Allergy to Lipid Transfer Protein or Hypersensitivity to Non-Steroidal Anti-Inflammatory Drugs?
Abstract
1. Introduction
2. Case Report
2.1. Patient-Relevant Clinical Data
2.2. Standard Diagnostic Laboratory Test Results
2.3. Skin Prick Test (SPT) and Intradermal Test (IT) Results
2.4. Spirometry and Challenge Test Results
2.5. Non-Standard Experimental Laboratory Test Results
2.6. Final Diagnosis and Recommendations for the Patient
3. Discussion
3.1. Drug Hypersensitivity
3.2. Non-Steroidal Anti-Inflammatory Drugs
3.3. Hypersensitivity to NSAIDs
3.4. NSAIDs as a Cofactor
3.5. Lipid Transfer Proteins
3.6. Non-Standard Experimental Laboratory Tests
4. Materials and Methods
4.1. Standard Diagnostic Laboratory Tests
4.2. Skin Prick Tests, Intradermal Test, Challenge Tests, and Spirometry
4.3. Non-Standard Laboratory Assays
5. Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Cardona, V.; Ansotegui, I.J.; Ebisawa, M.; El-Gamal, Y.; Fernandez Rivas, M.; Fineman, S.; Geller, M.; Gonzalez-Estrada, A.; Greenberger, P.A.; Sanchez Borges, M.; et al. World allergy organization anaphylaxis guidance 2020. World Allergy Organ. J. 2020, 13, 100472. [Google Scholar] [CrossRef] [PubMed]
- Makowska, J.; Bochenek, G.; Glück, J.; Nittner-Marshalian, M.; Porębski, G.; Rymarczyk, B.; Kowalski, M.L. Hypersensitivity to nonsteroidal anti-inflammatory drugs. Guidelines of the Section of Drug Hypersensitivity of the Polish Society of Allergology. Alergol. Pol. 2018, 5, 10–22. [Google Scholar] [CrossRef]
- Doña, I.; Pérez-Sánchez, N.; Eguiluz-Gracia, I.; Muñoz-Cano, R.; Bartra, J.; Torres, M.J.; Cornejo-García, J.A. Progress in understanding hypersensitivity reactions to nonsteroidal anti-inflammatory drugs. Allergy 2020, 75, 561–575. [Google Scholar] [CrossRef] [PubMed]
- Ukleja-Sokołowska, N. Pathomechanism of allergy induced by cofactors—What do we know currently. Alergia 2019, 2, 37–40. [Google Scholar]
- Rydzyńska, M.; Grześk-Kaczyńska, M.; Rosada, T.; Ukleja-Sokołowska, N. Food-dependent anaphylaxis induced by exercise—What is currently known? Allergy Asthma Immunol. 2024, 29, 61–72. [Google Scholar]
- Pascal, M.; Muñoz-Cano, R.; Reina, Z.; Palacín, A.; Vilella, R.; Picado, C.; Juan, M.; Sánchez-López, J.; Rueda, M.; Salcedo, G.; et al. Lipid transfer protein syndrome: Clinical pattern, cofactor effect and profile of molecular sensitization to plant-foods and pollens. Clin. Exp. Allergy 2012, 42, 1529–1539. [Google Scholar] [CrossRef]
- Johansson, S.G.; Bieber, T.; Dahl, R.; Friedmann, P.S.; Lanier, B.Q.; Lockey, R.F.; Motala, C.; Ortega Martell, J.A.; Platts-Mills, T.A.; Ring, J.; et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J. Allergy Clin. Immunol. 2004, 113, 832–836. [Google Scholar] [CrossRef]
- Demoly, P.; Adkinson, N.F.; Brockow, K.; Castells, M.; Chiriac, A.M.; Greenberger, P.A.; Khan, D.A.; Lang, D.M.; Park, H.S.; Pichler, W.; et al. International Consensus on drug allergy. Allergy 2014, 69, 420–437. [Google Scholar] [CrossRef]
- Kowalski, M.; Bochenek, G.; Bodzenta-Łukaszyk, A.; Glück, J.; Kurek, M.; Nittner-Marszalska, M.; Porębski, G.; Poziomkowska-Gęsicka, I.; Rymarczyk, B.; Sławeta, G.; et al. Introduction to management of drug hypersensitivity. Guidelines of the Section of Drug Hypersensitivity of the Polish Society of Allergology. Alergol. Pol. 2018, 5, 3–9. [Google Scholar] [CrossRef]
- Kowalski, M.L.; Makowska, J.S.; Blanca, M.; Bavbek, S.; Bochenek, G.; Bousquet, J.; Bousquet, P.; Celik, G.; Demoly, P.; Gomes, E.R.; et al. Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs)—Classification, diagnosis and management: Review of the EAACI/ENDA(#) and GA2LEN/HANNA*. Allergy 2011, 66, 818–829. [Google Scholar] [CrossRef]
- Kowalski, M.L.; Asero, R.; Bavbek, S.; Blanca, M.; Blanca-Lopez, N.; Bochenek, G.; Brockow, K.; Campo, P.; Celik, G.; Cernadas, J.; et al. Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs. Allergy 2013, 68, 1219–1232. [Google Scholar] [CrossRef] [PubMed]
- Romano, A.; Gaeta, F.; Caruso, C.; Fiocchi, A.; Valluzzi, R.L. Evaluation and Updated Classification of Acute Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): NSAID-Exacerbated or -Induced Food Allergy. J. Allergy Clin. Immunol. Pract. 2023, 11, 1843–1853.e1. [Google Scholar] [CrossRef] [PubMed]
- Barbaud, A.; Garvey, L.H.; Torres, M.; Laguna, J.J.; Arcolaci, A.; Bonadonna, P.; Scherer Hofmeier, K.; Chiriac, A.M.; Cernadas, J.; Caubet, J.C.; et al. EAACI/ENDA position paper on drug provocation testing. Allergy 2024, 79, 565–579. [Google Scholar] [CrossRef]
- Brockow, K.; Garvey, L.H.; Aberer, W.; Atanaskovic-Markovic, M.; Barbaud, A.; Bilo, M.B.; Bircher, A.; Blanca, M.; Bonadonna, B.; Campi, P.; et al. Skin test concentrations for systemically administered drugs—An ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2013, 68, 702–712. [Google Scholar] [CrossRef]
- Doña, I.; Sáenz de Santa María, R.; Moreno, E.M.; Bartra, J.; Torres, M.J. An algorithm for the diagnosis and treatment of nonsteroidal antiinflammatory drugs hypersensitivity, 2024 update. Allergy 2025, 80, 1183–1186. [Google Scholar] [CrossRef]
- Bjarnason, I.; Takeuchi, K. Intestinal permeability in the pathogenesis of NSAID-induced enteropathy. J. Gastroenterol. 2009, 44 (Suppl. 19), 23–29. [Google Scholar] [CrossRef] [PubMed]
- Lambert, G.P.; Boylan, M.; Laventure, J.P.; Bull, A.; Lanspa, S. Effect of aspirin and ibuprofen on GI permeability during exercise. Int. J. Sports Med. 2007, 28, 722–726. [Google Scholar] [CrossRef]
- Muñoz-Cano, R.; San Bartolome, C.; Casas-Saucedo, R.; Araujo, G.; Gelis, S.; Ruano-Zaragoza, M.; Roca-Ferrer, J.; Palomares, F.; Martin, M.; Bartra, J.; et al. Immune-Mediated Mechanisms in Cofactor-Dependent Food Allergy and Anaphylaxis: Effect of Cofactors in Basophils and Mast Cells. Front. Immunol. 2021, 11, 623071. [Google Scholar] [CrossRef]
- Aihara, M.; Miyazawa, M.; Osuna, H.; Tsubaki, K.; Ikebe, T.; Aihara, Y.; Ikezawa, Z. Food-dependent exercise-induced anaphylaxis: Influence of concurrent aspirin administration on skin testing and provocation. Br. J. Dermatol. 2002, 146, 466–472. [Google Scholar] [CrossRef]
- Ukleja-Sokołowska, N.; Zacniewski, R.; Gocki, J.; Zbikowska-Gotz, M.; Lis, K.; Sokolowski, L.; Bartuzi, Z. LTP allergy or food-dependent exercise-induced anaphylaxis? Allergy Asthma Immunol. 2017, 22, 87–92. [Google Scholar]
- Hoffmann, H.J.; Santos, A.F.; Mayorga, C.; Nopp, A.; Eberlein, B.; Ferrer, M.; Rouzaire, P.; Ebo, D.G.; Sabato, V.; Sanz, M.L.; et al. The clinical utility of basophil activation testing in diagnosis and monitoring of allergic disease. Allergy 2015, 70, 1393–1405. [Google Scholar] [CrossRef] [PubMed]
- Bahri, R.; Custovic, A.; Korosec, P.; Tsoumani, M.; Barron, M.; Wu, J.; Sayers, R.; Weimann, A.; Ruiz-Garcia, M.; Patel, N.; et al. Mast cell activation test in the diagnosis of allergic disease and anaphylaxis. J. Allergy Clin. Immunol. 2018, 142, 485–496.e16. [Google Scholar] [CrossRef]
- Squire, T.L.; Lee, H.J. Lysis in vitro of sensitized leucocytes by ragweed antigen. J. Allergy 1947, 18, 156–163. [Google Scholar] [CrossRef]
- Black, A.P. A New diagnostics method in allergic disease. Pediatrics 1956, 17, 716–724. [Google Scholar] [CrossRef] [PubMed]
- Bryan, W.T.K.; Bryan, M.P. The application of in vitro cytotoxic reactions to clinical diagnosis of food allergy. Laryngoscope 1960, 70, 810–824. [Google Scholar] [CrossRef]
- Demoly, P.; Lebel, B.; Arnoux, B. Allergen-induced mediator release tests. Allergy 2003, 58, 553–558. [Google Scholar] [CrossRef] [PubMed]
- Wüthrich, B. Unproven techniques in allergy diagnosis. J. Investig. Allergol. Clin. Immunol. 2005, 15, 86–90. [Google Scholar]
- Muraro, A.; Werfel, T.; Hoffmann-Sommergruber, K.; Roberts, G.; Beyer, K.; Bindslev-Jensen, C.; Cardona, V.; Dubois, A.; duToit, G.; Eigenmann, P.; et al. EAACI Food Allergy and Anaphylaxis Guidelines Group. EAACI food allergy and anaphylaxis guidelines: Diagnosis and management of food allergy. Allergy 2014, 69, 1008–1025. [Google Scholar] [CrossRef]
- Santos, A.F.; Riggioni, C.; Agache, I.; Akdis, C.A.; Akdis, M.; Alvarez-Perea, A.; Alvaro-Lozano, M.; Ballmer-Weber, B.; Barni, S.; Beyer, K.; et al. EAACI guidelines on the diagnosis of IgE-mediated food allergy. Allergy 2023, 78, 3057–3076. [Google Scholar] [CrossRef]
- Singh, A.; Holvoet, S.; Weiss, M.; Beaumont, M.; Zuercher, A.W.; Mercenier, A. Increased IL-5 and IL-13 cytokine level in ex vivo stimulated whole blood cells from grass pollen allergic donors correlate with seasonal exposure. Results Immunol. 2011, 1, 18–23. [Google Scholar] [CrossRef]
- Spinozzi, F.; Agea, E.; Piattoni, S.; Bistoni, O.; Grignani, F.; Bertotto, A. Co-stimulation-induced release of pro-inflammatory cytokine interleukin-8 by allergen-specific T cells. Scand. J. Immunol. 1996, 44, 80–84. [Google Scholar] [CrossRef] [PubMed]
- Nukada, Y.; Miyazawa, M.; Kosaka, N.; Ito, Y.; Sakaguchi, H.; Nishiyama, N. Production of IL-8 in THP-1 cells following contact allergen stimulation via mitogen-activated protein kinase activation or tumor necrosis factor-alpha production. J. Toxicol. Sci. 2008, 33, 175–185. [Google Scholar] [CrossRef] [PubMed]
- Summer, B.; Ständer, S.; Thomas, P. Cytokine patterns in vitro, in particular IL-5/IL-8 ratio, to detect patients with nickel contact allergy. J. Eur. Acad. Dermatol. Venereol. 2018, 32, 1542–1548. [Google Scholar] [CrossRef] [PubMed]
- KleinJan, A.; Dijkstra, M.D.; Boks, S.S.; Severijnen, L.A.; Mulder, P.G.; Fokkens, W.J. Increase in IL-8, IL-10, IL-13, and RANTES mRNA levels (in situ hybridization) in the nasal mucosa after nasal allergen provocation. J. Allergy Clin. Immunol. 1999, 103, 441–450. [Google Scholar] [CrossRef]
- El-Mezzein, R.E.; Matsumoto, T.; Nomiyama, H.; Miike, T. Increased secretion of IL-18 in vitro by peripheral blood mononuclear cells of patients with bronchial asthma and atopic dermatitis. Clin. Exp. Immunol. 2001, 126, 193–198. [Google Scholar] [CrossRef]
- Savolainen, J.; Laaksonen, K.; Rantio-Lehtimäki, A.; Terho, E.O. Increased expression of allergen-induced in vitro interleukin-10 and interleukin-18 mRNA in peripheral blood mononuclear cells of allergic rhinitis patients after specific immunotherapy. Clin. Exp. Allergy 2004, 34, 413–419. [Google Scholar] [CrossRef]
Parameter | Result | Unit | Reference Value |
---|---|---|---|
Blood count with white blood cell differential | |||
White Blood Cells (WBC) | 5.80 | G/L | 3.9–10.2 |
Red Blood Cells (RBC) | 4.31 | T/L | 4.0–5.0 |
Hemoglobin (Hb) | 13.0 | g/dL | 12.0–16.0 |
Hematocrit (HCT) | 38.0 | % | 37.0–47.0 |
Mean Corpuscular Volume (MCV) | 90.5 | fL | 80.0–99.0 |
Mean Corpuscular Hemoglobin (MCH) | 30.2 | pg | 27.0–33.5 |
Mean Corpuscular Hemoglobin Concentration (MCHC) | 33.3 | g/dL | 31.0–37.0 |
Platelets (PLT) | 252 | G/L | 130–400 |
Mean Platelet Volume (MPV) | 11.8 | fL | 8.5–12.5 |
Neutrophils | 3.77 | G/L | 1.5–1.7 |
Basophils | 0.11 | G/L | 0.02–0.55 |
Eosinophils | 0.03 | G/L | 0.00–0.20 |
Lymphocytes | 1.41 | G/L | 1.1–4.5 |
Monocytes | 0.46 | G/L | 0.1–1.0 |
Inflammation parameters | |||
Erythrocyte Sedimentation Rate (ESR) | 8 | mm/h | <11 |
C-Reactive Protein (CRP) | <0.6 | mg/L | <5.0 |
Basic biochemistry | |||
Sodium | 137 | mmol/L | 135–145 |
Potassium | 4.44 | mmol/L | 3.5–5.0 |
Creatinine | 0.71 | mg/dL | 0.51–0.95 |
eGFR (Estimated Glomerular Filtration Rate; according to CKD-EPI) | 118 | mL/min | >90 |
Urea | 30 | mg/dL | 17–48 |
Glucose (serum) | 81 | mg/dL | 70–99 (fasting) |
Immunochemical tests | |||
Thyrotropin (TSH; 3rd generation test) | 0.627 | mU/L | 0.270–4.200 |
25-(OH) vitamin D | 10.83 | ng/mL | Deficit: <20 Low: 20–30 Optimal: 30–50 High: 50–100 |
Anti-Peroxidase Antibodies (anti-TPO) | 107.2 | IU/mL | <34 |
Anti-Thyroglobulin Antibodies (anti-TG) | 85.6 | IU/mL | <115 |
Coagulation and fibrinolysis parameters | |||
Prothrombin Time (PT) | 11.2 | seconds | 9.6–14.3 |
International Normalized Ratio (INR) | 0.95 | 0.8–1.2 | |
Activated Partial Thromboplastin Time (APTT) | 33.0 | seconds | 23–37 |
Source | Allergen | Extract (E)/Molecule (M) | Protein Family | sIgE [kUA/L] |
---|---|---|---|---|
London plane (Platanus acerifolia) | Pla a 3 | M | nsLTP | 2.7 |
Hemp (Cannabis sativa) | Can s 3 | M | nsLTP | 7.48 |
Hemp (Cannabis sativa) | Can s | E | - | 1.1 |
Common mugwort (Artemisia vulgaris) | Art v 3 | M | nsLTP | 2.23 |
Peanut (Arachis hypogaea) | Ara h 9 | M | nsLTP | 1.31 |
Maize (Zea mays) | Zea m 14 | M | nsLTP | 7.73 |
Maize (Zea mays) | Zea m | E | - | 5.23 |
Strawberry (Fragaria × ananassa) | Fra a 1 + Fra a 3 | M + M | PR-10 + nsLTP | 1.98 |
Apple (Malus domestica) | Mal d 3 | M | nsLTP | 1.79 |
Peach (Prunus persica) | Pru p 3 | M | nsLTP | 1.26 |
Grape (Vitis vinifera) | Vit v 1 | M | nsLTP | 0.68 |
Celery (Apium graveolens) | Api g 2 | M | nsLTP | 2.12 |
Tomato (Solanum lycopersicum) | Sola l 6 | M | nsLTP | 0.36 |
Common walnut (Juglans regia) | Jug r 3 | M | nsLTP | 10.37 |
Blue mussel (Mytilus edulis) | Myt e | E | nsLTP | 0.38 |
Common wasp (Vespula vulgaris) venom | Ves v 5 | M | Antigen 5 | 0.55 |
Inhalant Allergens | Food Allergens | ||
---|---|---|---|
Allergen | SPT result | Allergen | SPT result |
Hazel (pollen) | Negative | Peanut | Positive |
Silver birch (pollen) | Negative | Orange | Positive |
Alder (pollen) | Negative | Cow milk (full extract) | Negative |
Common mugwort (pollen) | Negative | Hen’s egg yolk | Negative |
Common rye (pollen) | Negative | Hen’s egg white | Negative |
Grass—mix (pollen) | Negative | Cow milk—casein | Negative |
Cat dander | Negative | Cod | Negative |
Dermatophagoides farinae | Negative | Shrimp | Negative |
Dermatophagoides pteronyssinus | Negative | Hazelnut | Negative |
Alternaria alternata | Negative | Wheat flour | Negative |
Cladosporium herbarum | Negative | Soy flour | Negative |
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Share and Cite
Rydzyńska, M.; Lis, K.; Bartuzi, Z.; Rosada, T.; Grześk-Kaczyńska, M.; Ukleja-Sokołowska, N. Allergy to Lipid Transfer Protein or Hypersensitivity to Non-Steroidal Anti-Inflammatory Drugs? Int. J. Mol. Sci. 2025, 26, 5988. https://doi.org/10.3390/ijms26135988
Rydzyńska M, Lis K, Bartuzi Z, Rosada T, Grześk-Kaczyńska M, Ukleja-Sokołowska N. Allergy to Lipid Transfer Protein or Hypersensitivity to Non-Steroidal Anti-Inflammatory Drugs? International Journal of Molecular Sciences. 2025; 26(13):5988. https://doi.org/10.3390/ijms26135988
Chicago/Turabian StyleRydzyńska, Magdalena, Kinga Lis, Zbigniew Bartuzi, Tomasz Rosada, Magdalena Grześk-Kaczyńska, and Natalia Ukleja-Sokołowska. 2025. "Allergy to Lipid Transfer Protein or Hypersensitivity to Non-Steroidal Anti-Inflammatory Drugs?" International Journal of Molecular Sciences 26, no. 13: 5988. https://doi.org/10.3390/ijms26135988
APA StyleRydzyńska, M., Lis, K., Bartuzi, Z., Rosada, T., Grześk-Kaczyńska, M., & Ukleja-Sokołowska, N. (2025). Allergy to Lipid Transfer Protein or Hypersensitivity to Non-Steroidal Anti-Inflammatory Drugs? International Journal of Molecular Sciences, 26(13), 5988. https://doi.org/10.3390/ijms26135988