What is ige allergy

What is an allergy blood test?

Allergies are a common and chronic condition that involves the body’s immune system. Normally, your immune system works to fight off viruses, bacteria, and other infectious agents. When you own an allergy, your immune system treats a harmless substance, love dust or pollen, as a threat. To fight this perceived threat, your immune system makes antibodies called immunoglobulin E (IgE).

Substances that cause an allergic reaction are called allergens.

Besides dust and pollen, other common allergens include animal dander, foods, including nuts and shellfish, and certain medicines, such as penicillin. Allergy symptoms can range from sneezing and a stuffy nose to a life-threatening complication called anaphylactic shock. Allergy blood tests measure the quantity of IgE antibodies in the blood. A little quantity of IgE antibodies is normal. A larger quantity of IgE may mean you own an allergy.

Other names: IgE allergy test, Quantitative IgE, Immunoglobulin E, Entire IgE, Specific IgE

Allergen Standardization and Characterization

Posted: September
Updated: January,

Josefina Zakzuk, MD, PhD
Institute for Immunological Research, University of Cartagena
Jonathan Kilimajer, MD
Medical Department, Inmunotek SL, Spain
Enrique Fernández-Caldas, PhD
Scientific Director, Inmunotek SK, Madrid, Spain
Clinical Professor of Medicine,
University of South Florida College of Medicine, Tampa, Florida
Richard F.

Lockey, MD
Professor of Medicine,
University of South Florida, College of Medicine, Tampa, Florida

Key words: allergens, allergen immunotherapy, vaccines, standardization, recombinant allergens.


There is a worldwide increase in atopic diseases, which include allergic rhinoconjunctivitis, allergic asthma, atopic dermatitis and food allergies[1],[2]. Although the reasons for this increase are unclear, exposure to mite allergens and diesel exhaust particles is recognized as an significant environmental risk factor in genetically predisposed individuals[3].

The diagnosis of allergic disease requires a detailed history, physical examination, and allergy testing, i.e., skin testing or in vitro determination of allergen-specific immunoglobulin E (IgE). Skin testing is performed by applying an allergen extract to the skin and then scratch or pricking it with an appropriate needle-like instrument. In sensitized individuals, it results in the formation of a raised wheal surrounded by an erythematous flair within 15 to 20 minutes, indicating a positive test reaction. In vitro specific IgE also supports the clinical diagnosis and helps to guide the allergist in the management of allergic diseases.

Once an individual is sensitized, symptomatic and long-term strategies, such as environmental control and immunomodulatory treatments using specific allergen immunotherapy (SIT) frolic an significant role in treatment.

SIT is the practice of istering gradually increasing doses of allergen vaccines to reduce allergic symptoms and the need for medications. It is currently classified as therapeutic vaccines with scientific support of its effectiveness to prevent and relieve allergic symptoms[4]. SIT is the only known treatment that affects the natural course of allergic diseases, especially when introduced early in life. This biological response modifier is capable of influencing allergen-driven immunological responses and restoring, to a certain degree, the Th1/Th2 balance in allergic subjects. B and T cells, blocking antibodies, IL and other cytokines frolic an significant role in the response to SIT[5].

Accuracy of SIT depend on the availability of well-characterized allergen vaccines. So too does effective skin tests and in vitro determinations; allergen standardization and characterization are paramount to achieve these goals.

Allergen-specific immunotherapy was first described by Noon in [6]. From these early days, numerous attemps own been undertaken to establish a dependable, common method of allergen standardization[7]. Standardization of allergen vaccines/extracts used for therapy and diagnosis is necessary because their qualities may vary, depending on production and control methods of the manufactured batches[8].

Does FPIES Require Epinephrine?

Not generally, because epinephrine reverses IgE-mediated symptoms, and FPIES is not IgE-mediated.

Based on the patient’s history, some doctors might prescribe epinephrine to reverse specific symptoms of shock (e.g., low blood pressure). However, this is only prescribed in specific cases.

Is FPIES A Lifelong Condition?

Typically, no. Numerous children outgrow FPIES by about age three. Note, however, that the time varies per individual and the offending food, so statistics are a guide, but not an absolute.

In one study, % of children with FPIES reactions to barley had outgrown and were tolerating barley by age three. However, only 40% of those with FPIES to rice, and 60% to dairy tolerated it by the same age.

What are Some Common FPIES Triggers?

The most common FPIES triggers are traditional first foods, such as dairy and soy. Other common triggers are rice, oat, barley, green beans, peas, sweet potatoes, squash, chicken and turkey. A reaction to one common food does not mean that every of the common foods will be an issue, but patients are often advised to proceed with caution with those foods.

Note that while the above foods are the most prevalent, they are not exclusive triggers. Any food has the potential to trigger an FPIES reaction. Even trace amounts can cause a reaction.

Conclusions and Current challenges

Allergen standardization strategies should be uniform throughout the world. The diverse units, which vary among manufacturers as well as global regions, are confusing and unreliable with the potential to underestimate or overestimate the potency of allergen extracts.

The variations can be attributed to the variability of the raw materials used, the production methods and the lack of consistent and dependable quantification of allergy content. Major allergen measurements are essential to overcome these problems. Some recombinant allergens are found to be suitable as certified reference materials and are currently released for allergen standardization. But, results from the CREATE and the BSP Project protest that the process of obtaining recombinants and immunoassays which filfull requirements for standardization is slow.

The limitations of recombinant allergens as CRM due to incorrect folding, aggregation, poor solubility and insufficient stability. However, evidence gathered in studies identifies the complexity of this approach. The European Medicines Agency (EMEA) recommends proving that each allergen extract contains the relevant allergens by antibody-based techniques or mass spectrometry. New techniques, such as nuclear magnetic resonance and little angle X ray scattering, are commonly applied to characterize allergenic molecules in the laboratory. They are slowly affecting the methods by which allergen extracts are standardized. This would be an significant step forward towards a comprehensive characterization of allergen products.

Future enhancements of SIT, using RAs, also require allergen standardization, which in turn, requires development of standardized methods to measure allergen content, homogeneity, folding, aggregation, solubility and stability of recombinant products. Allergen standardization will advance rapidly in the future, improving the effectiveness and safety of allergen vaccines. Allergen immunotherapy will remain an effective and safe treatment for allergic respiratory diseases.


[1]. Deckers IA,McLean S,Linssen S,Mommers M,van Schayck CP,Sheikh A.

Investigating international time trends in the incidence and prevalence of atopic eczema A systematic review of epidemiological studies. PLoS One.;7(7):e

[3]. Zhang X, Chen X, Weirauch MT, Zhang X, Burleson JD, Brandt EB, Ji H. Diesel exhaust and home dust mite allergen lead to common changes in the airway methylome and hydroxymethylome. Environ Epigenet, 4(3): p. dvy

[4]. Dhami S,Kakourou A,Asamoah F,Agache I,Lau S. et al. Allergen immunotherapy for allergic asthma: A systematic review and meta-analysis. Allergy. Dec;72(12)

[6]. Noon L. Prophylactic inoculation against hayfever. Lancet e3.

[7]. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases.

A WHO position paper. J Allergy Clin Immunol ;

[8]. Takai T, Okamoto Y, Okubo K, Nagata M, Sakaguchi M, Fukutomi Y et al. Japanese Society of Allergology task force report on standardization of home dust mite allergen vaccines — Secondary publication. Allergology International 64 ()

[9]. Pollens for allergen products. European Pharmacopoeia ; 01/;

[10]. Codina R, Lockey RF. Pollen used to produce allergen extracts. Ann Allergy Asthma Immunol. Feb;(2)

[11]. Mites for allergen products. Acari ad producta allergenica. European Pharmacopoeia ; 01/;

[12]. Fernández-Caldas E.

Towards a more finish standardization of mite allergen extracts. Int Arch Allergy Immunol. ;(1)

[13]. Moulds for allergen products. European Pharmacopoeia ; 01/;

[14]. Esch RE. Manufacturing and standardizing fungal allergen products. J Allergy Clin Immunol. Feb;(2)

[15]. Esch RE, Codina R. Fungal raw materials used to produce allergen extracts. Ann Allergy Asthma Immunol. Apr;(4)

[17]. Animal epithelia and outgrowths for allergen products. European Pharmacopoeia ; 01/;

[18]. Guideline for Allergen Products: Production and Quality Issues (EMEA/CHMP/BWP//)”


European Directorate for the Quality of Medicines (EDQM). Monograph: Allergen Products – Producta Allergenica 01/ In: Council of Europe (ed.) European Pharmacopoeia, Strasbourg, ed. 6, , supplement 6: , as implemented of

[20]. Slater, J. E. Standardized allergen vaccines in the United States. Clin. Allergy Immunol. 21, ().

[21]. Committee for Medicinal Products for Human Use. Guideline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases. European Medicines Agency ().


What is ige allergy

Zimmer J, Vieths S, Kaul S. Standardization and Regulation of Allergen Products in the European Union. Curr Allergy Asthma Rep. Mar;16(3)

[23]. Committee for Medicinal Products for Human Use. Guideline on allergen products: production and quality issues. European Medicines Agency ()

[25]. Codina R, Crenshaw RC, Lockey RF. Considerations About Pollen Used for the Production of Allergen Extracts.

What is ige allergy

J Allergy Clin Immunol Pract. Sep-Oct;3(5)

[27]. Yasueda H, Okuda M, Yoshida H, Ito K, Baba M, Iikura Y, et al. A basic policy for allergen standardization in our country and standardization of Japanese cedar (Cryptomeria japonica) pollen extracts). Allergol Int ;

[29]. Yu W, Freeland DMH, Nadeau KC. Food allergy: immune mechanisms, diagnosis and Rev Immunol. Dec;16(12)

[30]. Hill DA, Grundmeier RW, Ram G, Spergel JM. The epidemiologic characteristics of healthcare provider-diagnosed eczema, asthma, allergic rhinitis, and food allergy in children: a retrospective cohort study.

BMC Pediatr. ;

[31]. Jakob T, Forstenlechner P, Matricardi P, Kleine-Tebbe J. Molecular allergy diagnostics using multiplex assays: methodological and practical considerations for use in research and clinical routine: part 21 of the series molecular allergology. Allergo J Int.;

[35]. Chan TF,Ji KM,Yim AK,Liu XY,Zhou JW, et al. The draft genome, transcriptome, and microbiome of Dermatophagoides farinae reveal a wide spectrum of dust mite allergens. J Allergy Clin Immunol. Feb;(2)

[36]. Randall TA, Mullikin JC, Mueller GA. The draft genome assembly of Dermatophagoides pteronyssinus supports identification of novel allergen isoforms in Dermatophagoides species.

Int. Arch. Allergy Immunol. (3): –

[37]. Weghofer M, Grote M, Casset A, Kneidinger M, Resch Y, Kopec J, et al. Identification of Der p 23, a peritrophin-like protein, as a new major Dermatophagoides pteronyssinus allergen associated with the peritrophic matrix of mite fecal pellets J Immunol. Apr 1;(7)


What is ige allergy

Posa D, Perna S, Resch Y, Lupinek C, Panetta V, Hofmaier S et al. Evolution and predictive worth of IgE responses toward a comprehensive panel of home dust mite allergens during the first 2 decades of life. J Allergy Clin Immunol. Feb;(2)

[39]. Banerjee S, Weber M, Blatt K, Swoboda I, Focke-Tejkl M, Valent P, Valenta R, Vrtala S. Conversion of Der p 23, a new major home dust mite allergen, into a hypoallergenic vaccine. J Immunol. May 15;(10)

[40]. Chen KW, Zieglmayer P, Zieglmayer R, Lemell P, Horak F, Bunu ion of home dust mite allergic patients by molecular diagnosis may enhance success of specific immunotherapyJ Allergy Clin Immunol.

Nov pii: S(18) doi: / [Epub ahead of print].

[41]. Douladiris N, Garib V, Focke-Tejkl M, Valenta R, Papadopoulos NG, Linhart B. Detection of genuine grass pollen sensitization in children by skin testing with a recombinant grass pollen hybrid. Pediatr Allergy Immunol. Oct doi: /pai [Epub ahead of print]

[45]. Park JW,Kim KS,Jin HS,Kim CW,Kang DB,et al. Der p 2 isoallergens own diverse allergenicity, and quantification with 2-site ELISA using monoclonal antibodies is influenced by the isoallergens. Clin Exp Allergy. Jul;32(7)

[46]. Meyer W, Narkus A, Salapatek AM, Häfner D. Double‐blind, placebo‐controlled, dose‐ranging study of new recombinant hypoallergenic Bet v 1 in an environmental exposure chamber.

Allergy Jun, 68 (6): –

[50]. Himly M,Nony E,Chabre H,Van Overtvelt L,Neubauer A,et al. Standardization of allergen products: 1. Detailed characterization of GMP-produced recombinant Bet v as biological reference preparation. Allergy. Jul;64(7)

[52]. Himly M,Nandy A,Kahlert H,Thilker M,Steiner M, et al. Standardization of allergen products: 2. Detailed characterization of GMP-produced recombinant Phl p as European Pharmacopoeia reference standard. Allergy. Apr;71(4)

[53]. Chapman MD, Briza P. Molecular approaches to allergen standardization.

Curr Allergy Asthma Rep. Oct;12(5)

[54]. Riechelmann H, Schmutzhard J, Van Der Werf J F, Distler A, Kleinjans H. Efficacy and safety of a glutaraldehyde-modified home dust mite extract in allergic rhinitis. Am J Rhinol Allergy. Sep-Oct;24(5):e


[56]. García-Robaina J, C., Sánchez I, de la Torre F, Fernández-Caldas E, Casanovas M.

What is ige allergy

Successful management of mite-allergic asthma with modified extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae in a double-blind, placebo-controlled study. J Allergy Clin Immunol. Nov;(5)

[59]. Zimmer J, Bonertz A, Vieths S. Quality requirements for allergen extracts and allergoids for allergen immunotherapy. Allergol Immunopathol (Madr). Dec;45 Suppl


title = «Characterization of the allergen(s) in latex protein extracts»,

abstract = «Background: Immediate hypersensitivity to latex, induced by natural latex proteins remaining on the finished products, may lead to severe anaphylactic reactions.

Methods: We investigated the distribution of latex proteins by molecular weight and identified the specific allergenic molecules. Proteins extracted from various latex products were compared with those extracted from raw latex sap, both ammoniated and nonammoniated. Results: Variations in the levels of extractable protein, as well as in the number of molecules and the molecular weight distribution, were observed especially among finished latex products. To identify allergenic (i.e., IgE-binding) molecules, we performed immunoblots with the sera from latex-sensitive persons. The results indicated that antigenic molecule profiles differed among the products and also between the finished products and the raw material.

In addition, specificities of the anti-latex IgE antibodies varied among the sensitized persons. Conclusions: It appeared that persons with the same history of sensitization had similar patterns of antigenic specificities. If the history of exposure, as well as genetic predisposition and medical history of the patient, plays a significant role in the specific IgE response, it may be hard to select a {«}standard{«} antigen and a {«}standard{«} antiserum for the evaluation of the latex sensitivity and allergenicity.

What is ige allergy


keywords = «allergen, anaphylaxis, gel electrophoresis, IgE antibodies, immunoblotting, latex, type I allergic reaction»,

author = «Tomazic, {Vesna J.} and Withrow, {Thomas J.} and Hamilton, {Robert G}»,

year = «»,

doi = «/S(95)»,

language = «English (US)»,

volume = «96»,

pages = «»,

journal = «Journal of Allergy and Clinical Immunology»,

issn = «»,

publisher = «Mosby Inc.»,

number = «5»,


Frequently Asked Questions about Food Protein-Induced Enterocolitis Syndrome (FPIES)

Other techniques which could be used for standardization

Beyond the use of monoclonal antibodies, other physico-chemical approaches own been explored for allergen standardization and offer new possibilities.

Evaluation of mass spectrometry (MS) has been performed to determine its capacity to characterize the composition of allergen extracts. One advantage offered by the use of MS includes the measurement of several diverse allergenic components (allergens and isoforms) simultaneously rather than measuring individual allergens. This is advantageous while working with allergen preparations that contain a wide group of IgE binding proteins, such as mite extracts. Additionally, MS-based methods are available to discriminate between allergen isoforms, which is hard to achieve using immunologic based methods.

This method could also be useful for the standardization of allergoids, since measuring major allergens is not possible in these preparations due to their chemical modification with aldehyde. One disadvantage of MS is that even though it may protest the presence of allergen peptides inside the complicated mixture, it is not a genuine quantitative method. Another issue is the high costs of instruments and the requirement highly trained personnel.

How is FPIES Diagnosed?

FPIES is hard to diagnose, unless the reaction has happened more than once, as it is diagnosed by symptom presentation.

Typically, foods that trigger FPIES reactions are negative with standard skin and blood allergy tests (SPT, RAST) because they glance for IgE-mediated responses. However, as stated before, FPIES is not IgE-mediated.

Atopy patch testing (APT) is being studied for its effectiveness in diagnosing FPIES, as well as predicting if the problem food is no longer a trigger. Thus, the outcome of APT may determine if the kid is a potential candidate for an oral food challenge (OFC).

APT involves placing the trigger food in a metal cap, which is left on the skin for 48 hours. The skin is then watched for symptoms in the following days after removal. Please consult your child’s doctor to discuss if APT is indicated in your situation.

Characterization of allergoids

"Allergoid" is a term used to describe natural allergen products that own been modified with aldehydes (formaldehyde and glutaraldehyde) to decrease their allergenicity and potentially increase their safety. Allergoids are commercially available in Europe from the s and own demonstrated successful clinical results[54].

Allergoids represent the fasted growing sector of the allergen immunotherapy market in Germany and Spain[55].

Numerous double-blind placebo-controlled studies using allergoids (modified allergens) own demonstrated efficacy[56].

Chemical modifications of allergenic extracts aims to reduce its allergenicity in order to increase safety, albeit preserving its immunogeniticy. In this sense, determination of entire allergenic activity and measurement of allergen content is not applicable for standardization. Some quality control procedures are also unsuitable; for example, SDS-PAGE visualization of allergoids is completely diverse to the natural extract before polimerization due to coupling to high molecular weight compounds. As a consequence, specific requirements for quality control of these products are requested in the regulatory framework.

According to the Guideline on Allergen Products: Production and Quality Issues, retention of immunogenicity needed to be demonstrated in vivo by means of animal models[57]. However, high heterogeneity has been observed in these results. Furthermore, the evaluation of every batch of allergoid produced is conflictive with ethical principles in regard to animal testing. This gap on allergoid characterization may be overcome by the use of in vitro IgG inhibition ELISA, which is now mandatory for registration purposes in Europe.

Other methods, such as peptide content analysis of allergen sequences by mass spectrometry, own been applied for allergoid characterization. Capillary liquid chromatography-tandem mass spectrometry based peptide mapping can be used to confirm the presence of allergens in allergoids of Betula alba. Peptide sequencing could even discriminate at the level of isoforms[58]. Size-exclusion chromatography can also be used to show consistency of the modification process, being applicable for batch release[59].

When Do FPIES Reactions Occur?

FPIES reactions often show up in the first weeks or months of life, or at an older age for the exclusively breastfed kid.

Reactions generally happen upon introducing first solid foods, such as baby cereals or formulas, which are typically made with dairy or soy. (Infant formulas are considered solids for FPIES purposes.) While a kid may own allergies and intolerances to food proteins they are exposed to through breastmilk, FPIES reactions generally don’t happen from breastmilk, regardless of the mother’s diet. An FPIES reaction typically takes put when the kid has directly ingested the trigger food(s).

What Does IgE vs Cell Mediated Mean?

IgE stands for Immunoglobulin E. It is a type of antibody, formed to protect the body from infection, that functions in allergic reactions.

IgE-mediated reactions are considered immediate hypersensitivity immune system reactions, while cell mediated reactions are considered delayed hypersensitivity. Antibodies are not involved in cell mediated reactions. For the purpose of understanding FPIES, you can disregard every you know about IgE-mediated reactions.

What is a Typical FPIES Reaction?

As with every things, each kid is diverse, and the range, severity and duration of symptoms may vary from reaction to reaction. Unlike traditional IgE-mediated allergies, FPIES reactions do not manifest with itching, hives, swelling, coughing or wheezing, etc.

Symptoms typically only involve the gastrointestinal system, and other body organs are not involved. FPIES reactions almost always start with delayed onset vomiting (usually two hours after ingestion, sometimes as tardy as eight hours after). Symptoms can range from mild (an increase in reflux and several days of runny stools) to life threatening (shock). In severe cases, after repeatedly vomiting, children often start vomiting bile. Commonly, diarrhea follows and can final up to several days.

In the worst reactions (about 20% of the time), the kid has such severe vomiting and diarrhea that s/he rapidly becomes seriously dehydrated and may go into shock.

What is Shock and What are the Symptoms?

Shock is a life-threatening condition. Shock may develop as the result of sudden illness, injury, or bleeding. When the body cannot get enough blood to the vital organs, it goes into shock.

Signs of shock include:
Weakness, dizziness, and fainting.
Cool, pale, clammy skin.
Weak, quick pulse.
Shallow, quick breathing.
Low blood pressure.
Extreme thirst, nausea, or vomiting.
Confusion or anxiety.

How Do You Care for a Kid With FPIES?

Treatment varies, depending on the patient and his/her specific reactions.

Often, infants who own reacted to both dairy and soy formulas will be placed on hypoallergenic or elemental formula. Some children do well breastfeeding. Other children who own fewer triggers may just strictly avoid the offending food(s).

New foods are generally introduced extremely slowly, one food at a time, for an extended period of time per food. Some doctors recommend trialing a single food for up to three weeks before introducing another.

Because it’s a rare, but serious condition, in the event of an emergency, it is vital to get the correct treatment.

Some doctors provide their patients with a letter containing a brief description of FPIES and its proper treatment. In the event of a reaction, this letter can be taken to the ER with the child.

The CREATE Project

A project financed by the European Union, "Development of Certified Reference Materials for Allergenic Products and Validation of Methods for their Quantification", (the CREATE Project), explored the thought of introducing standardized techniques to quantify major allergen content into standardized protocols. Mass units of major allergens would be used to quantify the athletic ingredients of the allergen while allowing comparison among manufacturers.

The goals of the CREATE Project were to assess the potential of purified recombinant allergens as certified reference materials (CRMs) and to assess available ELISAs for the measurement of major allergens using the candidate CRMs as a standard. Eight major allergens originating from four of the most significant inhalant allergen sources were selected: Bet v 1 from birch pollen, Phl p 1 and Phl p 5 from grass pollen, Ole e 1 from olive pollen and Der p 1 and 2 and Der f 1 and Der f 2 from home dust mites. Three were found to be suitable as biological reference materials; the relax, except rPhl p 1a, indicate potential for optimization, provided aspects of their protein expression processes are modified.

As a result of this study, recombinant Bet v 1 and Phl p 5 were produced under "Good Manfacturing Practice" and evaluated by the European Directorate for the Quality of Medicines as biologic reference preparations to be included in the European Pharmacopoeia as international standards. Consequently, standardization of these allergen products will become global permitting comparisons among diverse manufacturing sources[50]. The project BSP, sponsored by the Biological Standardisation Programme of the EDQM (European Directorate for the Quality of Medicines & HealthCare), was the continuation of the CREATE project and intended to establish biological reference preparations for Bet v 1 and Phl p 5 as well as to validate reference ELISA methods for their quantification.

As a result of thiw work, the EMEA published that recombinant Bet v 1 is intended for use as standard for calibration of secondary standards and/or in home reference preparations for determination of the Bet v 1 content in allergen extracts from birch (Betula verrucosa) pollen and recombinant Bet v 1 preparations by ELISA. A reference ELISA method for its quantification has also been selected after validation in multi-center studies[51], [42].

According to extensive physico-chemical analyses, recombinant Phl p is produced as a highly stable, monomeric, and immunologically equivalent to its natural counterpart and is also available as European Pharmacopoeia allergen reference standard for grass pollen products[52].

For allergen sources with numerous epidemiologically significant allergens identified, such as HDM extracts, the development of numerous reference preparations for standardization is a genuine need. The use of multiplex platforms for quantification may overcome the expensive and time consuming activity of measuring several allergens for standardization of only one source[53].

How Do You Treat an FPIES Reaction?

Always follow your doctor’s emergency plan pertaining to your specific situation.

Rapid dehydration and shock are medical emergencies. If your kid is experiencing symptoms of FPIES or shock, immediately contact your local emergency services (). If you are uncertain if your kid is in need of emergency services, contact or your physician for guidance. The most critical treatment during an FPIES reaction is intravenous (IV) fluids, because of the risk and prevalence of dehydration. Children experiencing more severe symptoms may also need steroids and in-hospital monitoring. Mild reactions may be capable to be treated at home with oral electrolyte re-hydration (e.g., Pedialyte®).

What Does FPIES Stand For?

FPIES is Food Protein-Induced Enterocolitis Syndrome.

It is commonly pronounced «F-Pies», as in «apple pies», though some physicians may refer to it as FIES (pronounced «fees», considering food-protein as one word). Enterocolitis is inflammation involving both the little intestine and the colon (large intestine).

How Do I know If My Kid Has Outgrown FPIES?

Together with your child’s doctor, you should determine if/when it is likely that your kid may own outgrown any triggers. Obviously, determining if a kid has outgrown a trigger is something that needs to be evaluated on a food-by-food basis.

As stated earlier, APT testing may be an option to assess oral challenge readiness. Another factor for you and your doctor to consider is if your kid would physically be capable to handle a possible failed challenge.

When the time comes to orally challenge an FPIES trigger, most doctors familiar with FPIES will desire to schedule an in-office food challenge. Some doctors (especially those not practicing in a hospital clinic setting) may select to challenge in the hospital, with an IV already in put, in case of emergency. Each doctor may own his or her own protocol, but an FPIES trigger is something you should definitely NOT challenge without discussing thoroughly with your doctor.

Be aware that if a kid passes the in-office portion of the challenge, it does not mean this food is automatically guaranteed «safe.» If a child’s delay in reaction is fairly short, a kid may fail an FPIES food challenge while still at the office/hospital.

For those with longer reaction times, it may not be until later that day that symptoms manifest. Some may react up to three days later. Delay times may vary by food as well. If a kid has FPIES to multiple foods, one food may trigger symptoms within four hours; a diverse food may not trigger symptoms until six or eight hours after ingestion.

Testing and Standardizing Allergen Products

Allergen products to diagnose and treat allergic diseases own been used for over years. Allergen extracts are biological products that are istered to humans, and pets, to diagnose, prevent and treat allergic diseases.

Allergen products are pharmaceutical preparations derived from extracts of naturally occurring source materials containing allergens, which are substances that cause, or provoke allergic (hypersensitivity) diseases.

Allergen standardization begins by the controlled selection af the source (raw) material which is going to be used in the preparation of allergen extracts. Allergen source materials are obtained from validadated and audited suppliers and are obtained with a certificate of analysis confirming collection methods and source. Pollens from trees, weeds and grasses are collected under controlled conditions by certified suppliers; quality and purity must be documented.

Source materials should be assigned an expiration date based on stability studies and get a code to enable testing and tracking according to Excellent Manufacturing Practices (GMP) requirements. Pollen source materials are subjected to strong quality regulations and processes, and include purity, foreign contaminations, and stability data[9],[10]. Raw materials from mites and molds are grown in specialized facilities and are also subjected to regulatory controls[11],[12],[13].

In spite of recent progress, standardization of fungi allergenic extracts continuous to be an unmeet need. Grand differences own been shown among unstandardized mold allergen extracts[14],[15]. Wurth et al reported that only one from the 4 comercially available Aspergillus extracts in USA contained detectable quantities of the major allergen Asp f 1, coinciding with results showing that this product was unique with potential to induce experimental anaphylaxis in sensitized mice[16].

Animal dander is collected from housed animals and is accompanied with a certificate from a veterinary doctor stating that the animals are healthy and free of infectious and contagious agents[17].

In most European countries, national regulations permit marketing of allergen products as "Named Patient Preparations" (NPPs), although in the final few years, registration procedures own been started. NPPs are industrially prepared allergen vaccines following the prescription issued by an allergy specialist. It is regulated mainly by the Guideline on Allergen Products: Production and Quality Issues[18] and the Monograph on Allergen Extracts of the European Pharmacopoeia[19].

European manufacturers of allergen extracts develop their own methods and in-house reference preparations for standardization. In the USA, the FDA Middle for Biologics Evaluation and Research (CBER) reference preparations, standardized by approved methods, are used. The quality of allergen products is a key issue for both diagnosis and therapy, and the standardization of allergen extracts is of primary importance to improve their quality and offer physicians worldwide a dependable method to diagnose and treat allergic respiratory diseases.

Effective diagnosis and treatment, using skin test reagents and SIT, requires the optimal quantity of allergens for testing and the maintenance dose of vaccine for treatment. Skin test reactions should be large enough to propose clinical sensitivity but not so large as to produce excessive discomfort or the risk for a serious systemic reaction.

The heterogeneity of allergen extracts makes it necessary to develop methodologies to assess their potency and ensure their consistency, stability and safety.

Allergen products are legally considered medicines that require registration by government institutions[20], such as the Food and Drug istration (FDA) in the United States and the Paul Ehrlich Institute in Germany, further increasing the need for standardization. Basic researchers, physicians, regulatory authorities and manufacturers own tried to define a common methodology to standardize allergen vaccines[21].

In Europe, manufacturers own implemented company-specific protocols to standardize the production and quality control of the allergen extracts and to compare production batches to guarantee batch-to-batch consistency[22].

Every these production and quality control issues are controlled by strict protocols and adhered to Excellent Manufacturing Practices[23]. Thus, current allergen standardization requirements concentrate on the consistency of production and the safety and potency of allergen products. These protocols usein vivoandin vitrostandardization techniques, a representative allergic patient population, and dose-response studies to assign biological activities. Dose-response studies are mandatory and are primarily based on skin testing (intradermal or prick tests) and on inhibition of allergen-specific IgEs compared to reference extracts known as in-house reference preparations (IHRPs).

Furthermore, guidelines own been issued for the clinical development of products for specific immunotherapy for the treatment of allergic diseases. The IgE-binding potencies of the IHRPs are quantified by skin test reactivity (in vivostandardization) and by competitive IgE tests, such as RAST, ImmunoCAP, or ELISA inhibition assays (in vitrostandardization). Although they may be similar, they are expressed in company-specific units. The quality of mite and pollen allergen extracts is better defined today than it was in the past, and the quality of food and epithelial allergen extracts has also improved[24],[25].

In the United States, allergen standardization is based on intradermal testing of allergic patients and the potencies of sequential batches are sure by appropriate surrogate in vitro assays, which are based on inhibition of binding of IgE from pooled allergic sera to solid phase reference allergen extracts, or measurement of specific allergen contents in the allergen vaccines8,20.

Extracts in the United States are more homogenous with honor to entire allergenic potency than the extracts produced in Europe, mainly because the FDA provides the same standardized reagent for internal use by every manufacturing companies. However, these standards are only limited to 19 sources, including the most clinically relevant in the country (hymenoptera venoms, cat hair and pelt, home dust mites, pollens from 8 grass species and short ragweed). These preparations are licensed by the Middle for Biologics Evaluationand Research and their number has not raised since 10 years. In case of non-standardized extracts, calculation of manteinance doses is more hard because weight by- volume (w/v) or protein nitrogen unit (PNU) labelling may not correlate with biological potency.

The FDA organized an Steering Commitee to compile evidence about the safety and evidence of non-standardized allergenic extracts[26] finding that although most commercially available products were safe for clinical use, for about a half there was no evidence about their efficacy. It is expected that the number of currently available extracts in the market will be drastically reduced.

In Japan, the Japanese Society of Allergology standardized Japanese cedar pollen allergen vaccines[27]. The in vivo allergenic potency of the reference extract was sure by intradermal testing and measurement of the content of the major allergen Weep j 1 was selected as the surrogate in vitro assay.

In Korea the allergen extracts manufactured at the Research Middle for the Standardization of Allergic Diseases, Department of Internal Medicine and Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea, exhibit excellent allergen potency, in terms of in vitro (ELISA inhibition) and in vivo (intradermal skin test) tests, when compared with commercially available extracts, even detecting low levels of major allergens[28] .

The prevalence of food allergies is rising. The standard of care consists of food-allergen avoidance and treatment of allergen-induced systemic reactions with adrenaline.

Thus, precise diagnosis, prevention and treatment are pressing needs. Research is needed to enable an understanding of the mechanisms involved in food allergy at the cellular and molecular levels and to design prevention and intervention strategies[29] as well as food oral immunotherapy, in wich significant progress has been observed in promoting immunomodulatory effects that lead to the clinical outcome of desensitization. Studies in the USA own revealed that the presence of food allergy in children may be of %[30].

What is FPIES?

FPIES is a non-IgE mediated immune reaction in the gastrointestinal system to one or more specific foods, commonly characterized by profuse vomiting and diarrhea.

FPIES is presumed to be cell mediated. Poor growth may happen with continual ingestion. Upon removing the problem food(s), every FPIES symptoms subside. (Note: Having FPIES does not preclude one from having other allergies/intolerances with the food.) The most common FPIES triggers are cow’s milk (dairy) and soy. However, any food can cause an FPIES reaction, even those not commonly considered allergens, such as rice, oat and barley.

A kid with FPIES may experience what appears to be a severe stomach bug, but the «bug» only starts a couple hours after the offending food is given. Numerous FPIES parents own rushed their children to the ER, limp from extreme, repeated projectile vomiting, only to be told, «It’s the stomach flu.» However, the next time they feed their children the same solids, the dramatic symptoms return.

Monoclonal Antibodies and Recombinant Allergens (RAs)

Allergenic extracts consist of complicated mixtures of substances with a variation in allergenic activity and allergen composition.

Patients are often not sensitized to every allergens in one extract and there may be grand variability among individuals. Advances in the field of microarrays containing purified native and recombinant allergens (RAs) may be useful to identify more precise sensitization profiles and further personalization of allergen composition in the vaccine [31],[32]. The characterization of major allergen components and the development of techniques to quantify them, such as ELISA systems based on monoclonal antibodies, own led more manufacturers to provide information on the major allergen content of their extracts, even though identification of major allergen content is not currently mandatory, except for a limited number of extracts, such as cat and ragweed.

EMEA guidelines now recommend that allergen manufacturers state the content of representative major allergens in mass units for their allergen products using antibody-based techniques. However, this could not be mandatory due to the limited number of standards and immunoassays in comparison with the wide quantity of allergenic extracts. As noted above, differences in assays and methodologies for measuring the major allergens may preclude direct comparisons among products of diverse manufacturers.

Larenas-Linnemann and Cox reviewed the information obtained on unit definition and dosage of allergens from European manufacturers of allergen extracts used for sublingual immunotherapy (SLIT).

They concluded that the monthly maintenance dose the manufacturers recommended for SLIT was times higher than the recommended dose for subcutaneous immunotherapy. However, since each manufacturer in Europe uses its own IHRPs and its own units to express potencies, the comparison of diverse products from diverse companies at national and international levels is almost impossible. Even if the quantity of major allergens is stated, differences in the quantification technique, the reference extracts and antibodies used can influence the outcome.

Thus, for comparison of diagnostics and immunotherapeutics from diverse manufacturers, the same analytical methods and materials ideally should be used[33]. Another study quantified and compared the allergen content of diverse grass pollen preparations for skin prick testing (SPT) and SLIT used in Europe[34]. Protein concentrations of SPT solutions ranged from 15 to µg/ml, and Phl p 5 concentrations, a major grass allergen, ranged from to µg/ml. Protein content of the maintenance doses of the immunotheurapeutics ranged from 5 to µg and Phl p 5 content ranged from to µg. SDS-PAGE and immunoblots confirmed the differences in protein and allergen contents.

Since allergen extracts or vaccines may contain hundreds of allergenic determinants, and individuals can be sensitized to diverse combinations of these proteins, sensitization profiles in atopic populations are extremely heterogeneous.

Therefore, before RAs are utilized in routine clinical practice, epidemiological studies using RAs to identify the immune response to specific allergens in the population at large and to clarify cross-reactivity are necessary. The number of cloned and purified allergens has increased substantially over the past two decades. The incorporation of Omic disciplines to Experimental Allergology has led to the identification of new allergens, some of them being significant in terms of IgE binding frequency or allergenic potential[35],[36]. In this sense, the fact of reducing the allergenicity of one source to a few molecules for SIT is far from reality for some allergenic species such as home dust mites.

Recently, it has been demonstrated that Der p 23 is an new and clinically relevant home dust mite allergen.

IT has sequence homology with peritrophins, which contains chitin-binding domains and is part of the peritrophic matrix lining the gut of arthropods. Recombinant Der p 23 reacted with IgE antibodies from 74% of D. pteronyssinus allergic patients (n = ) at levels comparable to the two major HDM allergens, Der p 1 and Der p 2. The allergen is localized in the peritrophic matrix lining the midgut of D. pteronyssinus as well as on the surface of the fecal pellets. The high allergenic activity of Der p 23, and its frequent recognition as a respiratory allergen, may be explained by the fact that it becomes airborne and respirable through its association with mite feces[37].

The availability of high quality recombinant allergens, is significant for the follow-up of mite allergic patients, to establish clinical risk factors[38] and develop new vaccines[39]. The correct selection of candidate patients is also of landmark importance[40],[41].

Nowdays the use of RAs in diagnosis has made significnt progress, and when combined with precision medicine (PM) can change the scope of allergy diagnosis. One prototype PM method using recombinants components in the test for an in vitro IgE assay, ImmunoCAP®ISAC, was developed in the sixties and has attracted increasing interest. These microarrays of allergen components own significantly improved the way to describe the IgE binding profile of a patient.

Lately a macroarray containing both “whole” allergens and molecular components has been developed, namely the Allergy Explorer (ALEX). This method allows the acquisition of an IgE biniding profile comprising reagents ( allergen extracts and individual allergen components), resulting in the widest screening available of potential allergens [42].

To improve safety and efficacy of SIT, an alternative approach may be to use individual allergens for tailored immunotherapy after identifying the specific sensitization causes [43]. The possibility of obtaining allergens as recombinant products makes it possible to produce hundreds of allergens in large quantities and quicker than the laborious purification of natural extracts.

Molecular cloning has provided an efficient way to obtain pure polypeptides. This has distinct advantages over using native sources which form complicated mixtures and are often present in extremely little amounts. There has been considerable progress in understanding the molecular characteristics of allergens. Numerous allergens own been purified from aqueous extracts or produced as recombinant molecules.

What is ige allergy

Allergen sequence information is available from diverse databases (). These polypeptides enable the mapping of B- and T-cell epitopes and the identification of their binding sites. Sequence polymorphisms that influence antibody binding and T-cell recognition own also been established for several allergens, finding isoforms of clinical relevance in restricted geographical areas[44],[45].

The expectation of using RAs for SIT is to overcome some of the pitfalls of using natural allergen products for immunotherapy.

These approaches may enable physicians to ister only the clinically relevant allergen, thus avoiding exposure to unnecessary antigens. Moreover, RAs could also be rendered hypoallergenic using a variety of techniques. Several immunotherapy studies own been conducted with recombinant allergens with clinical benefits [46],[47],[48],[49]. More clinical trials are needed to compare the potential advantages and benefits of SIT with RAs versus current standard therapy with natural vaccines. This process will take years; in the meantime, optimizing SIT with naturally occurring vaccines is required to guarantee efficacy and safety.

For sources with few significant allergens, the use of single RAs for SIT is a more promising scenario.

How is FPIES Diverse From MSPI, MSPIES, MPIES, Etc.?

MPIES (milk-protein induced enterocolitis syndrome) is FPIES to cow’s milk only. MSPIES (milk- and soy-protein induced enterocolitis syndrome) is FPIES to milk and soy. Some doctors do create these subdivisions, while others declare that milk and soy are simply the two most common FPIES triggers and give the diagnosis of «FPIES to milk and/or soy.»

MSPI is milk and soy protein intolerance.

Symptoms are those of allergic colitis and can include colic, vomiting, diarrhea and blood in stools. These reactions are not as severe or immediate as an FPIES reaction.


Fogg MI, Brown-Whitehorn TA, Pawlowski NA, Spergel JM. (). Atopy Patch Test for the Diagnosis of Food Protein-Induced Enterocolitis Syndrome. Pediatric Allergy and Immunology – Retrieved on December 31, from

Burks, AW. (). Don’t Feed Her That! Diagnosing and Managing Pediatric Food Allergy. Pediatric Basics. Gerber Products Company: Retrieved on December 31, from

Moore, D. Food Protein-Induced Enterocolitis Syndrome.

(, April 11). Retrieved on December 31, from

Sicherer, SH. (). Food Protein-Induced Enterocolitis Syndrome: Case Presentations and Management Lessons. Journal of Allergy and Clinical Immunology Vol. , Retrieved on December 31, from

Nowak-Wegrzyn, A., Sampson, HA, Wood, RA, Sicherer, SH. MD, Robert A. Wood, MD and Scott H. Sicherer, MD. (). Food Protein-Induced Enterocolitis Syndrome Caused by Solid Food Proteins. Pediatrics. Vol. 4: Retrieved on December 31, from #T1.

Nocerino, A., Guandalini, S.

(, April 11). Protein Intolerance. Retrieved on December 31, from WebMD Medical Reference from Healthwise. (, May 31). Shock, Topic Overview. Retrieved on December 31, from

American Academy of Allergy, Asthma and Immunology. (). Tips to Remember: What is an Allergic Reaction? Retrieved on December 31, from

Sicherer, SH. (). Understanding and Managing Your Child’s Food Allergies. A Johns Hopkins Press Health Book.

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