Allergen-component Diagnostics Food-pollen Allergy

April 12, 2022
Allergen-component Diagnostics Food-pollen Allergy

 

Question
We are encouraged to utilize allergen-component diagnostics for food-pollen allergy in order to guide advice. But these tests are expensive in our country. What is the minimum test profile you would recommend to identify PR-10, profilin, and LTP components. For example, would Pru p 1,3 and 4 be sufficient?

 

Answers
From the Editors: The following discussion addressing allergen component assessment in food-pollen allergy raises several issues:  First is the significant worldwide regional differences for pollen sensitization, food cross reactivity and its clinical expression. Second, is the importance of clinical correlation with available and emerging diagnostic testing for allergic diseases, and third is demonstrating the different "styles" physicians have in approaching clinical problems.

 

By Dra. Iris E. Hidalgo Nicho

Pollen Food Allergy Syndrome (PFAS) is a hypersensitivity reaction in patients with seasonal allergic rhinitis (SAR) caused by cross-reaction among pollens and homologous epitopes in plant-derived food allergens. The prevalence of PFAS varies from 9.6% to 55% worldwide according to geographic location, local diet, and the regional prevalence of atopic diseases. PFAS is the most frequent food allergy in adults and the typical comorbidity of pollinosis. The frequency of PFAS in childhood is higher than previously recognized, including those who suffer from pollen-induced seasonal allergic rhinoconjunctivitis.

PFAS is much higher in northern Europe because of birch pollen allergy. Osterballe et al. estimated that 40–50% of birch-allergic patients also had PFAS. Dreborg and Erikson showed in large adult and pediatric studies that over 70% of patients with birch allergy had symptoms of PFAS, and 20% of those were allergic to grass and mugwort.

Plant–food allergens share similarities with pollen allergens in their sequence, structure, and function, triggering the symptoms. Due to their widespread nature, these are known as panallergens. The principal pan-allergens comprise three protein families: profilins, pathogenesis-related protein type 10 (PR-10), and non-specific lipid transfer proteins (nsLTPs, PR-14). In Northern and Central Europe, where pollen allergy is mainly related to birch and alder pollen, the symptoms are triggered mainly by PR-10-containing Rosaceae. The Rosaceae family includes many edible fruits, where apple, cherry, and peach are the best-known species. People's reactions to certain foods will depend on the birch component they are sensitized to; for example, Bet v1 has been associated with Mal d 1 (apple), while Pru p 4 (peach) with Bet v 2.

PFAS is typically characterized by isolated oral and pharyngeal symptoms of immediate onset following food intake, clinically known as oral allergy syndrome (OAS). Symptoms typically last for a few minutes to half an hour. Systemic reactions occur in 2–10% of PFAS cases, including nausea, abdominal discomfort, diarrhea, rhinitis, difficulty breathing, skin rash, urticaria-angioedema, hypotension, and anaphylaxis (1–2% of reactions). Clinical history is fundamental for diagnosis, combined with skin prick tests and open/blind oral food challenges (OFC), which can identify the syndrome with high sensitivity and specificity. OFC is mandatory when history is unclear and systemic reactions occur. It is essential to mention that it has been extensively documented that the sensitivity and specificity of SPTs with fresh fruit using the prick-by-prick technique are higher than those of SPTs using commercial extract. This is very useful if specific IgE cannot be measured or molecular tests cannot be performed.

Component-resolved diagnostics (CRD) represents a reliable instrument in diagnosing PFAS, as it offers the opportunity to establish and compare individual sensitization profiles based on the cross-reactive proteins. High cost is the major limitation to use CRD worldwide. Due to high cross-reactivity between PR-10 proteins, profilins, and nsLTPs, the corresponding allergens derived from peach are usually applied for diagnostic approaches in all Rosaceae fruit allergies. So, it would be possible that allergens like Pru p1, Pru p3, and Pru p4 are enough. Furthermore, it would be necessary to consider allergens such as Mal d1, Mal d3, and Mal d4 from apples due to several studies showing that 70% of patients with birch pollinosis develop an allergy to apples or other foods, taking into consideration the different geographical scenarios.

References

  1. Carlson G, Coop C. Pollen food allergy syndrome (PFAS): A review of current available literature. Ann Allergy Asthma Immunol. 2019;123(4):359-365. doi:10.1016/j.anai.2019.07.022
  2. Poncet P, Sénéchal H, Charpin D. Update on pollen-food allergy syndrome. Expert Rev Clin Immunol. 2020;16(6):561-578. doi:10.1080/1744666X.2020.1774366
  3. Mastrorilli C, Cardinale F, Giannetti A, Caffarelli C. Pollen-Food Allergy Syndrome: A not so Rare Disease in Childhood. Medicina (Kaunas). 2019;55(10):641. Published 2019 Sep 26. doi:10.3390/medicina55100641
  4. Yagami A, Ebisawa M. New findings, pathophysiology, and antigen analysis in pollen-food allergy syndrome. Curr Opin Allergy Clin Immunol. 2019;19(3):218-223. doi:10.1097/ACI.0000000000000533
  5. Lipp T, Acar Şahin A, Aggelidis X, et al. Heterogeneity of pollen food allergy syndrome in seven Southern European countries: The @IT.2020 multicenter study. Allergy. 2021;76(10):3041-3052. doi:10.1111/all.14742
  6. Matricardi PM, Kleine-Tebbe J, Hoffmann HJ, et al. EAACI Molecular Allergology User's Guide. Pediatr Allergy Immunol. 2016;27 Suppl 23:1-250. doi:10.1111/pai.12563

Iris E. Hidalgo Nicho, MD
Allergy and Clinical Immunology

 

By Doctor Robert Wood

It is true that allergen component diagnostics can be very helpful in the management of some patients with food-pollen allergy. However, for the vast majority of patients a careful history supplemented by select skin and / or IgE testing will be completely sufficient to make accurate diagnoses and prescribe effective management. In the United States, the availability of component based testing is relatively limited and most allergists here – including myself – are very comfortable managing most patients with the currently available tools. This is truly an area where a careful history will yield far more clinically relevant information than any laboratory test.

Robert A. Wood, MD
Professor of Pediatrics and International Health
Director, Pediatric Allergy and Immunology
Johns Hopkins University School of Medicine
Baltimore, MD, USA

 

By Professor Anna Pomes

Patterns of sensitization to PR--‐10, profiling and lipid transfer protein (LTP) allergens show a wide geographical variability, depending on the exposure to pollens and ingested foods in each particular area. The minimum test profile to identify sensitivities to these three groups of proteins in component--‐resolved diagnosis (CRD) should be selected according to the patterns of sensitization to these allergens in that specific country.

Two main patterns of sensitization to PR--‐10, profilins and LTPs have been well described in Europe (1, 2). In northern and central areas, allergies to Rosaceae fruits, Apiaceae vegetables and hazelnut are associated with birch pollinosis, and patients present with mild oropharyngeal symptoms known as oral allergy syndrome (OAS). The allergens responsible for this pollen--‐food cross--‐reactivity are Bet v 1 and pollen profilins, whose sensitivity to pepsin digestion explains the restriction of symptoms to the oral cavity. In contrast, in areas of southern Europe free of birch pollen exposure, peach (Pru p allergens) and certain pollens, such as those from mugwort and plane tree, might contribute to sensitization to LTPs. These are very stable proteins, resistant to digestion, and associated with consequent systemic reactions, that are often severe. One might anticipate that testing for IgE reactivity to only birch and peach allergens would allow distinguishing between both patterns of sensitization. A strong reactivity to Bet v 1 (PR--‐10) could indicate the possibility of mostly mild reactions to cross--‐reacting foods (i.e. apple), but also serious reactions to cross--‐reacting allergens from peanut, hazelnut, celery and soybean (3). On the contrary, a confirmed sensitization to the LTP Pru p 3, considered a primary sensitizer and marker of reactivity to LTPs from the Rosaceae family, combined with a lack of IgE to Bet v 1, would be an indicator of a possible development of systemic reactions to LTPs.

Unfortunately, polysensitization to additional allergens from plants and pollens, even from distantly related botanical species, occurs, and can influence the IgE reactivity to these three groups of allergens in specific areas. Even within the same country, several patterns of sensitization have been described (i.e. to LTPs, profilins) (4, 5). There is a low positive predictive value of skin prick test in diagnosis of fruit and pollen allergies, precisely due to the cross--‐reactivity among allergens from different species. Ideally, allergens should be classified in groups or clusters of cross--‐reactive molecules. A minimum set of at least one representative allergen from each cluster, relevant to the patients from the country in question, should be selected for CRD. This strategy would assure that most relevant cross--‐reactivities for that area would be covered in the test. A multicenter study illustrated this approach by classifying LTPs into cross--‐reactive groups, depending on their IgE reactivities in microarrays (6). This analysis confirmed several non--‐cross--‐reactive LTPs (such as Pha v 3, Par j 1, Ole e 7, Tri a 14 and Lac s 1), in agreement with known routine clinical observations (4, 6). The addition of these allergens to the test would increase the diagnostic potential of CRD, especially for patients showing a clinical history of reactivity to any of them, or if those allergens are important sensitizers in that specific area (i.e. allergens associated with olive pollinosis in southern Spain). Even minor allergens should be 2 included in certain cases, such as Ole e 7, which is a clinically relevant marker of olive allergy due to its associated risk of asthma (4). In Iran, a poor predictive value of sequence homology for profilins cross--‐ reactivity has been observed, illustrated by a lack of clinical reactivity to watermelon among most melon allergic patients (7). In this case, the addition of profilins from both sources in CRD would be advised. Although the symptoms induced by profilins tend to be mild, strong reactions have been described against profilins from melon, banana, tomato and/or citrus fruits (3). The use of these fruits as markers of profiling sensitization would be recommended in certain areas. Profilins have also been described as markers of severity for grass allergy sensitization (4).

Yet not all the reactivities detected by in vitro CRD are clinically relevant. CRD is meant to complement in vivo assays, hopefully by increasing their sensitivity and/or specificity, and by informing about the molecule/s causing sensitization and the patient--‐specific IgE reactivity profiles (2, 3). Algorithms have been suggested to correctly diagnose these complex allergies, by combining in vivo and in vitro tests (3, 5). Representative molecules from cross--‐reactive groups of allergens, which will differ with the geographical areas, should be selected for CRD analysis. The use of arrays or multiplex technologies, instead of individual allergen tests, may also contribute to cost reduction in the long term, using small amounts of sera. The selection of the minimum set of allergens to be used for component resolved diagnosis should result from a careful analysis of sensitization patterns in that particular country.

References

  1.  Fernandez--‐Rivas M1, Bolhaar S, Gonzalez--‐Mancebo E, Asero R, van Leeuwen A, Bohle B, Ma Y, Ebner C, Rigby N, Sancho AI, Miles S, Zuidmeer L, Knulst A, Breiteneder H, Mills C, Hoffmann--‐Sommergruber K, van Ree R. Apple allergy across Europe: how allergen sensitization profiles determine the clinical expression of allergies to plant foods. J Allergy Clin Immunol. 2006; 118(2):481--‐8.
  2. 2- Ballmer--‐Weber BK, SkamstrupnHansen K, Sastre J, Andersson K, Bätscher I, Ostling J, Dahl L, Hanschmann KM, Holzhauser T, Poulsen LK, Lidholm J, Vieths S. Component--‐resolved in vitro diagnosis of carrot allergy in three different regions of Europe. Allergy. 2012; 67(6):758--‐66.
  3. 3- Asero R. Plant food allergies: a suggested approach to allergen--‐resolved diagnosis in the clinical practice by identifying easily available sensitization markers. Int Arch Allergy Immunol. 2005; 138(1):1--‐11.
  4. Barber D, de la Torre F, Feo F, Florido F, Guardia P, Moreno C, Quiralte J, Lombardero M, Villalba M, Salcedo G, Rodríguez R. Understanding patient sensitization profiles in complex pollen areas: a molecular epidemiological study. Allergy. 2008; 63(11):1550--‐8.
  5. Barber D, de la Torre F, Lombardero M, Antépara I, Colas C, Dávila I, Tabar AI, Vidal C, Villalba M, Salcedo G, Rodríguez R. Component--‐resolved diagnosis of pollen Allergy based on skin testing with profilin, polcalcin and lipid transfer protein pan--‐allergens. Clin Exp Allergy. 2009; 39(11):1764--‐73.
  6. Palacín A, Gomez--‐Casado C, Rivas LA, Aguirre J, Tordesillas L, Bartra J, Blanco C, Carrillo T, Cuesta--‐ Herranz J, de Frutos C, Alvarez--‐Eire GG, Fernández FJ, Gamboa P, Muñoz R, Sanchez--‐Monge R, Sirvent S, Torres MJ, Varela--‐Losada S, Rodríguez R, Parro V, Blanca M, Salcedo G, Diaz--‐Perales A. Graph based study of allergen cross--‐reactivity of plant lipid transfer proteins (LTPs) using microarray in a multicenter study. PLoS One. 2012; 7(12):e50799.
  7. Sankian M, Varasteh A, Pazouki N, Mahmoudi M. Sequence homology: a poor predictive value for profilins cross--‐reactivity. Clin Mol Allergy. 2005; 10; 3:13.

Anna Pomes, PhD, FAAAAI
Research Director
INDOOR Biotechnologies, Inc.
Charlottesville, VA, USA

 

By Professor Wayne Thomas

Allergic sensitivity to rosaceous fruits in the Mediterranean region shows an interesting and clinically useful pattern when the IgE binding is measured by component resolved diagnosis (1, 2). Sensitisation to the non-specific lipid transfer protein (LTP) from peach, Pru p 3, is associated with a higher likelihood that subjects will experience systemic symptoms and not just oral allergy symptoms and in addition allergic symptoms from ingesting other fruits and vegetables. These not only include other rosaceous fruits but a long list of genetically disparate plants including celery, carrot, walnut, fennel, peanut, cereals and tomato. The LTP sensitisation is not only best measured with Pru p 3 but it appears that the sensitisation is driven by peach allergen. Sensitisation to the PR-10-like proteins (Bet v 1 homologues) and profilins without LTP is associated with oral allergy syndrome and not systemic reactions and curiously subjects co-sensitised with these specificities and LTP are have fewer symptoms than those sensitised to LTP alone (3). Knowledge that LTP is usually found in the peal of the fruit and vegetable and that profilin sensitisation is associated with melon allergy provides further assistance with the clinical management. There are additional associations of symptoms with sensitisation to the aeroallergen LTPs of the mugwort and plane-tree pollens with the risk of more severe allergy (4) and LTP induced rhinitis (5). This again appears to dependent on the primary peach sensitization because higher IgE titres are found to Pru p 3 (5) and is not found for pollens with the evolutionary more disparate LTP sequences like those found in olive, Parieteria spp. and ragweed pollens. With respect to diagnostic/prognostics tests within the Mediterranean region, Pru p 3 is the LTP of choice. Also within this region profilins from disparate pollen sources have essentially the same IgE binding for subjects sensitised by different species even for subjects selected for peach allergy (6). Grass (Phl p 12), birch (Bet v 2) and date palm (Pho d 2) all appear suitable and a large study of pan allergens (7) showed a good association of titres to diverse pollen profilins. The PR-10 proteins do not exhibit the same concordance of cross reactivity amongst diverse species and allergen source (7) and indeed the food and pollen PR-10 can be divided into food and pollen groups. Mal d 1 from apple detects anti-PR-10 antibodies in fruit allergic subjects better than Bet v 1(8) although in Europe titres of Bet v 1-reactive antibodies are high with pollen sensitisation plus LTP allergy. Sensitisation to Mal d 1 could be used measure PR-10 sensitisation to the food group and Bet v 1 for pollen sensitisation, although they do cross-react. From published reports Pru a 1 and 4 would probably be suitable for PR-10 food markers and profilin but have not been as extensively used.

The findings above have not been ascertained outside of the Mediterranean region and there are reports to show that they do not necessarily apply. LTP sensitisation of hazelnut-allergic children living in northern Europe have IgE reactivity to Cor a 8, the hazelnut LTP, but not to Pru p 3 (9). In the geographically more distant northern China there is an association of mugwort sensitisation and peach allergy but in contrast to the Mediterranean allergy it is driven by IgE produced to the mugwort Art v 3 with little reactivity to Pru p 3 (10). It follows that Pru p 3 would not be suitable for diagnosis in China although the clinical spectrum of the LTP sensitisation has not been studied to the same degree in this region. A smaller group with LTP peach allergy with no association or sensitisation to mugwort was also found (10).

References

  1. Egger M. Hauser M. Mari A. Ferreira F. Gadermaier G. The role of lipid transfer proteins in allergic diseases. Current Allergy & Asthma Reports. 10(5):326-35, 2010
  2. Asero R. Pravettoni V. Anaphylaxis to plant-foods and pollen allergens in patients with lipid transfer protein syndrome. Current Opinion in Allergy & Clinical Immunology. 13(4):379-85, 2013
  3. Pastorello EA1, Farioli L, Pravettoni V, Scibilia J, Mascheri A, Borgonovo L, Piantanida M, Primavesi L, Stafylaraki C, Pasqualetti S, Schroeder J, Nichelatti M, Marocchi A. Pru p 3-sensitised Italian peach-allergic patients are less likely to develop severe symptoms when also presenting IgE antibodies to Pru p 1 and Pru p 4. Int Arch Allergy Immunol. 2011;156(4):362-72
  4. Pascal M. Munoz-Cano R. Reina Z. Palacin A. Vilella R. Picado C. Juan M. Sanchez-Lopez J. Rueda M. Salcedo G. Valero A. Yague J. Bartra J. Lipid transfer protein syndrome: clinical pattern, cofactor effect and profile of molecular sensitization to plant-foods and pollens. Clinical & Experimental Allergy. 42(10):1529-39, 2012
  5. Sanchez-Lopez J. Tordesillas L. Pascal M. Munoz-Cano R. Garrido M. Rueda M. Vilella R. Valero A. Diaz-Perales A. Picado C. Bartra J. Role of Art v 3 in pollinosis of patients allergic to Pru p 3. Journal of Allergy & Clinical Immunology. 133(4):1018-25, 2014
  6. Pastorello EA. Farioli L. Stafylaraki C. Mascheri A. Scibilia J. Pravettoni V. Primavesi L. Piantanida M. Nichelatti M. Asero R. Anti-rPru p 3 IgE levels are inversely related to the age at onset of peach-induced severe symptoms reported by peach-allergic adults. International Archives of Allergy & Immunology. 162(1):45-9, 2013.
  7. Scala E. Alessandri C. Palazzo P. Pomponi D. Liso M. Bernardi ML. Ferrara R. Zennaro D. Santoro M. Rasi C. Mari A. IgE recognition patterns of profilin, PR-10, and tropomyosin panallergens tested in 3,113 allergic patients by allergen microarray-based technology. PLoS ONE [Electronic Resource]. 6(9):e24912, 2011.
  8. Vieira T. Cunha L. Neves E. Falcao H. Diagnostic usefulness of component-resolved diagnosis by skin prick tests and specific IgE to single allergen components in children with allergy to fruits and vegetables. Allergologia et Immunopathologia. 42(2):127-35, 2014
  9. Flinterman AE, Akkerdaas JH, den Hartog Jager CF, et al. Lipid transfer protein-linked hazelnut allergy in children from a non-Mediterranean birch-endemic area. Journal of Allergy & Clinical Immunology 121:423–28, 2008
  10. Gao ZS. Yang ZW. Wu SD. Wang HY. Liu ML. Mao WL. Wang J. Gadermaier G. Ferreira F. Zheng M. van Ree R. Peach allergy in China: a dominant role for mugwort pollen lipid transfer protein as a primary sensitizer. Journal of Allergy & Clinical Immunology. 131:224-6, 2013

Wayne Thomas, PhD
Division of Molecular Biotechnology
Telethon Institute for Child Health Research
West Perth, Australia

 

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