INTRODUCTION — Allergens in this topic review will be defined as molecules capable of eliciting immunoglobulin E (IgE) mediated hypersensitivity reactions. Allergen extracts are used in a variety of diagnostic and therapeutic applications, including diagnostic skin testing, provocation testing, and in vitro tests, as well as allergen-specific immunotherapy (both oral and subcutaneous). In all applications, the active ingredient is theoretically the relevant allergens from that source, although the formulation may differ among applications.
The production and standardization of allergen extracts are discussed in this topic review. The choice of specific extracts for use in clinical practice and other issues related to the use of allergen extracts are reviewed in more detail separately. (See "SCIT: Preparation of allergen extracts for therapeutic use", section on 'Types of allergen extracts' and "SCIT: Standard schedules, administration techniques, adverse reactions, and monitoring".)
COMPONENTS OF ALLERGEN EXTRACTS — Allergen extracts are complex mixtures of allergenic and nonallergenic substances, including proteins, glycoproteins, polysaccharides, lipids, nucleic acids, low-molecular-weight metabolites, salts, and pigments. Most allergens are proteins or glycoproteins, but, in certain rare circumstances, pure carbohydrates or low-molecular-weight chemicals can act as allergens. All foreign proteins are potential allergens in theory, although only a limited number of proteins are confirmed to be allergenic in humans. No structural properties have been identified that distinguish allergenic from nonallergenic proteins.
Allergen extracts are usually prepared by aqueous extraction of allergenic source materials obtained from natural sources. The composition and biologic properties may be influenced by the quality and purity of the source material, as well as their processing, extraction, and storage conditions. For batch-to-batch consistency, it is sufficient to consider the proteins as active ingredients.
Crude aqueous allergen extracts containing all of the extractable components of the source material can be used without further modification or subjected to further processing, including fractionation, physicochemical modification, and combination with other allergen extracts . Most commercially available extracts are crude extracts.
Major allergens — A limited number of allergens bind IgE antibodies in the serum of the majority of patients allergic to that allergen source. These molecules are called "major allergens." A major allergen is defined as an antigen that binds to the IgE in the serum of ≥50 percent of a clinically allergic group of patients . Other antigens, which account for <50 percent of IgE binding, are called "minor allergens" (picture 1 and figure 1 and figure 2). A list of allergens important to human disease is maintained by the World Health Organization and the International Union of Immunologic Societies (WHO-IUIS).
Proteases — Allergen extracts also contain proteases capable of degrading the desirable allergens. Although these are unwanted, it is not possible to remove them without also destroying important allergenic proteins in the process. The presence of proteases confers inherent instability to allergen extracts, which must be stored either freeze dried or stabilized by the addition of glycerol. Alternatively, chemical or physical modification can be applied. These steps are described below. (See 'Modification of extracts' below.)
The paradox of extract refinement — Allergen extracts are relatively crude mixtures of allergenic and nonallergenic molecules. This complexity mirrors that of the allergen source as it is encountered during natural exposure. The challenge to industry and to investigators is to preserve the complexity of allergens in an extract while enhancing the concentration of the individual allergens that are important to the majority of patients and, at the same time, minimizing inert or unwanted pharmacologically active components, as well as destructive protease activities.
An effective allergen extract contains both a full spectrum of the allergens relevant to human allergic disease, as well as sufficient amounts of the major allergens. There is variability among patients in their individual patterns of reactivity to the spectrum of allergens in a given source. Specifically, individuals do not respond to the same components in the allergen extract. As an example, the major allergen in cat dander (ie, Fel d 1) is the most important allergen for approximately 90 percent of cat-allergic patients, although a fraction of patients react more strongly to other allergens. In addition, most patients show significant reactivity to a large number of minor allergens in different combinations. This variability is even more pronounced for other allergen sources, such as grass pollen and house dust mite. Standardization is a process that ensures a comprehensive qualitative complexity in the allergen extract in order to optimize effectiveness in diagnosis and treatment of a range of allergic individuals. (See 'Standardization of allergen extracts' below.)
For some allergen sources, one or two major allergens account for a significant percentage of the IgE binding, although patients may also react to various minor allergens. It is not clear if treatment with one or two major allergens alone, such as has been proposed for recombinant or purified allergens, will achieve efficacy comparable with treatment with traditional allergen extracts. (See "Experimental therapies for food allergy: Immunotherapy and nonspecific therapies", section on 'Subcutaneous immunotherapy' and "Experimental therapies for food allergy: Immunotherapy and nonspecific therapies", section on 'Immunotherapy with modified proteins and adjuvants'.)
SOURCE MATERIALS FOR ALLERGEN EXTRACTS — Allergenic source materials are derived from pollens, fungi (mycelia and/or spores), animals (hair, dander, pelt, or feathers), arthropods (whole insect bodies, house dust mites, Hymenopteran venoms), and foods (fresh, with or without skin or seeds). The assurance of the identity and purity of allergen source materials requires their proper collection, identification, handling, and processing [3,4].
Pollens — Pollens are collected from more than 100 species of grasses, weeds, trees, shrubs, and cultivated agricultural plants. Pollen from properly identified plants can be harvested by several methods that may lead to variation in quality and allergen content. Contamination with plant parts should be limited to less than 1 percent, if possible .
Other materials — Purity and identity assessments of source materials derived from fungal, animal, and house dust mite source materials can be challenging. The collection and processing of the source materials must be performed or supervised by qualified personnel. The methods employed should ensure that no unintended substances, including microbial organisms or other contaminants, are introduced into the materials. Source materials should be processed when fresh or stored in a manner that prevents decomposition. The quality control tests used and their acceptance limits should be defined and justified. At a minimum, tests ensuring the identity and purity of source materials should be included.
Fungi — Fungi display a high degree of genetic variability, even among strains of the same species. In addition, culture conditions can affect the morphologic, biochemical, and allergenic characteristics of fungi .
Animals — Allergens of animal origin can be isolated from their dander, skin, saliva, serum, or urine. The most suitable source for preparing diagnostic extracts varies according to the animal. Commercial extracts are prepared using different source materials. Most extracts are based upon epithelia. However, with the exception of cat extracts, these extracts are not standardized, and some may not contain adequate concentrations of major allergens . In addition, urinary rather than epithelial proteins appear to be important in respiratory allergies and asthma caused by rodents, particularly in urban children and in laboratory workers. The relevant urinary proteins have not been purified or well-characterized for use in immunotherapy, although this is an area of active research. Despite these areas of uncertainty, case reports and small series describe patients with respiratory allergy to rodents and other animals who were treated successfully with commercially available extracts [8,9].
Insects and house dust mites — Arthropod materials commonly used in immunotherapy include house dust mite, Hymenopteran venoms, and whole body extracts of imported fire ants.
House dust mite — House dust mite source materials are derived from laboratory cultures using different growth media and harvesting methods. This leads to varying degrees of purity as determined by residual growth media, percent mite whole body, and fecal pellet content, which introduces significant variability in the quality of the source material .
Hymenopteran venoms — Pure honey bee (Apis mellifera) venom is collected using direct electrostimulation of live insects. The released venom is dried and requires minimal processing other than reconstitution and filtration. In contrast, the source materials for venom from yellow jackets (Vespula spp), hornets (Dolichovespula spp), and wasps (Polistes spp) are their venom sacs obtained by dissection. The sacs are extracted, and the venom proteins from multiple species may be blended prior to filtration and freeze drying .
Fire ant whole body extracts — Extracts derived from whole bodies of fire ants (Solenopsis invicta and Solenopsis richteri) contain sufficient venom to make a clinically useful product for diagnosis and treatment. The insects are collected from nests, freeze dried, and stored frozen until extracted. Purified venom preparations have been produced but were deemed not to be commercially viable .
Food extracts — Food source materials are obtained from vendors that supply food suitable for consumption. Proper identification requires minimal or no processing of fruits, vegetables, and meats (especially fish) that rely on visual appearance for determining their identity and purity .
Accounting for natural variability — Source materials collected in nature are subject to natural variability, which can be considerable. This problem can be circumvented by analysis and mixing. Source materials are analyzed to verify antigen and allergen profiles, and differences in composition can then be minimized by mixing source materials from different suppliers, different harvests, different years, and/or different geographic regions. For example, dog extracts can be produced by mixing hair and dander from multiple dog breeds. Subsequent standardization ensures that the variation in the final product is within predefined limits. (See 'Standardization of allergen extracts' below.)
MANUFACTURE OF ALLERGEN EXTRACTS — Source materials are processed using a variety of methods. The goal of this processing is to recover as much of the allergens into solution as possible in roughly the same ratio (major to minor allergens) as they occur in nature while minimizing the quantity of undesirable components in the resulting extract.
Extraction and quality control of allergen extracts — Source materials are typically defatted to remove fats, oils, and waxes prior to extraction. This increases the efficiency of the extraction process and removes pollen oleoresins that can induce type IV contact dermatitis reactions. Milling, grinding, and homogenizing either prior to or during extraction also increases the recovery of allergens from the source material. The extraction ratio, temperature, and time can be varied to achieve the optimal yield and efficiency.
The soluble portion of the extract is recovered by centrifugation and filtration followed by additional processing, as required. Removal of low-molecular-weight material (<5000 Da), such as pigments, vasoactive amines, and other nonallergenic components, is achieved by dialysis, ultrafiltration, or by proprietary processes (eg, "depigmentation"). Extraneous nonallergenic components can interfere with chemical modification steps, and, thus, their removal is critical in the manufacture of allergoids.
Depending on the end use of the extract, the allergenic components may be concentrated using a variety of processes. Each of the processes needs to be validated to ensure that the purity, identity, and quality of the extract was not adversely affected. The in-process controls, including the acceptance criteria, should be defined and justified.
The characterization and quality control of allergen extracts should be performed based on their intended use. For example, specific regulations apply to extracts that are intended for parenteral administration. Sterility and safety testing for each batch must be performed prior to release for clinical use. For nonsterile oral formulations, the absence of objectionable organisms must be established. If the relevant allergens have been defined for an allergenic extract, validated assays should be developed to ensure their presence at appropriate concentrations for either diagnostic or therapeutic use [13,14].
Recombinant allergens — Recombinant allergens are of interest as a potentially safer form of immunotherapy, and, when used diagnostically, they could allow for greater specificity. (See "Overview of in vitro allergy tests", section on 'Component-resolved diagnostics'.)
With this technology, it may become possible to administer immunogenic or tolerogenic peptides of an allergen without exposing the patient to the entire allergen with the accompanying risk of an anaphylactic reaction. Hypoallergenic variants produced by site-directed mutagenesis could also potentially provide safer and more specific immunotherapy. Allergens produced by recombinant deoxyribonucleic acid (DNA) technology may not vary according to the quality of the natural source materials but depend on the cell systems, fermentation processes, and purification procedures employed for their manufacture. The in-process controls for these products are as critical as for naturally derived extracts. Recombinant allergens are discussed briefly elsewhere. (See "Toll-like receptors: Roles in disease and therapy", section on 'Allergen immunotherapy'.)
Formulations of allergen extracts — In most cases, allergen extracts are available as aqueous, glycerinated, or lyophilized formulations:
●Aqueous extracts have been the most common prescribed dose form for immunotherapy. They are usually a buffered saline solution containing a preservative. Because aqueous extracts can be unstable, stabilizers such as human serum albumin (0.03%) or glycerin are added to extend the shelf-life.
●Glycerinated extracts are aqueous extracts to which glycerin up to 50% volume by volume (v/v) has been added to stabilize the proteins. Glycerinated extracts are becoming more widely used because of their superior shelf-life and reduced formation of precipitates, which is a common problem with aqueous extracts. Also, glycerinated extracts are preferred for use in diagnostic prick tests and sublingual immunotherapy because they are more viscous. The disadvantage of this increased viscosity is injection-site pain when these extracts are injected. (See "SCIT: Standard schedules, administration techniques, adverse reactions, and monitoring", section on 'Local reactions'.)
●Lyophilized extracts are highly stable while the product remains in the freeze-dried state, and lyophilization is used to extend the shelf life of extracts. However, their increased cost for manufacture and the extra handling required for reconstitution has limited their general use in clinical practice. Hymenopteran venoms are the only lyophilized extracts that are commercially available.
Modification of extracts — Allergen extracts may be modified by chemical or physical processes or both to enhance the efficacy-safety ratio, meaning that higher doses can be administered without compromising safety.
Chemical modification (allergoids) — Allergen extracts for use in immunotherapy may be chemically modified using formaldehyde or glutaraldehyde . The chemical reaction results in intra- and intermolecular crosslinking, which yields high-molecular-weight complexes referred to as allergoids. Allergoids are not available in the United States but are licensed and commonly used in Europe. Chemical modification enhances the stability of the allergen extract. Although intended to reduce IgE binding while preserving immunogenicity, chemical modification, in practice, does not seem to increase safety . The likely explanation is that the chemical modification not only reduces allergenicity but also immunogenicity, necessitating the use of higher doses.
Other chemical modifications, such as coupling to biodegradable polymers, denaturation, fragmentation, or synthetic peptides representing individual allergens, have shown varying degrees of efficacy and safety in human immunotherapy trials [17-19].
Coupling with inorganic gels — Use of allergen extracts or allergoids coupled to inorganic gels, such as aluminum hydroxide, increases the safety of immunotherapy through dual effects of the carrier. Coupling creates a depot effect, resulting in slow release of allergens to the tissue, and the gel provides an adjuvant effect, resulting in a more pronounced immune response to the vaccine [20-22]. Physical modification enhances the stability of the allergen extract. In Europe, most products for subcutaneous injection immunotherapy are absorbed to aluminum hydroxide (ie, "alum precipitated"). There is only one line of alum-precipitated extracts approved in the United States (from ALK), and only pollen extracts are available in this line.
Coupling is performed simply by mixing the intermediate product with the gel for a few minutes at room temperature. Coupling conditions need to be empirically determined for each extract as the binding capacity of individual proteins varies with buffer composition, ionic strength, pH, and additives . Residual unbound protein must be verified to be below predefined thresholds.
Over the past decades, European manufacturers have commercialized allergoids that are linked to depot adjuvants, such as aluminum hydroxide, calcium phosphate, or L-tyrosine. A novel allergy vaccine, Pollinex Quattro, incorporates L-tyrosine-absorbed allergoids derived from grass or tree pollen allergens with the specific Toll-like receptor 4 (TLR-4) agonist and adjuvant monophosphoryl lipid A (MPL). This combination has enabled the safe and efficacious use of an ultra-short course immunotherapy regimen with only four injections . Similar combination approaches utilizing synthetic peptides, recombinant allergens, and specific adjuvants could also potentially lead to improved forms of allergy vaccines by improving patient compliance, in addition to reducing adverse reactions.
Molecular modification — Approaches to modification based on molecular and structural biology have shown promise, although they are largely limited to research [25,26].
Special considerations for different routes of administration
●Tablets and solid dose forms are used in sublingual oral immunotherapy and in double-blind, placebo-controlled food challenges. These preparations contain carriers and/or excipients to maintain texture, mask taste/odor, or to improve stability. (See "Sublingual immunotherapy for allergic rhinitis and conjunctivitis: SLIT-tablets" and "Oral food challenges for diagnosis and management of food allergies".)
●Epicutaneous patches are being evaluated for the treatment of both respiratory and food allergies. The allergen preparations incorporated in the patches must be optimized to be compatible with the specific formulation or technology used for their manufacture. (See "Experimental therapies for food allergy: Immunotherapy and nonspecific therapies", section on 'Epicutaneous immunotherapy'.)
●Multidose parenteral products must contain bacteriostatic and fungistatic compounds to prevent growth of bacteria and fungi. Phenol (0.2 to 0.5%) or glycerin (50%) is used in this capacity.
●Glycerin is added to extracts intended for skin prick or puncture testing to increase the surface tension to allow drops to stay on the skin and not drain away. Glycerin is also an effective stabilizer of allergenic activity. (See 'Formulations of allergen extracts' above.)
●Human serum albumin (0.03%) is added to highly diluted extracts intended for intradermal skin testing to reduce adsorption of allergenic proteins to the vial surface and to protect the allergenic proteins from phenol denaturation.
STANDARDIZATION OF ALLERGEN EXTRACTS — Standardized allergen products have documented composition and potency.
In clinical practice, the use of standardized extracts has two main advantages compared with nonstandardized extracts:
●The clinician can be relatively certain that a known amount of the important allergen(s) is being delivered to the patient.
●The risk of inducing a systemic reaction when changing between vials or manufacturers is lower because there is predictable lot-to-lot potency.
With respect to the manufacturing process, standardization eliminates the need to perform in vivo testing of each batch to ensure consistent biologic activity. Once the biochemical and allergenic properties of the reference standard are highly characterized and a specific unitage assigned, subsequent in vitro comparative testing of extracts produced from the same source can be used to assign units based on the relative potency with respect to the reference [27,28].
The process of standardization has several goals:
●To assure batch-to-batch consistency in composition, biochemical properties, and allergenic potency and to set limits for variability.
●To improve safety through requirements and dose units consistent with effective diagnostic and treatment practices.
●To define the stability of manufacturers' stock concentrates and patient-specific therapeutic products.
In the United States, standardized extracts have a unit of potency assigned, and each lot is tested for conformance to a single United States standard:
●Hymenopteran venoms are standardized on the basis of hyaluronidase and phospholipase activity.
●Short ragweed pollen and cat hair/pelt extracts are standardized on the basis of major allergen (Amb a 1 and Fel d 1, respectively) content.
●The potency of house dust mite and grass pollen extracts are standardized by enzyme-linked immunosorbent assay (ELISA) inhibition relative to a corresponding reference standard extract.
In Europe, standardized extracts have a unit of potency assigned with respect to a corresponding in-house reference standard extract that is unique to each manufacturer. An advantage of using "in-house" reference standards instead of a single, national potency standard is that it is more efficient to implement and allows for a diversity of products. On the other hand, the use of a single, national potency standard may reduce the risk of adverse events when switching from one manufacturer's product to another.
The World Health Organization and the International Union of Immunologic Societies (WHO-IUIS) Allergen Standardization Subcommittee has taken an initiative (the CREATE Project) to develop certified reference materials based on purified natural and recombinant allergens . ELISA for allergen measurement is being evaluated and validated. Other methods, such as mass spectrometry, could also be considered for this purpose . Providing international allergen references and reference assays may allow for a common system of units in absolute mass units of major allergen. However, a system based on labeling with major allergen content alone does not take into account the heterogeneity of individual patients' responses with variable reactivity to minor allergens and, thus, does not obviate the need for overall potency determinations.
UNITS OF MEASURE — Several units of measure are in use around the world.
Units that do not reflect potency — The majority of the available allergen extracts are nonstandardized and have no standard of potency. They are labeled using a weight by volume (w/v) or protein nitrogen unit (PNU) designation, which do not necessarily reflect their allergenic activity:
●Protein nitrogen units – PNU is a measure of total protein content and does not distinguish between allergenic and nonallergenic proteins.
●Weight by volume ratio – W/v is the ratio of the weight (in grams) of the source material to the volume (in mL) of extraction fluid used to produce the extract. As an example, a 1:100 extract of oak pollen is produced by adding 1 gram of oak pollen to 100 mL of extraction fluid.
These units are relatively uninformative because two extracts of the same allergen source labeled as the same strength in PNU or w/v may not be of equivalent potency if produced by different manufacturers. Thus, these units of measure are gradually being replaced by units that provide information about potency. The clinician should understand that nonstandardized extracts from different manufacturers should not be considered as interchangeable, and care should be taken when switching from one supplier to another. This is discussed elsewhere. (See "SCIT: Standard schedules, administration techniques, adverse reactions, and monitoring", section on 'Change in supplier of allergen extracts'.)
Units that reflect potency — Determining the biologic potency of an allergen extract is complicated due to the intrinsic variability among patients, as well as among naturally occurring plant and animal products, combined with the fact that different allergens are important to individual patients. Thus, potency is ultimately determined based upon tests performed on a group of patients allergic to the substance in question.
Bioequivalent allergy unit — In the United States, the US Food and Drug Administration (FDA) and the Center for Biologics Evaluation and Research (CBER) endorse the bioequivalent allergy unit (BAU). Standardized extracts are most commonly labeled in BAU.
The method for assigning BAU is named the ID50EAL method (ie, intradermal dilution for 50 mm sum of erythema diameters determines bioequivalent allergy units) . This method involves intradermal skin tests with a series of threefold dilutions of a reference extract in subjects maximally reactive to the respective reference concentrates. The dilution that induces an area of erythema with the sum of the longest diameter and midpoint (orthogonal) diameter equaling 50 mm is the D50. The result is used to calculate the potency based on a D50 of 14, designated as 100,000 BAU/mL.
Biologic unit — In Europe, the potency unit is based on the dose of allergen extract, resulting in a wheal comparable in size with the wheal produced by a given concentration of histamine in a group of patients allergic to the substance in question. This unit was originally called histamine equivalent potency (HEP). However, in the Nordic guidelines, the unit is termed the biologic unit (BU) . However, the BU is not used in the European market, as each manufacturer uses company-specific units based on in-house reference preparations. This means that, in Europe, the potency of allergen extracts from different manufacturers cannot be compared, as they have a different composition. Instead, the clinical documentation for each product should be compared.
CHOOSING EXTRACTS FOR USE IN PRACTICE — Standardized extracts should be used when available. Other considerations in choosing extracts for use in immunotherapy are discussed separately. (See "SCIT: Preparation of allergen extracts for therapeutic use", section on 'Types of allergen extracts'.)
ALLERGEN EXTRACT PRODUCTION AROUND THE WORLD — As allergen immunotherapy becomes more widely practiced around the world, the need for high-quality, standardized allergenic extracts has been increasing. Those products manufactured and licensed in the United States and within the European Union are in demand around the world, especially in resource-limited countries. Bulk, concentrated products are imported through medical product distributors or clinicians and formulated into patient-specific immunotherapy prescriptions. Depending on the geographic locations, important pollen species may not be available from United States or European manufacturers. For example, in subtropical and tropical regions of the world, medical centers and university laboratories with access to the relevant source materials, facilities, and technical expertise may manufacturer extracts specific to those areas. The basic procedures employed are essentially the same as those described in this topic. However, the regulatory and standardization requirements vary significantly among different countries, which make comparisons and relative quality assessments extremely difficult.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Allergen immunotherapy for the treatment of respiratory allergy".)
●Components of allergen extracts – Allergen extracts are complex mixtures of allergenic and nonallergenic proteins, glycoproteins, polysaccharides, proteases, and low-molecular-weight substances. They are usually prepared by aqueous extraction of materials obtained from natural sources. The challenge of manufacture is to preserve the complexity of the allergen repertoire, enhance the concentration of the individual allergens that are important to the majority of patients, and, at the same time, minimize inert or unwanted components. (See 'Components of allergen extracts' above.)
●Types of extracts – Allergenic source materials include pollens, fungi (mycelia and/or spores), animal materials (hair, dander, pelt, or feathers), arthropods (whole insect bodies, house dust mites, Hymenopteran venoms), and foods (fresh, with or without skin or seeds). The collection and processing of the source materials must be performed by qualified personnel to ensure that no unintended substances, including microbial organisms or other contaminants, are introduced. (See 'Source materials for allergen extracts' above.)
●Accounting for variation in source materials – Source materials collected in nature are subject to considerable variation. This problem can be circumvented by analysis and mixing. Differences in composition can be minimized by combining source materials from different suppliers, different harvests, different years, and/or different geographic regions. (See 'Accounting for natural variability' above.)
●Manufacturing – Source materials are processed using a variety of methods. The goal of this processing is to recover as much of the allergens into solution as possible in roughly the same ratio (major to minor allergens) as they occur in nature while minimizing the quantity of undesirable components in the resulting extract. (See 'Manufacture of allergen extracts' above.)
●Formulations – Most allergen extracts are available as aqueous, glycerinated, or lyophilized formulations. Aqueous extracts are the most commonly used for immunotherapy. They typically contain a preservative (eg, phenol) and a stabilizer (eg, human serum albumin or glycerin). Glycerinated extracts are aqueous extracts to which up to 50% glycerin has been added to prolong shelf life and reduce formation of precipitates, although high concentrations of glycerin can cause injection-site pain. Lyophilized extracts are highly stable while the product remains in the freeze-dried state but require extra handling to reconstitute and must be used promptly afterwards. (See 'Formulations of allergen extracts' above.)
●Standardization – Standardized allergen products have documented composition and potency and are preferred for clinical use when available because the lot-to-lot potency is more predictable and the safety is improved as compared with nonstandardized extracts. However, most of the extracts in use are not standardized. (See 'Standardization of allergen extracts' above.)
●Units of measure – Several different units of measure are in use around the world. Nonstandardized extracts are labeled using a weight by volume (w/v) or protein nitrogen unit (PNU) designation. These are units that do not necessarily reflect the allergenic activity of the extract. Standardized allergen extracts are labeled either in bioequivalent allergy units (BAU; United States) or in company-specific units (Europe). (See 'Units of measure' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Jørgen Nedergaard Larsen, PhD and Henning Løwenstein, PhD, DSc, who contributed to earlier versions of this topic review.
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