediated by neuronal reflex mechanism (producing flare), and stimulation of sensory nerves (producing sensory itching).

Histamine causes smooth muscle contraction in the airways (broncho constriction) and the GI track (increase GI motility) and increases salivary and bronchial gland secretions.

When released systemically, it is a potent arteriolar dilator and can cause extensive peripheral pooling of blood and hypotension, cerebral vasodilatation may be a factor in vascular headache.

Histamine increases capillary permeability, the resulting loss of plasma and plasma proteins from the vascular space can worsen circulatory shock.

It triggers a compensatory catecholamine surge from adrenal chromaffin cells.

Symptoms and signs
Common symptoms include rhinorrhea , sneezing, and nasal congestion (upper respiratory tract)
Wheezing and dyspnea (lower respiratory tract), and itching (eyes, skin).
Signs may include nasal turbinate edema, sinus pain on palpation, wheezing, conjunctival hyperemia and edema ,and skin lichenification, stridor, wheezing and sometimes hypotension are life threatening signs of anaphylaxis.

In some children, a narrow and high – arched palate, narrow chin, and elongate maxilla with overbite (allergic facies) are thought to be associated with chronic allergy.

Diagnosis
A Thorough history is generally more reliable than testing or screening .History should include questions about frequency and duration of attacks and changes over time, triggering factors if identifiable, relational to seasonal or situational settings (e.g predictably occurring during pollen seasons, after exposure to animals, hay ,or dusts, during exercises or in particular places) , family history of similar symptoms or of atopic disorders and responses to attempted treatments.

Age at onset may be important in asthma because childhood asthma is like to be atopic and asthma beginning after ag 30 is not.

Non specific tests:

• Certain tests can suggest but not confirm an allergic origin of symptoms 
• CBC should be ordered to detect eosinophilia in all patients except those taking corticosteroids, which reduces the eosinophil count.  
• An eosinophil differential of 5 – 15 % of total WBC suggests atopy but is nonspecific .  
• 16 – 40 % may reflect atopy or other conditions ( eg drug hypersensitivity , cancer, autoimmune disorders, parasitic infections)  
• A differential of 50 - 90 % almost never occurs in atopic disorders and is more characteristic of hypereosinophillic syndrome or visceral larva migrans.  
• Total WBC is usual normal  
• Conjunctival or nasal secretions or sputum can be examined for leukocytes.  
• Finding any eosinophils indicates that 2T –mediated allergic inflammation is likely.  
• Serum lgE levels are elevated in atopic disorders but are of little help in diagnosis because they are also elevated in parasitic infections ,infectious mononucleosis,autoimmune disorders ,drug reactions, immunodeficiency disorders , drugs reactions and some forms of multiple myeloma.
•  lgE levels are probably most helpful for following response to therapy in allergic broncho pulmonary aspergillosis.

Non-specific tests

• Skin testing use standardized concentrations of antigen introduced directly into skin and is indicated when a detailed history and physical examination don’t identify the cause and triggers for symptoms. 
• Skin testing has higher testing predictive values for diagnosing allergic rhinosinusitis and conjunctivitis than for diagnosing allergic asthma or food allergy  
• Negative predictive value for food allergy is high.  
• The most commonly used antigens are pollen (weed, grass and trees), molds,house dusts mites, nimal danders and sera, insect venom , foods and beta –lactam antibiotics.  
• Choice of antigens to include is based on patient history and geographic prevalence.  
• Two techniques can be used , percutaneous and intradermal test is more sensitive but less specific ,it can be used to evaluate sensitivity to allergens with negative or equivocal prick test results  
• For the prick technique, a drop of antigen extract is placed on the skin which is then pricked or punctured through the extract by tenting up the skin with a tip of a 27- gauge needle held at 20 degree angle or with a commercially available prick device.  
• For the intradermal technique, just enough extract to produce a 1 or 2 mm bleb (typically 0.02ml) is injected intradermally with 0.5 or 1mL syringe and a 27-gauge short-bevel needle.
•  Prick and intradermal skin testing should include the diluents alone as a negative control and histamine (10 mg/mL for prick test , 0.01 mL of a 1:1000 solution for for intradermal tests) a positive control.  
• For patient who have had recent (less than one year) generalized reaction to the test antigen, testing begins with the standard reagent diluted 100-fold, then 10-fold, and then the standard concentration.  
• A test is considered positive if a wheel and a flare reaction occur and a wheel diameter is 3 to 5 mm greater than that of the negative control after 15 to 20 minutes.  
• False positive occur in dermatographism ( a wheal and flare reaction provoked by stroking or scraping the skin) .
• A false negative occurs when allergen extracts are improperly stored or outdated or when drugs (antihistamine) suppress reactivity.  
• Radioallergosorbent testing (RAST) detects the presence of allergen specific serum lgE in the serum binds the conjugate and can be quantified by measuring the 125-labelled antibody.
•  Provocative testing involves direct exposure of the mucosae to allergen and is indicated for patients who must document their reaction(e.g for occupation or disability claims) and sometimes for diagnosis of food allergy .  
• Ophthalmic testing has no advantage over skin testing and is rarely used.  
• Nasal and bronchial challenge are primarily research tools,but bronchial challenge is sometimes used when the clinical significance of positive skin test is unclear or when no antigen extracts are available eg for occupation related asthma.

Treatment  

Enviromental control:

•  Removal or avoidance of allergic triggers is the primary treatment of allergy. 
• Strategies include use of synthetic fiber pillows and impermeable mattress covers.  
• Frequent wash of bed sheets, pillowcases and blankets in hot water  
• Removal of upholstered furniture, soft toys, carpets, and pets.  
• House cleaning and extermination (to eliminate cockroaches’ exposure)  
• And to use of dehumidifiers in basements and other poorly aerated damprooms.  
• Other measures may include treating homes with heat steam, using high efficiency particulate air (HEPA) vacuum and filters, avoiding food triggers, limiting pets to a certain rooms, and frequently cleaning cloth furniture and carpets.  
• Adjunctive non allergic triggers ( eg cigarette smoke, strong odors, irritating fumes, air pollution, cold temperatures, high humidity) should also be avoided or controlled when possible.

Antihistamine:-

• An antihistamine does not affect histamine production or metabolism but block receptors. 
• H1 blockers are mainstay of treatment for allergic disorders.  
• H2 blockers are used primarily for gastric acid suppression and have limited usefulness for allergic reactions.  
• They may be indicated for a certain atopic disorders, especially chronic urticaria  
• Oral H1 blockers provide symptomatic relief in various atopic and allergic disorders (seasonal hay fever, allergic rhinitis, conjunctivitis, urticaria, other dermatoses, minor reactions to blood transfusion incompatibilities and to x-ray radiopaque dyes).  
• They are less effective for allergic bronchoconstriction and vasodilation.  
• Onset of action is usually 15 to 30min with peak effect in 1 hour  
• Duration of action is usually 3 to 6 hours  
• Oral H1 blockers are classified as sedating or no sedating (better thought of as less sedating).
•  Sedating antihistamine is widely available without prescription.  
• All have significant sedative and anticholinergic properties.  
• They pose particular problems for the elderly and patients with glaucoma, benign prostatic hyperplasia, constipation, and dementia.  
• Non sedating (non-anticholinergic) antihistamine are preferred except when sedative effects may be therapeutic (eg for nighttime relief of allergy or short term treatment of insomnia in adults or nausea younger patients).  
• Anticholinergic effects may also partially justify use of sedating antihistamine for symptomatic relief of rhinorrhea in URIs  
• Antihistamine solution may be intranasal (ezelastine to treat rhinitis) or ocular (azelastine, emedastine, ketotifen, levocabastine and olopatadine to trat conjunctivitis)  
• Topical diphenhydramine is available but should not be used  
• Its efficacy is unproved, drug sensitization (allergy) may occur and anticholinergic toxicity can develop in young children who are simultaneously taking oral H1 blockers.
  

Mast cell stabilizers  

• Cromolyn and nedocromil are examples . 
• These drugs block the release of mediators from mast cells.  
• They are used when other drugs (eg antihistamines topical corticosteroids) are ineffective or not tolerated.  
• Ocular forms (eg Iodoxamide,olopatadine,pemirolast) are also available.
  
  

Anti-inflamatory drugs  

• NSAIDs are not useful 
• Corticosteroids can be given intranasally or orally  
• Oral corticosteroids are indicated for systemic allergic disorders that are severe but self-limited fore example seasonal asthma flares, severe wide spread contact dermatitis) and for disorders refractory to other measures.  
• Leukotriene modifiers are indicated for treatment of mild persistent asthma and seasonal allergic rhinitis.  
• Anti –lgE antibody (omalizumab) is indicated for moderately persistent or severe asthma refractory to standard treatment.  
• It may also be useful for treatment of refractory allergic rhinitis.
  

Immunotherapy

• Exposure to allergen in gradually increasing doses (hyposensitization or desensitization) via injection or in high doses sublingually can induce tolerance and is indicated when allergen exposure cannot be avoided and drug treatment is inadequate 
• Mechanism is unknown but may involve induction of lgG antibodies, which compete with lgE for allergen or block lgE from binding with mast cell lgE receptors.  
• Induction of interferon gamma, IL-12, and cytokines secreted by TH1 cells.  
• Or induction of regulatory T cells.  
• For full effect injection must be given monthly.  
• Dose typically starts at 0.1 to 1.0 biologically active units (BAU), depending on initial sensitivity and is increased weekly or biweekly by les or equal to 2 times with each injection until a maximum tolerated concentration is reached.  
• Patients should be observed for about 30 min during dose escalation because anaphylaxis may occur after injection.  
• Maximum dose should be given q 4 to 6 wk year round.  
• Year around treatment is better than preseasonal or coseasonal treatment even for seasonal allergies  
• Allergens used are those that typically cannot be avoided, pollens, house dust mites, molds and venom of stinging insects.  
• Insect venoms are standardized by weight.  
• A typical starting dose Is 0.01 micrograms and usual maintenance dose is 100 to 200 microgram.  
• Animal dander desensitization is ordinarily limited to patients who cannot avoid exposure (eg veterinarians, laboratory workers) , but there is a little evidence that it is useful .  
• Food desensitization is not indicated.  
• Desensitization for penicillin and foreign (xenogeneic) serum can be done.  
• Adverse effects are most commonly related to overdose, occasionally via an inadvertent IM or IV injection, and range from mild cough or sneezing to generalized urticaria ,severe asthma ,anaphylactic shock and rarely death.  
• They can be prevented by increasing the dose in small increments, repeating or decreasing the dose if local reaction to the previous injection is large (greater or equal to 2 cm in diameter), and reducing the dose when a fresh extract is used.  
• Reducing the dose of pollen extract during pollen season is recommended
  

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