nAna c 2 Bromelin, Pineapple

Further Reading

Pineapple f210

Code: k202
Common names: Bromelin/Bromelain
Occupational
An occupational allergen, which may result in allergy symptoms in sensitised individuals.
 
Bromelin is a natural plant-derived proteolytic enzyme found in members of the Bromeliaceae family.

Allergen Exposure

Geographical distribution
Bromelin is a natural plant-derived proteolytic enzyme found in members of the Bromeliaceae family, typified by Pineapple. The Pineapple plant (Ananas comosus), like other members of this family, contains a number of proteolytic enzymes – also called cysteine proteinases – which are immunologically distinct. The major proteinase present in extracts of the plant stem is Stem bromelin, while Fruit bromelin is the major proteinase in the fruit. Two additional cysteine proteinases are found only in the stem: ananain and comosain (1).
 
Because of their catalytic activity, cysteine proteinases are commonly used in the food and pharmaceutical industries and in diagnostic laboratories.
 
Environment
Bromelin is sold as a white to light tan amorphous powder. It is soluble in water, the solutions ranging from colourless to light yellow; it is practically insoluble in alcohol, chloroform and ether.
 
Together with Papain, Bromelin is used in the industrial preparation of meat (tenderising) and in brewing beer (clarifying) (2). It is also used as an anti-inflammatory drug (3).
 
Bromelin has been used to manufacture hypoallergenic bread (4). In Pineapples themselves, the Bromelin is destroyed in the canning process.
 
Bromelin is used medicinally in concentrated tablet form to aid the digestion of protein. It is also used as an anti-inflammatory for osteo- and rheumatoid arthritis.
 
Unexpected exposure
See under Environment.
 
Allergens
In the Pineapple plant (f210), Bromelin is characterised as the Ana c 2 allergen. The Pineapple plant contains a number of proteolytic enzymes (cysteine proteinases), which are immunologically distinct (1).
 
Bromelin is a protein with cross-reactive carbohydrate determinants, which have been shown to cross-react with several glycoallergens. Bromelin can be used to detect IgE to the carbohydrate side chain of glycoproteins (5). (See under Potential Cross-reactivity.)

Potential Cross-Reactivity

The presence of IgE to Bromelin could be a useful and simple marker of the presence of IgE to carbohydrate epitopes (6). About 41% of patients multiallergic to pollens have been reported to have serum-specific IgE for a glycoprotein, without a positive skin-specific IgE test response to the same molecule. These glycoproteins, or cross-reactive carbohydrate determinants (CCDs), may need to be considered during evaluation of the clinical relevance of positive results of in vitro specific IgE assays, in particular in the diagnosis of patients with pollen allergy, in order to avoid false-positive or clinically irrelevant results (7).
 
Earlier studies have shown that IgE specific for CCDs occurs in about 25% of Celery-allergic patients, and may represent the major proportion of specific IgE directed against Celery (8). Other studies have similarly reported that Celery-allergic and Cypress pollen-allergic patients have IgE directed against carbohydrate epitopes that seem to be shared by Bromelin (3, 9). The presence of skin-specific and/or serum-specific IgE for Celery, Papain, Carrot, Fennel, Cypress pollen, grass pollen, and Compositae may be a result of cross-reactivity between Bromelin and these substances (8-9). An early study of individuals hypersensitive to Papain and asthmatic patients with allergies to other inhalant and food allergens concluded that there appeared to be a relation between the antibody reactions to Papain and Bromelin, and in several cases also between the reactions to these proteases and to grass pollen and flour. Studies using RAST inhibition showed that Papain, Bromelin, Wheat flour, Rye flour, grass pollen and Birch pollen mutually inhibit IgE antibody to each antigen; but the degree of inhibition varied among the different sera and allergens. These results suggested that these allergens from various plants, besides having specific antigenic determinants, also possess similar or even identical antigenically active regions, leading to immunological cross-reactivity from so-called CCDs (10).
 
CCDs may play a role in cross-reactivity in Cupressaceae-allergic individuals (11), and other proteases such as Papain (12). It has been reported that Hymenoptera stings can induce specific IgE to carbohydrate determinants on venom glycoproteins, resulting in cross-reactivity with carbohydrate determinants in pollen. Specific IgE to such CCDs is believed to have little or no biological activity and thus may cause misdiagnosis of pollen sensitisation after a sting. The risk for misdiagnosis of multivalent pollen sensitisation in Hymenoptera venom-allergic patients is 16%: sting-induced anti-pollen specific IgE may be directed to similar CDs in venoms and pollen. Importantly, a positive Bromelin CAP test did not exclude clinical reactivity to venom in “CCD-positive” Hymenoptera venom-allergic patients (13). Similarly, CCD-specific IgE was found to be a major cause for the double positivity to Honey bee and Yellow jacket venom seen in patients with Hymenoptera allergy. The study suggested that because these antibodies may have low clinical relevance, they may severely impede the correct diagnosis of Hymenoptera venom allergy (14).

Clinical Experience

IgE-mediated reactions
Adverse reactions to Bromelin are characterised mainly by allergic asthma after inhalation of the substance, and mainly in occupational settings (15-16). Bromelin is a powerful sensitising substance, but sensitisation usually follows its inhalation and not its ingestion. Bromelin causes IgE-mediated reactions of both the immediate and the “late phase” type (17). As Papain and Bromelin are used to tenderise meat and clarify beer, it has been suggested that these enzymes are also potential ingestive allergens and may represent an unrecognised cause of allergic reactions following meals (18).
 
Most reports of adverse reactions to Bromelin are found in early studies. It may well be that, as this allergen has been identified as a significant occupational allergen, protective measures instituted have resulted in a decrease in adverse reactions.
 
Early reports of adverse reactions to Bromelin include a report of 2 individuals with asthma caused by inhalation of Bromelin. Skin-specific IgE test results with Bromelin extract were positive. Inhalation tests resulted in immediate reactions, which were blocked by sodium cromoglycate but not corticosteroids (19).
 
Four cases of occupational allergy to Bromelin in workers at a blood grouping laboratory were described (17). The authors caution that skin-specific IgE testing with relatively pure allergens such as Bromelin may induce systemic reactions, even at very high dilutions (17).
 
A 47-year-old woman developed generalised urticaria and angioedema, palpebral-labial oedema, nausea, abdominal pain and diarrhoea 10 minutes after ingesting an Ananase tablet which contained Bromelin. Skin-specific IgE was not detected for Pineapple and was not done for Bromelin. Serum-specific IgE was positive for, among others, Bromelin (15.4 kU/l) and Papain (3.1 kU/l). A patch test was negative (3).
 
A 58-year-old pharmaceutical worker who regularly developed asthma and rhinitis when handling Bromelin was shown to have skin- and serum-specific IgE to Bromelin. Both an inhalation test with 0.03 mg Bromelin and a perioral challenge by ingestion of 190 g Pineapple resulted in asthma; the latter challenge was accompanied by gastrointestinal symptoms. Five of 6 workers sensitised to Papain were shown to have serum- and skin-specific IgE to Bromelin. Immediate asthmatic reactions after bronchial challenge with Bromelin occurred in 2. Out of 60 asthmatic individuals who had not been exposed to airborne proteases but probably to proteases as constituents of foods, 2 had positive skin-specific IgE tests, and 8 had serum-specific IgE to Bromelin. In no case was there clear evidence for clinical sensitisation (10, 20).
 
Ten sensitised and 10 nonsensitised workers from a pharmaceutical factory who had been exposed to powdered trypsin, chymotrypsin, Bromelin, Papain, amylase, and lipase were investigated. Skin-specific IgE determination demonstrated sensitisation to multiple proteolytic enzymes, i.e., Papain (specifically sensitised/total number of sensitisations: 9/10), trypsin (8/10), chymotrypsin (8/10), and Bromelin (7/10), and appeared to be more frequent and more pronounced than sensitisations to amylase (3/10) or lipase (3/10) (2).
Bromelin has been reported to be an unusual cause of allergic contact cheilitis (21).
 
Other reactions
Bromelin may result in skin irritation; workers in the Pineapple industry wear protective clothing to prevent skin damage.
 
Bromelin, present in a herbal product, may potentially increase the risk of bleeding or potentiate the effects of warfarin therapy (22).
 
Compiled by Dr Harris Steinman, harris@zingsolutions.com.

References

  1. Rowan AD, Buttle DJ, Barrett AJ. The cysteine proteinases of the pineapple plant. Biochem J 1990;266(3):869-75
  2. Zentner A, Jeep S, Wahl R, Kunkel G, Kleine-Tebbe J Multiple IgE-mediated sensitizations to enzymes after occupational exposure: evaluation by skin prick test, RAST, and immunoblot. Allergy 1997;52(9):928-934
  3. Nettis E, Napoli G, Ferrannini A, Tursi A. IgE-mediated allergy to bromelain. Allergy 2001;56(3):257-8
  4. Tanabe S, Arai S, Watanabe M. Modification of wheat flour with bromelain and baking hypoallergenic bread with added ingredients. Biosci Biotech  Biochem 1996;60(8):1269-72
  5. Ebo D, Hagendorens M, Bridts C, De Clerck L, Stevens W. Sensitization to cross-reactive carbohydrate determinants and the ubiquitous protein profilin: mimickers of allergy. Clin Exp Allergy 2004;34(1):137-144
  6. Mari A. IgE to Cross-Reactive Carbohydrate Determinants: Analysis of the Distribution and Appraisal of the in vivo and in vitro Reactivity. Int Arch Allergy Immunol 2002;129(4):286-95
  7. Mari A, Iacovacci P, Afferni C, Barletta B, Tinghino R, Di Felice G, Pini C. Specific IgE to cross-reactive carbohydrate determinants strongly affect the in vitro diagnosis of allergic diseases. J Allergy Clin Immunol 1999;103(6):1005-11.
  8. Fotisch K, Altmann F, Haustein D, Vieths S. Involvement of carbohydrate epitopes in the IgE response of celery-allergic patients. Int Arch Allergy Immunol 1999;120(1):30-42
  9. Batanero E, Villalba M, Monsalve RI, Rodriguez R. Cross-reactivity between the major allergen from olive pollen and unrelated glycoproteins: evidence of an epitope in the glycan moiety of the allergen. J Allergy Clin Immunol 1996;97(6):1264-71.
  10. Baur X. Studies on the specificity of human IgE-antibodies to the plant proteases papain and bromelain. Clin Allergy 1979;9:451-457
  11. Afferni C, Iacovacci P, Barletta B, Di Felice G, Tinghino R, Mari A, Pini C. Role of carbohydrate moieties in IgE binding to allergenic components of Cupressus arizonica pollen extract. Clin Exp Allergy 1999;29(8):1087-94
  12. Tanabe S, Tesaki S, Watanabe M, Yanagihara Y Cross-reactivity between bromelain and soluble fraction from wheat flour. [Japanese] Arerugi 1997;46(11):1170-3
  13. Kochuyt AM, Van Hoeyveld EM, Stevens EA. Prevalence and clinical relevance of specific immunoglobulin E to pollen caused by sting-induced specific immunoglobulin E to cross-reacting carbohydrate determinants in Hymenoptera venoms. Clin Exp Allergy 2005;35(4):441-7.
  14. Hemmer W, Focke M, Kolarich D, Wilson IB, Altmann F, Wohrl S, Gotz M, Jarisch R. Antibody binding to venom carbohydrates is a frequent cause for double positivity to honeybee and yellow jacket venom in patients with stinging-insect allergy. J Allergy Clin Immunol 2001;108(6):1045-52
  15. Cortona G, Beretta F, Traina G, Nava C. Preliminary investigation in a pharmaceutical industry: bromelin-induced pathology (author's transl). [Italian] Med Lav 1980;71(1):70-5.
  16. Mattei O, Fabri G, Farina G. Occupational health experience regarding four cases of asthma due to bromelain (author's transl). [Italian] Med Lav 1979;70(5):404-9.
  17. Gailhofer G, Wilders-Truschnig M, Smolle J, Ludvan M. Asthma caused by bromelain: an occupational allergy. Clin Allergy 1988;18(5):445-50.
  18. Wüthrich B. Proteolytic enzymes: potential allergens for the skin and respiratory tract? [German] Hautarzt 1985;36(3):123-125
  19. Galleguillos F, Rodriguez JC. Asthma caused by bromelin inhalation. Clin Allergy 1978;8(1):21-4.
  20. Baur X, Fruhmann G. Allergic reactions, including asthma, to the pineapple protease bromelain following occupational exposure. Clin Allergy 1979;9(5):443-50
  21. Raison-Peyron N, Roulet A, Guillot B, Guilhou JJ. Bromelain: an unusual cause of allergic contact cheilitis. Contact Dermatitis 2003;49(4):218-9.
  22. Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm 2000;57(13):1221-7

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.