IMMUNOLOGY

Skin Test Wheal and Flare Mechanism: 

• Introduction of antigen into the skin causes local mast cell activation via cross-linking of preformed, antigen-specific, membrane-bound IgE.

• The release of preformed histamine from mast cells causes increased vascular permeability via smooth muscle contraction and development of wheal; inflammatory mediators initiate neural reflex vasodilation, leading to development of flare.

CLINICAL PEARLS 

• Skin testing is a practical, reliable, and well-tolerated method of establishing IgE-mediated disease. • Interpretation of skin testing should be done by an experienced practitioner, in the presence of positive and negative controls, and may be confounded by dermatographism or antihistamine use.

• The presence of a positive skin test documents the presence of allergen-specific IgE antibody. Diagnosis of allergy can be made only by correlating skin testing results with the presence of clinical symptoms.

Allergen immunotherapy: Definition, indication, and reactions

Specific allergen immunotherapy is the administration of increasing amounts of specific allergens to which the patient has type I immediate hypersensitivity. It is a disease modifying therapy, indicated for the treatment of allergic rhinitis, allergic asthma, and hymenoptera hypersensitivity. Specific IgE antibodies for appropriate allergens for immunotherapy must be documented. Indications for allergen immunotherapy include (1) inadequate symptom control despite pharmacotherapy and avoidance measures, (2) a desire to reduce the morbidity from allergic rhinitis and/or asthma or reduce the risk of anaphylaxis from a future insect sting, (3) when the patient experiences undesirable side effects from pharmacotherapy, and (4) when avoidance is not possible. Furthermore, patients may seek to benefit from economic savings of allergen immunotherapy compared with pharmacotherapy over time. Several studies have reported that immunotherapy in children with allergic rhinitis appears to prevent the development of new allergic sensitizations and/or new-onset asthma. Humoral, cellular, and tissue level changes occur with allergen immunotherapy including large increases in antiallergen IgG4 antibodies, a decrease in the postseasonal rise of antiallergen IgE antibodies, reduced numbers of nasal mucosal mast cells and eosinophils, induction of Treg cells, and suppression of Th2 more than Th1 lymphocytes. There is a corresponding increase in IL-10 and transforming growth factor beta. In the United States, allergen immunotherapy is administered by the subcutaneous route in the physician’s office, whereas primarily in some countries in Europe, it is administered for allergic rhinitis and asthma by the sublingual route by the patient at home.

Specific allergen immunotherapy, often called “allergy shots,” has been defined as the administration of increasing amounts of specific allergens to which the patient has type I immediate hypersensitivity. The purpose of allergen immunotherapy is to provide protection against the allergic symptoms and inflammatory reactions associated with natural exposure to these allergens. Although the single best marker that explains immunotherapy’s efficacy is unknown, there are many immunologic changes that occur with immunotherapy

INDICATION AND DURATION

 Immunotherapy is indicated for patients who have clinically significant IgE-mediated allergic rhinitis,asthma,4 and hymenoptera sensitivity.5 Specific IgE for appropriate allergens must be documented and symptoms should correlate with exposure to those specific allergens selected for immunotherapy.6–8 Other indications for allergen immunotherapy include inadequate symptom control despite pharmacotherapy and avoidance measures, undesirable side effects from pharmacotherapy, and when avoidance is not possible.In addition, immunotherapy may prevent the development of new sensitizations and/or new-onset asthma. The relative contraindications to allergen immunotherapy include severe or uncontrolled asthma, significant cardiovascular disease, and
-blocker use.Immunotherapy is not currently approved for food allergy or chronic urticaria and/or angioedema. However, the most recent immunotherapy practice parameter suggests an expanded indication, atopic dermatitis in subjects with aeroallergen sensitization. Multiple controlled studies have shown that immunotherapy is effective treatment for allergic rhinitis due grass, ragweed, and birch pollen.Immunotherapy with house-dust mite vaccines is an effective treatment for both allergic asthma and allergic rhinitis. Studies favoring allergen immunotherapy in patients with asthma have been published for grasses, trees (birch),ragweed, cat, and fungi (Alternaria and Cladosporium).Patients with mild asthma are more likely to benefit from immunotherapy than patients with moderate or severe asthma who may be at increased risk for adverse reactions to immunotherapy. To appropriately choose allergens for cutaneous testing and immunotherapy, it is important to be familiar with the significant aeroallergens in a patient’s geographic location

Immunologic changes with immunotherapy

Antibody changes 

Increase in allergen-specific IgG (specifically IgG4) 

Early increase and late decrease in serum-specific IgE 

Decrease in seasonal rise of specific IgE 

Cellular changes 

Decreased mediator release from mast cells, 

basophils, and eosinophils 

Reduction of tissue mast cells and eosinophils 

Induction of regulatory T cells and suppression of Th2 Th1 cells 

Increased secretion of IL-10 and TGF-
 

Decrease in histamine-releasing factors 

Skin testing in allergy

Skin tests are used in addition to a directed history and physical exam to exclude or confirm IgE-mediated diseases such as allergic rhinitis, asthma, and anaphylaxis to aeroallergens, foods, insect venoms, and certain drugs. There are two types of skin testing used in clinical practice. These include percutaneous testing (prick or puncture) and intracutaneous testing (intradermal). Prick testing involves introducing a needle into the upper layers of the skin through a drop of allergen extract and gently lifting the epidermis up. Other devices are available for prick testing. Intracutaneous (intradermal) testing involves injecting a small amount of allergen (0.01–0.02 mL) into the dermis. The release of preformed histamine from mast cells causes increased vascular permeability via smooth muscle contraction and development of a wheal; inflammatory mediators initiate a neural reflex causing vasodilatation, leading to erythema (the flare). Prick testing methods are the initial technique for detecting the presence of IgE. They may correlate better with clinical sensitivity and are more specific but less sensitive than intradermal testing. Sites of skin testing include the back and the volar aspect of the arm. Although the back is more reactive, the difference is minimal. By skin testing on the arm, the patient can witness the emergence and often sense the pruritus of the skin test reaction. Because more patients are sensitized (have IgE antibodies and positive skin test reactions) than have current symptoms, the diagnosis of allergy can be made only by correlating skin testing results with the presence of clinical symptoms.

Skin tests are used in addition to a directed history and physical exam to exclude or confirm IgEmediated diseases1 such as allergic rhinitis,2 asthma,3 and anaphylaxis4 to aeroallergens,5 foods,6 insect venoms,7 and certain drugs.8 Skin testing attempts to detect the presence of allergen-specific IgE bound to mast cells by eliciting mast cell degranulation to the specific allergen being tested. This may help confirm the suspicion that a patient’s symptoms are related to immediate hypersensitivity to this allergen. Currently, two types of skin testing are used in clinical practice. These include percutaneous testing (prick or puncture) and intracutaneous testing (intradermal). Prick testing involves introducing a needle into the upper layers of the skin through a drop of allergen extract and gently lifting the epidermis up. Several other percutaneous skin testing implements are available commercially. Intracutaneous (intradermal) testing involves injecting a small amount of allergen (0.01–0.02 mL) into the dermis.

Prick testing methods are the initial technique for detecting the presence of IgE. They may correlate better with clinical sensitivity and are more specific but less sensitive than intradermal testing.9–11 In addition, intradermal testing carries a slightly higher risk of a systemic reaction (0.05% versus 0.03% for a prick test), although the risk is still low. Because of this risk, testing should begin with prick testing, and then proceed to intradermal testing if prick testing is negative and there remains a high degree of clinical suspicion. In the past 30 years, six fatalities have been attributed to intradermal testing; five of these patients had asthma and a lack of prior prick testing. One fatality from prick testing has ever been identified; this patient received over 90 prick tests to food allergens at one time and had preexisting asthma.12 Intradermal testing has not proven beneficial in the diagnosis of food allergy; therefore, the risk to patients is not justified. A physician should always be available to give emergency treatment if necessary, and patients should be observed for at least 20 minutes after testing

H1-receptor antagonists should be held for a minimum of 24–72 hours before skin testing based on the specific pharmacokinetics of each drug. Other drugs with antihistaminic properties, such as metoclopramide, histamine-2 receptor blockers, and tricyclic antidepressants, may affect test results and should be held before testing if possible.13 Refer to Table 1 for the elimination half-lives (t 1⁄2) of several commonly prescribed medications. Short courses of oral corticosteroids will not affect testing results; however, topical corticosteroids may decrease or inhibit skin reactivity. These should not be applied to the test site for at least 1 week before testing. Patients receiving immunotherapy may have decreased skin reactivity. Leukotriene antagonists do not significantly affect skin test reactivity.
2-Adrenergic agonists, decongestants, theophylline, and cromolyn will not affect skin testing

Sites of skin testing include the back and the volar aspect of the arm. Although the back is more reactive, the significance of this is minimal.10 Use of the arm as the test site has the advantage of being able to place a tourniquet above the site should a systemic reaction occur. Skin chosen for testing should be clear of dermatitisThe skin chosen is cleaned with alcohol. Allergen extracts, positive control (histamine), and negative control (saline or allergen diluent) are placed 2–5 cm apart. One source of skin testing error is placing sites too close together resulting in spread of one allergen extract to another site and inability to accurately record the extent of erythema from two positive sites close together. False negative or positive reactions may occur with insufficient or excessive skin penetration. If prick testing reveals minimal or equivocal reaction to an allergen, one might choose to proceed with intradermal testing with a 100- to 1000-fold dilution of allergen extract.

Standardized extracts should be used to facilitate comparisons between clinicians. Note that use of standardized doses does not always confer equal potency. One study found that the content of major allergen varied significantly among the 12 standardized extracts tested. Extracts should be refrigerated at 4°C. They should contain glycerin to decrease the loss of potency that occurs with time

Testing should be graded within 15–20 minutes.15 Several different grading systems exist, one of which is shown in Table 2. The mean diameter of the wheal and erythema are recorded with the presence or absence of pseudopodia. Physicians should quantitate the actual size on the data sheet and not solely a grade so that results might be better shared among practitioners. Clinicians also are urged to use a comprehensive data sheet recording the brand of extract, dilutions used, device chosen, mean diameters of wheal and erythema, and specific grading system key. 

Interpretation of skin tests may be more difficult in patients with dermatographism. False positive reactions with dermatographism can be distinguished from true positive reactions that are secondary to IgE because the former fade more quickly. Special attention should be paid to the difference between the sizes of the reactions from allergen extracts compared with the negative control. No significant differences in skin test reactivity have been noted for gender. Infants and the elderly, however, may have decreased skin reactivity and thus smaller wheal size. Additionally, darkly pigmented skin can have larger histamine wheals compared with light skin.

DRUGS

Medicines often are implicated in triggering undesired immunologic reactions. True drug allergy represents 6 –10% of all adverse drug reactions and is overreported by individuals. Most drugs are too small (
1000 Da) to incite allergic sensitization alone. To cause an allergic reaction, a reactive metabolite of the drug must bind to a macromolecular carrier for antigen processing. The drug metabolite in the carrier molecule complex is known as a hapten. This makes skin testing difficult for diagnostic accuracy. Large molecular weight drugs (heterologous antisera, insulin, streptokinase, and l-asparaginase), which are 4000 Da, and medicines that have enough distance between determinants to be bivalent (quaternary ammonium muscle relaxants and aminoglycosides), may provoke an allergic response without forming a hapten–protein complex. 

LATEX 

Natural rubber latex is a product of the rubber tree Hevea brasilensis. Sensitization is present in 75% of patients with spina bifida and 6.5% of the general population. Health care providers and patients with urological problems requiring catherization are also at increased risk. Clinical manifestations of IgE-mediated disease include allergic rhinitis, asthma, contact urticaria, and anaphylaxis. The incidence of IgE-mediated reactions to latex has declined mostly because of the development of powder-free, low-protein gloves. 

INGESTED ALLERGENS 

Food allergy is common and appears to be increasing; it can be divided into class 1 and class 2. Class 1 food allergy is considered “traditional” and occurs in the gastrointestinal tract. Class 2 food allergy is caused by allergic sensitization to inhalant allergens that cross-react with food allergens. Class 1 allergens are 10 –70 kDa and are heat, acid, and protease stable. Common class 1 allergens are cow’s milk, chicken egg, peanut, soybean, fish, and shrimp. Thirty-five percent of children with moderate to severe atopic dermatitis have an associated food allergy,15 and 6% of asthmatic children have associated food allergy. Peanut is the most common food allergy in individuals 4 years old. There has been a dramatic increase in the number of children with peanut allergy with one study noting peanut allergy prevalence of 1.4% in 2008 versus 0.8% in 2002 in the United States. Studies are currently looking at environmental factors that may result in this increased prevalence. 

Cross-reactivity between members of a food allergen group varies. Cross-reactivity between peanuts and other legumes is 5%, between tree nuts 35%, between different fish 50%, and 75% between members of the shellfish family. Cross-reactivity also occurs between aeroallergens and certain food allergy resulting in class 2 food allergies. This is known as pollen–food syndrome (previously oral allergy syndrome) and manifests as pruritus with or without angioedema of the lips, tongue, palate, and posterior oropharynx. Shared allergen sensitivities have been reported between ragweed and the gourd family (watermelon, cantaloupe, zucchini, and cucumbers) and bananas. Birch pollen shares allergen sensitivities with apples, carrots, parsnips, celery, hazelnuts, potatoes, celery, and kiwi. Tree and grass pollen share allergens with apples, tree nuts, peaches, oranges, pears, cherries, fennel, tomatoes, and carrots. Often, cooking or peeling these foods reduces symptoms of pollen–food syndrome.

Reviewing the properties of common allergens reinforces the foundation of controlling clinical allergy symptoms, which is avoidance of allergen exposure. Their properties also form the basis for developing diagnostic and therapeutic opportunities.

IMMUNOLOGY

 • An allergen is typically a protein or glycoprotein that can induce an IgE-mediated immune response with an associated clinical reaction. 

 • Size of pollen determines clinical manifestation of allergy. Particles between 20 and 60
m in diameter can be carried in the wind and cause nasal and ocular symptoms. Particles
7
m can deposit in the airways and cause symptoms of asthma. 

• True drug allergy represents 6 –10% of all adverse drug reactions. Skin testing is difficult because most drug allergens are small metabolites of the implicated drug and they must haptenize a carrier protein to induce an immune response. 

CLINICAL PEARLS

 • Most tree pollens do not have significant cross-reactivity and are released in the spring in the United States. In the upper midwestern United States, tree pollination occurs in mid to late March until May. 

• Grass pollen comes from the Poaceae family, has significant cross-reactivity, and is typically released in the late spring and early summer in the United States. In the upper midwestern United States, this time is from mid-May to the end of July. 

• Weed pollens are released mostly in the autumn in the United States with ragweed being the major allergen from August 15 to October 1 in the upper midwestern United States. 

• Global warming has shifted the floristic zones in North America to higher latitudes. Ragweed has increased in size and pollen production because of increased CO2 and temperature. 

• Fungal spores and mycelial elements are released preferentially in warm, humid environments. The first hard frost of late autumn decreases outdoor mold spores. 

• Dust mites thrive in warm, humid conditions and provide allergen through their fecal particles, enhanced by intrinsic enzymic activity. 

• Cat allergen may last in a home for up to 6 months after the source is removed. It can be isolated from saliva, urine, dander, and from sebaceous glands.

• The most common class I food allergens are cow’s milk, chicken egg, peanut, soybean, fish, and shrimp. There has been an increase in the prevalence of peanut allergy in children. 

• Pollen–food syndrome occurs because of cross-reactivity between aeroallergens and certain food proteins.

An overview of allergens

An allergen is any antigenic substance that can mediate an immediate hypersensitivity reaction with an associated clinical reaction in an individual. Common allergens include pollens, fungal spores, house-dust mites, and animal epithelial materials but can also include drugs, biological products, and insect venoms. Most allergens are proteins or glycoproteins that range in molecular weight from 5000 to 100,000 Da, although polysaccharides and low molecular weight substances also may be allergenic.1 Little is known, but much research is dedicated to determining the distinguishing facts that make an antigen capable of inducing IgE production (an allergen) in contrast to antigens that induce other immunologic responses (IgG and IgA). Factors that have already been shown to increase immunogenicity of an antigen include molecular size, solubility, stability, conformational fold, and duration of exposure

Allergens enter the body via inhalation, ingestion, or may be injected. Genetic predisposition and environmental factors determine if an individual will be sensitized to an allergen, and then subsequent allergen exposure of sufficient concentration triggers a physiological response by interacting with specific IgE bound to mast cells and basophils. The ensuing inflammatory cascade elicits a variety of signs and symptoms in the allergic spectrum. The allergic response is dependent on the route of exposure. If exposure is to an inhaled aeroallergen, the allergic response will be a respiratory reaction in nature. Ingested or injected exposure gives rise to gastrointestinal, cutaneous, or systemic reactions. 

An allergen is recognized by the International Union of Immunologic Societies as a protein that has allergenicity in at least five individuals.2 Individual allergens are further divided into major and minor allergens when it comes from the same source, e.g., giant ragweed pollen or cat dander. Major allergens result in an IgE response in 50% of allergic individuals allergic to the specific source, whereas minor allergens cause an allergic response in
50%. Although “minor” is in the name, they still cause a significant allergic response in an individual. 

Nomenclature for allergen proteins has been established by the International Union of Immunologic Societies. The standard nomenclature uses the first three letters of the genus, followed by the first letter of the species, and then an Arabic numeral; they are not italicized. 

POLLENS

For pollen to be clinically significant as an aeroallergen, it must be buoyant, present in significant numbers, and be allergenic. Most pollens that cause clinical disease are 20 – 60
m in diameter.2 This small size allows exposure through wind carriage and contact with the respiratory mucosa and conjunctiva. Particles
7
m tend to deposit in the airways, and those
3
m may enter the distal airways. Pollen immunogenicity, plant abundance, proximity to living environments, and regional geography determine specific pollens that are responsible for local allergic sensitization.2 

Grass pollen is the most common cause of allergic rhinitis and asthma worldwide because of the wide distribution of wind-pollinating grasses. Most are 20 –25
m in diameter and, therefore, tend to cause symptoms of rhinitis rather than asthma. Most grasses belong to the same family (Poaceae) and have significant cross-reactivity, with the exceptions of Bermuda and Bahia grass, which are subtropical grasses. Ryegrass (major allergen Lol p 1) and Timothy grass (major allergen Phl p1) are among the most important allergenic grasses. Grass pollen is typically released in the afternoon, and in the Midwest, is prevalent in the months of May through July. Many southern areas, such as Florida and southern California, have grass seasons lasting as long as 10 –11 months. 

Ragweed pollen is the most important cause of allergic rhinitis and pollen asthma in North America. Ambrosia artemisiifolia (short ragweed; major allergen Amb a 1) and Ambrosia trifida (giant ragweed; Amb t 5) are the most important ragweed pollen allergens. Pollen grains are 16 –20
m in diameter and are notorious for triggering allergic symptoms in the central and eastern United States; Ontario, Canada; and increasing locations in Europe.5,6 Weed pollen release depends on seasonal daylight variation and is released typically in the morning during the autumn season in the United States. A single ragweed plant may expel 1 million pollen grains in a single day. It possesses the ability to travel hundreds of miles from its source. In the Chicago area, ragweed pollen is prevalent from August 15 to October 1.

EVALUATION AND MANAGEMENT CODES

The E/M section of the CPT coding book describes patient encounters with the physician for all services other than procedures and miscellaneous services. The E/M services can be either problem-oriented or preventive in nature. The CPT book divides the E/M codes into multiple categories: office or other outpatient services; hospital observation; hospital inpatient services; consultations; emergency department services; critical care; nursing facilities − initial and subsequent; discharge; rest home; home services; prolonged services; case management; care plan oversight; preventive and special evaluation and management. The appropriate code selection from this section is dependent on the place of service for the patient and the type of service. The most common services used in the allergist office are outpatient services, consultations and, occasionally, inpatient hospital services. Many of the codes in this section of the book have a time component associated with the code. The time component is not applicable, however, for selection of the code unless the encounter is >50% counseling and coordination of care. In these instances, the time component of the code is used to determine the appropriate level of service.

Office or Other Outpatient Service Codes

The new patient codes(99201-99205) are forservices provided in the office and other outpatient facilities to evaluate a patient who is new to the practice. The CPT definition of a new patient vs. an established patient is a patient who has not received any faceto-face professional services by the physician or by another physician of the exact same specialty and subspecialty of the same group practice in the past three years. An established patient (codes 99211- 99215) is one who has ongoing services provided by the physician or any physician of the exact same specialty and subspecialty in the same group practice. If a physician is covering for another physician, the patient encounters will be considered as if the absent physician were treating the patient. The only setting in which there is no difference in new or established patients is in the emergency setting. The established patient encounter (code 99211, nurse visit) does not require a physician to see the patient. However, it requires a chief complaint and it requires the physician to be in the suite to support the “incident to” guidelines set for supervision of physician staff.

Inpatient Hospital Service Codes

Hospital services are not differentiated according to whether the patient seeing the physician is a new patient or an established patient. Hospital services codes differentiate between the services during the initial encounter while the patient is admitted to the hospital and the subsequent care of the patient while in the hospital for that encounter. The codes for initial encounters (99221-99223) are for the initial workup to place the patient in the hospital for care. The subsequent care codes (99231-99233) are for those services provided on a daily basis by the admitting physician and by any consulting physicians while the patient is hospitalized for the course of his/her illness. These codes are based on the patient history and exam and medical decision-making. Time is used to determine only the level of code if >50% of the encounter was counseling and coordination of care for the patient. If the CPT code is going to be determined by counseling and coordination of care, the counseling and coordination of care for the patient must be done by the physician, not the staff.

Monetary Value for CPT Procedure Codes

In 1992, Medicare established a value system for services provided to Medicare patients called the Resource-Based Relative Value System (or RBRVS). This system placed a value on each CPT code that was payable to Medicare based on resources. It replaced the old standard, which was “reasonable and customary” value. The resources the CMS used to determine a value for each code included physician work component, overhead component and malpractice. These values change on a yearly basis according to recommendations from the AMA and specialty societies. The Relative Value Scale Update Committee (or RUC) meets during the year to evaluate the recommendations and forward their recommendations to the CMS. In the fall of each year, the final rules and values are published by the CMS in the Federal Register, which establishes the CPT codes and the Medicare relative values assigned to those codes for the next year. Many third-party carriers also use these RVUs to determine how they will reimburse for services provided to their beneficiaries. The third-party payers will pay differently than Medicare, however, because the conversion factor per RVU will be based on contract negotiations with the payer or the contract offered by the carrier.

Suggestions for Coding and Reimbursement Techniques and Tools

Purchase new coding tools on a yearly basis. You should have a diagnosis coding book, a CPT book and a HCPCS book. You also need to have the Correct Coding Initiative (CCI), a free publication available on the CMS website (www.cms.hhs.gov). The CCI is a bundling program that gives information as to which codes may be charged together and which ones cannot be charged together on the same day of service.

Read payer billing manuals and local carrier directives. The Joint Council of Allergy, Asthma & Immunology website (www.jcaai.org) and publications provide up-to-date information appropriate for allergy practices. Also be aware of the different carrier billing guidelines and know the website for each carrier in order to find its specific guidelines. Each Medicare carrier will have local carrier directives that are accessible to every physician posted on their websites. The CMS also has national guidelines on their website, as well as information, tools and manuals.

1. Education regarding coding should be provided continually for all physicians and their staff. In light of ICD-10, this includes every staff member having a role to help ease this transition. Making a plan prior to this transition with different levels of the staff will ensure the most success. The guidelines for carriers may change, and you are held accountable for knowing the changes and for appropriately submitting claims.

2. A compliance plan should be implemented to support and define all the coding and billing policies of the practice. Designate someone, often the compliance officer, to be the recipient of all coding and reimbursement information and to inform involved individuals of any relevant coding changes. This person also should orient new staff, including physicians, to ensure that updated resources are available in the practice, and should research any changes pertinent to the practice

3. Electronic versions of several books and reference guides are now available for tablets/ IPads, as well as iOS and Android phones.

CPT index

The CPT index gives a listing of all the codes. The different methods you may use to find a code in the index are:

1. Name of the procedure 

2. Anatomic site or organ 

3. Condition 

4. Eponym – the name of the person who developed the procedure or service or who it is named for 
5. Symptom

6. Common abbreviation

Category I codes are used for reimbursement of physician services and procedures. However, use of a CPT Category I code does not guarantee payment. Each carrier may have specific reimbursement guidelines that will indicate that a Category I code is not payable. For example, CMS (Medicare) will not pay for a spirometry (94010) and a flow-volume curve (94375) when they are performed on the same day.

Category II codes provide information on performance measures and data collection. There is no monetary value for these codes. Category II codes are not required for submission of claims for reimbursement at this time. PQRS (Physician Quality Reporting System) is currently optional but it is proposed to be a required component of coding in the future by Centers of Medicare and Medicaid Services. For 2015, CMS has proposed taking a small percentage of deductions from their allowed amount of payment on claims if the PQRS information is not provided by the providers. For other payers, however, it may or may not be necessary to include these codes on a claim when submitting for reimbursement.

Category III codes are used to track new procedures and technology. These codes are not recognized by payers as payable codes. These codes need to be used in addition to an unlisted procedure code to indicate to the payer/carrier the type of service being provided. The payer/carrier then may make a determination as to whether it chooses to reimburse for the new procedure and/or technology. Two category codes that may be used in the allergy practice are the following:

• 0243T – Intermittent measurement of wheeze rate for bronchodilator or bronchial-challenge diagnostic evaluations(s), with interpretation and report 

• 0244T – Continuous measurement of wheeze rate during treatment assessment or during sleep for documentation of nocturnal wheeze and cough for diagnostic evaluation for three to 24 hours, with interpretation and report

The codes above have a sunset of January 2016. If there is not sufficient acceptance and use as a standard of care by January 2016, these codes will be deleted.

T CELLS AND THEIR RECEPTORS

Each T cell is also committed to a given antigen and recognizes it by one of two TCRs. They may have TCR2s composed of gamma (γ) and delta (δ) chains or TCR2s composed of another heterodimer of alpha (α) and beta (β) chains. These TCR2s are associated with a group of transmembrance proteins on the CD3 molecule, which takes the antigen recognition signal inside the cell. Signal transduction via the CD3 complex is regulated by a series of kinases, which are associated with the tails of the CD3–TCR complex and regulate phosphorylation. Defi ciencies or blocks in the T-cell signaling pathways either at the cell-surface complex or at the level of the kinases may result in various forms of immunodefi ciency. Two other important antigens present on TCR2 cells recognize histocompatibility antigens and will be discussed later. The genes for TCR chains are on different chromosomes with the β and α molecules on chromosome 7, while the α and δ are on chromosome 14. As seen in Figure 1.5, the four chains are made up of a variable region and a constant region similar to those observed with the immunoglobulins. The variable regions are also numerous and joined at D and J regions by RAG1 and RAG2. This permits a diversity of antigen recognition similar to that observed with immunoglobulin, but additional somatic mutation is not involved in T cells. These similarities have led to the concept that genes for antigen-specifi c T cells evolved in the same manner as immunoglobulin from a parent gene, and both are members of a superantigen family. 

The TCR complex recognizes small peptides presented to it by the MHC class I and II and depends on the type of T cell.  Helper T cells (CD4) recognize class II antigens while suppressor cytotoxic T cells (CD8) recognize class I antigens. Because of the rather low affi nity of the reactions, recognition of processed antigen alone is not suffi cient to activate T cells. Soluble interleukins are needed to complete the picture and are generated during the antigen processing.

The genetics of antibody production

The major mucosal immunoglobulin, IgA, consists of two basic units joined by a J chain. The addition of a secretion molecule prevents its digestion by enzymes present in mucosal and intestinal secretions. Thus, IgA2 is the major IgA molecule in secretions and is quite effective in neutralizing antigens that enter via these mucosal routes. IgA1, the main IgA molecule in serum, is, however, susceptible to inactivation by serum proteases and is thus less active for defense. Its function is unclear at present. 

Two other classes are worthy of note. IgD is synthesized by antigen-sensitive B cells and is involved in the activation of these cells by antigen. IgE is produced by plasma cells and binds to specifi c IgE receptors on most cells and basophiles. This molecule (see Chapter 9) plays an extremely important role in allergic reactions and expelling intestinal parasites, which is accomplished by increasing vascular permeability and inducing chemotactive factors following mast cell degranulation. 

Given this extraordinary ability to generate large numbers of antibody molecules, how does the immune system recognize all pathogens, including past, present, and future? This diversity is achieved by the way in which the genetics of antibody production is arranged (see Figure 1.3). The light and heavy chains are carried on different chromosomes. The heavy chain genes are carried on chromosome 14. These genes are broken up into coding systems called exons with intervening segments of silent segments called entrons. The exons represent the central region of the heavy chain and a large number of V regions. Between the V and D genes are two small sets of exons called the D and J. With each single B cell, one V gene is joined to one D and J in the chromosome. The product, the VH domain, is then joined at the level of RNA processing to Cu and the B cell makes an IgM molecule. By omitting the Cu gene and joining VHDJ to a Cλ an IgG molecule is produced. This enormous versatility allows the cell to make IgM, IgD, IgG, IgA, or IgE in sequence while using the same variable regions (see Figure 1.4). The heavy chain gene recombinations are controlled by two recombination activity genes called RAG1 and RAG2. If these genes are eliminated by “knock-out” techniques in mice, profound immunodefi ciency status occurs in these animals, characterized by absent mature B and T cells. 

Thus, the diversity of antigen binding is achieved by the large number of V genes available and their combination with different D and L genes to provide different antibodies. Furthermore, the inherited set of genes may be increased by somatic mutation during multiple divisions of lymphoid cells, thereby increasing the number of antibody specifi cities to 1014, which far exceeds the number of B cells (1010) in the body. 

Once a given B cell is preselected to produce a particular VH and VL domain, all the ensuing progeny of that B cell will produce the same VH or VL domain. The sequence of events is as follows: initially, the B cell produces intracellular antigen-specific IgM, which becomes bound to the cell surface. The B cell is now antigen responsive with exposure to a given antigen. The committed B cell begins producing a certain isotype or class of immunoglobulins and begins dividing, and all the progeny will produce the identical immunoglobulin molecules. These B cells will later mature into either plasma cells or long-term memory B cells.

ANTIGENS

Antigens are any substances that are capable, under appropriate conditions, of inducing the formation of antibodies and reacting specifi cally with the antibodies so produced. They react with both T-cell recognition receptors and with antibodies. These antigenic molecules may have several antigenic determinants, called epitopes, and each epitope can bind with a specifi c antibody. Thus, a single antigen can bind to many different antibodies with different binding sites.

Some low-molecular-weight molecules called haptens are unable to evoke an immune response but can react with existing antibodies. These molecules need to be coupled to a carrier molecule to be antigenic. 

For some molecules such as drugs, the molecule needs to be conjugated to a carrier. The carrier may be a host protein. The tertiary structure of the molecule as well as the amino acid sequence is important in determining antigenicity. Certain structures such as lipids and DNA are generally poor antigens. 

Most antigens are either thymusdependent or thymus-independent antigens. Thymus-dependent antigens require T-cell participation: Most proteins and foreign red cells are examples of these molecules. Thymus-independent antigens do not require T-cell participation for antibody production. Instead, they directly stimulate specifi c B lymphocytes by crosslinking antigen receptors on the surface of B cells. These molecules produce primarily IgM and IgG2 antibodies and do not stimulate long-lasting memory cells. Most bacterial polysaccharides (found in bacterial cell walls) fall into this category. Certain polysaccharides, such as LPS (lipopolysaccharide), not only induce specifi c B-cell activation but also can act as a polyclonal B-cell stimulant.

ANTIBODY

It consists of a four-chain structure divided into two identical heavy (H) chains with a molecular weight of 25 kDa. Each chain is composed of domains of 110 amino acids and is connected in a loop by a disulfide bond between two cysteine residues in the chain. 

The amino acid N-terminal domains of the heavy and light chains include the antigen-binding site. The amino acids of these variable domains vary between different antibody molecules and are thus known as the variable (V) regions. Most of these differences reside in the hypervariable areas of the molecule and are usually only six to ten amino acid residues in length. When the hypervariable regions in each chain come together along with the counterparts on the other pair of H and L chains, they form the antigen-binding site. This part of the molecule is unique to the molecule and is known as the idiotype determinant. In any individual, 106 to 107 different antibody molecules can be composed from 103 different heavy and light chains of the variable regions. The part of the molecule next to the V region is called the constant (C) region made up of one domain in the light chain (C1) and three or four in a heavy chain (CH). A Cl chain may consist of either two kappa (κ) or two lambda (λ) chains but never one of each. Of all the human antibody molecules, approximately 60%, are κ chains and 40% contain λ chains. Although there are no known differences in the functional properties of κ and λ chains, there are several different types of the CH domain. These differences are refl ected in determining the class (isotype) of the antibody and thereby the physiological function of a particular antibody molecule.

The IgM molecule is the oldest class of immunoglobulins, and it is a large molecule consisting of fi ve basic units held together by a J chain. The major role IgM plays is the intravascular neutralization of organisms, especially viruses. The reason for this important physiological role is that it contains fi ve complement-binding sites, resulting in excellent complement activation. This activation permits the segment removal of antigen–antibody complement complexes via complement receptors on phagocytic cells or complement-mediated lysis of the organism. However, in contrast to the IgG molecule, it has relatively low affi nity binding to the antigen in question. Second, because of its size, it does not usually penetrate into tissues. In contrast, IgG is a smaller molecule that penetrates easily into tissues. There are four major classes of IgG: IgG1 and IgG3 activate complement effi ciently and clear most protein antigens, including the removal of microorganisms by phagocytic cells. 

In contrast, IgG2 and IgG4 react mostly with carbohydrate antigens and are relatively poor opsonins. This is the only molecule that crosses the placenta to provide immune protection to the neonate.

Basic Components of the Immune System

It is generally believed that the immune system evolved as the host’s defense against infectious agents, and it is well known that patients with deficiencies in the immune system generally succumb to these infectious diseases

An immune response may be conveniently divided into two parts:

(1) a specifi c response to a given antigen and

(2) a more nonspecifi c augmentation to that response.

An important feature of the specific response is that there is a quicker response to the antigen during a second exposure to that antigen. It is the memory of the initial response that provides the booster effect. For convenience, the specific immune response may be divided into two parts:

(1) the humoral response and

(2) the cellular response to a given antigen. As we shall see, however, both responses are mediated through the lymphocyte. Humoral responses are antibodies produced in response to a given antigen, and these antibodies are proteins, have similar structures, and can be divided into various classes of immunoglobulins. Cellular responses are established by cells and can only be transferred by cells.

Up to the 1940s the general dogma held that only antibodies were involved in the immune response. Dr. Merrill Chase, who began his experiments in a laboratory devoted primarily to the humoral response, clearly showed in a series of elegant experiments that immunity was not just humoral but that a cellular response by the lymphocytes could also produce immunity. Some of the best examples of the power of cellular immunity may be found in the many experiments in which transfer of cells can induce autoimmune disease in animals and humans as well as rejection of an organ graft in both animals and humans by cells.

 The separation of human and cellular immunity was further advanced by the study of immuno      deficient humans and animals. For example, thymectomized or congenitally athymic animals as well as humans cannot carry out graft rejection, yet they are capable of producing some antibody responses. The reverse is also true. Children (and animals) who have an immune defi cit in the humoral response do not make antibodies but can reject grafts and appear to handle viral, fungal, and some bacterial infections quite well. An extraordinary fi nding by Good and colleagues in studying the cloacal lymphoid organ in chickens revealed that, with removal of the bursa Fabricius, these animals lost their ability to produce antibodies and yet retained the ability to reject grafts.

Out of these and many other contributions, a clearer picture of the division of efforts by lymphocytes begins to emerge. Since cellular immune responses require an intact thymus, cellular immune responses are mediated through the T lymphocytes (thymus), while antibody-producing cells, which are dependent on the bone marrow (the bursa equivalent), are known as B (bursa) cells.

Several types of molecules play a vital role in the immune response, and we will deal with each in detail. Antigens, both foreign and self, are substances that may or may not provoke an immune response. Both T cells and B cells have receptors that recognize these antigens. In the case of B cells, antibodies on the surface are a major source (but not the only one) of antigen recognition, and once activated, they differentiate into plasma cells that produce large quantities of antibodies that are secreted into blood and body fluids to block the harmful effects of the antigen.

T cells have similar receptors known as T-cell receptors (TCR), and in the context of the major histocompatibility complex (MHC) molecules provide a means of self-recognition and T-lymphocyte effector functions. Often these effector functions are carried out by messages transmitted between these cells. These soluble messengers are called interleukins or cytokines.

Allergy, Asthma and Immunology Services

Caring for adults and children with various problems including:

• Asthma  
• Allergies
• Allergic rhinitis/hay fever
• Anaphylaxis
• Angioedema
• Atopic dermatitis/eczema
• Drug allergy
• Food allergy & hypersensitivities
• Immune deficiency 
• Medical management of chronic sinusitis
• Stinging insect allergy
• Urticaria/hives 
• Immune evaluations for recurrent and unusual infections
• Primary immunodeficiency

Services and procedures are provided in the following areas:

• Allergy skin testing for pollens, indoor allergens, drugs and foods
• Allergy immunotherapy (shots)
• Spirometry (breathing tests)
• Oral challenges for food and drug allergy
• Desensitization for aspirin and drug allergy
• Intravenous (and subcutaneous) immune globulin infusion
• Patch testing for contact dermatitis and delayed hypersensitivity reactions
• Counseling on the use of inhaled medications

For patient convenience, spirometry can be performed directly in the clinic exam rooms.  Patients do not need to leave the clinic to have this test.  In addition, your specialist has access to test results immediately. 

Allergies - overview

An allergy is an immune response or reaction to substances that are usually not harmful.

Causes

Allergies are very common. Both genes and environment play a role. If both your parents have allergies, there is a good chance that you have them, too.

The immune system normally protects the body against harmful substances, such as bacteria and viruses. It also reacts to foreign substances called allergens. These are usually harmless and in most people do not cause a problem.

Allergic reactions

In a person with allergies, the immune response is oversensitive. When it recognizes an allergen, the immune system launches a response. Chemicals such as histamines are released. These chemicals cause allergy symptoms.

Common allergens include:

• Drugs
• Dust
• Food
• Insect venom
• Mold
• Pet and other animal dander
• Pollen

Some people have allergy-like reactions to hot or cold temperatures, sunlight, or other environmental triggers. Sometimes, friction (rubbing or roughly stroking the skin) will cause symptoms.

Allergies may make certain medical conditions, such as sinus problems, eczema, and asthma, worse.

Symptoms

Mostly, the part of the body the allergen touches affects what symptoms you develop. 

For example:

• Allergens that you breathe in often cause a stuffy nose, itchy nose and throat, mucus, cough, and wheezing.
• Allergens that touch the eyes may cause itchy, watery, red, swollen eyes.
• Eating something you are allergic to can cause nausea, vomiting, abdominal pain, cramping, diarrhea, or a severe, life-threatening reaction.
• Allergens that touch the skin can cause a skin rash, hives, itching, blisters, or skin peeling.
• Drug allergies usually involve the whole body and can lead to a variety of symptoms.
• At times, an allergy can trigger a response that involves the entire body.

Hives (urticaria) on the chest

Exams and Tests

The health care provider will perform a physical exam and ask questions, such as when the allergy occurs.

Allergy testing may be needed to find out whether the symptoms are an actual allergy or are caused by other problems. For example, eating contaminated food (food poisoning) may cause symptoms similar to food allergies. Some medicines (such as aspirin and ampicillin) can produce non-allergic reactions, including rashes. A runny nose or cough may actually be due to an infection.

Skin testing is the most common method of allergy testing:

The prick test involves placing a small amount of the suspected allergy-causing substances on the skin, and then slightly pricking the area so the substance moves under the skin. The skin is closely watched for signs of a reaction, which include swelling and redness.

The patch test involves placing a patch with the suspected allergen on your skin. The skin is then closely watched for signs of a reaction.

The intradermal test involves injecting tiny amount of allergen under your skin, then watching the skin for a reaction.

The doctor may also check your reaction to physical triggers by applying heat, cold, or other stimulation to your body and watching for an allergic response.

Blood tests that may be done include:

Immunoglobulin E (IgE), which measures levels of allergy-related substances

Complete blood count (CBC) during which an eosinophil white blood cell count is done

In some cases, the doctor may tell you to avoid certain items to see if you get better, or to use suspected items to see if you feel worse. 

This is called "use or elimination testing." This is often used to check for food or medicine allergies.

Treatment

Severe allergic reactions (anaphylaxis) need to be treated with a medicine called epinephrine. It can be life-saving when given right away. If you use epinephrine, call 911 and go straight to the hospital.

The best way to reduce symptoms is to avoid what causes your allergies. This is especially important for food and drug allergies.

There are several types of medicines to prevent and treat allergies. Which medicine your doctor recommends depends on the type and severity of your symptoms, your age, and overall health.

Illnesses that are caused by allergies (such as asthma, hay fever, and eczema) may need other treatments.

Introduction to allergy treatment

Medicines that can be used to treat allergies include:

ANTIHISTAMINES

Antihistamines are available over-the-counter and by prescription. They are available in many forms, including:

Capsules and pills

Eye drops

Injection

Liquid

Nasal spray

CORTICOSTEROIDS

These are anti-inflammatory medicines. They are available in many forms, including:

Creams and ointment for the skin

Eye drops

Nasal spray

Lung inhaler

Pills

Injection

Persons with severe allergic symptoms may be prescribed corticosteroid pills or injections for short periods.

DECONGESTANTS

Decongestants help relieve a stuffy nose. Do not use decongestant nasal spray for more than several days because they can cause a rebound effect and make the congestion worse. Decongestants in pill form do not cause this problem. People with high blood pressure, heart problems, or prostate enlargement should use decongestants with caution.

OTHER MEDICINES

Leukotriene inhibitors are medicines that block the substances that trigger allergies. Person with asthma and indoor and outdoor allergies may be prescribed these medicines.

ALLERGY SHOTS

Allergy shots (immunotherapy) are sometimes recommended if you cannot avoid the allergen and your symptoms are hard to control. Allergy shots keep your body from over-reacting to the allergen. You will get regular injections of the allergen. Each dose is slightly larger than the last dose until a maximum dose is reached. These shots do not work for everybody and you will have to visit the doctor often.

SUBLINGUAL IMMUNOTHERAPY TREATMENT (SLIT)

Instead of shots, medicine put under the tongue may help for grass and ragweed allergies.

Support Groups

Ask your provider if there are any asthma and allergy support groups in your area.

Outlook (Prognosis)

Most allergies can be easily treated with medicine.

Some children may outgrow an allergy, especially food allergies. But once a substance has triggered an allergic reaction, it usually continues to affect the person.

Allergy shots are most effective when used to treat hay fever and insect sting allergies. They are not used to treat food allergies because of the danger of a severe reaction.

Allergy shots may need years of treatment, but they work in most cases. However, they may cause uncomfortable side effects (such as hives and rash) and dangerous outcomes (such as anaphylaxis). Talk with your provider whether allergy drops (SLIT) are right for you.

Possible Complications

Complications that may result from allergies or their treatment include:

Anaphylaxis (life-threatening allergic reaction)

Breathing problems and discomfort during the allergic reaction

Drowsiness and other side effects of medicines

When to Contact a Medical Professional

Call for an appointment with your provider if:

Severe symptoms of allergy occur

Treatment for allergies no longer works

Prevention

Breastfeeding can help prevent or decrease allergies when you feed babies this way only for 4 to 6 months. However, changing a mother's diet during pregnancy or while breastfeeding does not seem to help prevent allergies.

For most children, changing the diet or using special formulas does not seem to prevent allergies. If a parent, brother, sister, or other family member has a history of eczema and allergies, discuss feeding with your child's doctor.

There is also evidence that being exposed to certain allergens (such as dust mites and cat dander) in the first year of life may prevent some allergies. This is called the "hygiene hypothesis." It came from the observation that infants on farms tend to have fewer allergies than those who grow up in more sterile environments. However, older children do not seem to benefit.

Once allergies have developed, treating the allergies and carefully avoiding allergy triggers can prevent reactions in the future.