nCar p 1 Papain, Papaya

Code: k201
Source material: nCar p 1 is purified from a Papaya extract
Enzyme
An enzyme, which may result in allergy symptoms in sensitised individuals.

Allergen Exposure

Geographical distribution
Papain is a proteolytic enzyme found mainly in the unripe fruit of the Papaya tree (1). It is made from the latex of the full grown but unripe Papaya fruit; it is also present in the leaves and trunk, and is found even during various stages of ripening after incision of the unripe fruit (2). Commercial Papain may contain, in addition to itself, chymopapain, lysozyme, a small amount of Papaya peptidase A, lipase and other constituents (3).
 
Among these, chymopapain, also a proteolytic enzyme, and extracted from a fraction of non-crystallized Papaya latex, has been used since 1965 as an injection for proteolysing herniated invertebral disks (chemonucleolysis).
 
Chymopapain has considerable structural similarity to Papain and Papaya proteinase (4). Because Papain and chymopapain have the same antigenic determinants, they exhibit cross-reactivity. In fact, chymopapain is the major active component of Papain and is more soluble and has greater proteolytic activity than Papain.
 
Environment
Papain has numerous uses and applications, including as a tenderiser for meat, and for Calamari/Squid and other cephalopods. Papain may also be used in the preparation of canned meats. It has been a clarifying agent in beer and a contact lens cleaner. It is often a reagent in the pharmaceutical, cosmetic and immunochemical industry. Papain is widely used by biochemists as a reagent in laboratories.
 
Unexpected exposure
See under Environment.
 
Allergens
No allergens from this substance have yet been characterised.
The latex of the unripe fruit of the Papaya plant contains 4 immunologically distinct cysteine proteinases: caricain, glycyl endopeptidase, chymopapain and Papain. In a study of Chymodiactin, a pharmaceutical preparation of chymopapain used in chemonucleolysis for the treatment of sciatica, all 4 Papaya cysteine proteinases were demonstrated to be present. In an examination of the sera or 12 individuals with specific IgE to chymodiactin that contained 70% chymopapain, 20% caricain, 4% glycyl endopeptidase, and 0.1% Papain, specific IgE was found to all 4 proteinases in most of the 12 sera, but in varying proportions. Antibodies to glycyl endopeptidase were predominant in 8 sera, and the mean amounts of IgE directed against each protein were the following: glycyl endopeptidase, 4.21 IU/ml; caricain, 2.9 IU/ml; chymopapain, 1.97 IU/ml; and Papain, 1.39 IU/ml (5). 

Potential Cross-Reactivity

Papain is a thiol protease. A thiol protease is a proteolytic enzyme with a cysteine residue in its active site. There are many families of thiol proteases. The best known is the Papain family. The following are possibly cross-reacting thiol proteases:
 
-  Bromelin/Bromelain, isolated from Pineapple stem;
-  Papain, isolated from Papaya;
-  Ficin, isolated from Fig.
 
Other thiol proteases include calpains and cathepsins.
 
Clinical evidence also suggests that Papain and chymopapain have common allergenicity. Patients who become sensitised to Papain may subsequently experience an allergic reaction when they are exposed to chymopapain. An early study demonstrated cross-antigenicity between Papain and chymopapain. Serum samples from 6 patients who had significant skin-specific IgE to Papain were shown to have specific IgE to both Papain and chymopapain. Sera from 12 patients who had discolysis treated with chymopapain, and who had no clinical hypersensitivity, were shown to have serum-specific IgE to Papain as well as to chymopapain (6).
 
The protease Bromelin/Bromelain has been reported to have a high similarity to other proteases such as Papain (7), and evidence for immunological cross-reactivity in human subjects has been reported between these 2 (8). Five of 6 workers sensitised to Papain were demonstrated to have serum- and skin-specific IgE to Bromelin, and two experienced immediate asthmatic reactions after bronchial challenge with Bromelin. Evidence for immunological cross-reaction between Bromelin and Papain in human subjects was demonstrated (8).
 
Sensitisation to Weeping fig (Ficus benjamina) latex in atopic individuals usually occurs independently of allergy to Latex (Hevea). Sensitisation is commonly associated with allergic reactions to Fig and other tropical fruits. In a study, sensitisation to Weeping fig was specifically associated with positive skin-specific IgE to fresh Fig (83%), dried Fig (37%), Kiwi fruit (28%), Papaya (22%), Avocado (19%), Banana (15%), and Pineapple (10%) (n = 54). The authors concluded that the cross-reactivity was mediated at least in part by the thiol proteases ficin and Papain (9). The same authors reported in a second study that of 5 patients with oral allergy syndrome (OAS) or anaphylaxis after the ingestion of Fig and 1 patient with symptoms from exposure to Weeping fig tree, serum-specific IgE to Papain was positive in 3 of the 5 patients (10). Similar findings have been reported by other authors, suggesting that associations between certain allergies – to Fig and Papain (11), to Natural rubber latex and Papain (12), and to Natural rubber latex, Papain and Papaya (13) – are likely due to cross-reactive allergen structures. Kiwi fruit contains Actinidin, a proteolytic enzyme, with physical and chemical properties similar to those of Papain, which can perhaps explain this hypersensitivity (14).
 
In 6 patients with seasonal rhinoconjunctivitis or asthma from Papaya (Carica papaya) tree pollen, commercial tests evaluating skin-specific IgE and serum-specific IgE to Papaya fruit and Papain were positive, suggesting the existence of common allergens among Papaya flower pollen, Papaya fruit, and Papain. This was also demonstrated by RAST inhibition studies (15).
 
In 29 patients with allergy to fruits or vegetables who lived in an area without Birch trees, 79.3% were allergic to grass pollen, and 2 had clinical allergy to Latex. Serum-specific IgE to Birch pollen was found in 65% of these patients, to Bet v 2 of Birch pollen in 51.7%, to Bet v 1 of Birch pollen in 3.4%, to Latex in 58.6%, to Bromelin/Bromelain in 51.7%, and to Papain in 17.2% (16). 

Clinical Experience

IgE-mediated reactions
Early reports frequently held that Papain may induce symptoms of allergy in sensitised individuals (17). The recent decreased frequency of such reports may indicate that the awareness of Papain’s sensitisation potential has resulted in improved safety precautions for individuals in the relevant settings.
 
Papain can induce IgE allergy reactions through different routes: respiratory, contact, or digestive (18-22). The most common sensitisation route is inhalation. The rate of sensitisation is high. Occupational allergy to Papain in exposed workers was described some years ago; workers presented with bronchial asthma, rhinitis or both. In most of the cases, specific IgE was positive (23-24). Contact with Papain may also result in anaphylaxis (3).
 
Papain hypersensitivity has often been reported among pharmacists and factory workers exposed to the substance, but few non-occupational cases have been described. One of the first reports of allergic reactions to Papain was in 1945, when an individual developed severe paroxysmal cough, rhinitis and dyspnoea as a result of caroid (commercial Papain) tooth powder (25). Other non-occupational reports have followed. A 28-year-old male who had previously experienced angioedema, urticaria, and acute dyspnoea after contact with rubber gloves developed angioedema after ingestion of Papaya cake during a party. Serum-specific IgE to Papain was found (13). An early report described a patient who experienced a severe systemic allergic reaction after ingesting meat tenderiser. Sensitisation to Papain was shown. The authors suggested that, as Papain-containing products are commonly used throughout society, Papain hypersensitivity may represent an unrecognised cause of allergic symptoms (26). The lead author, in a subsequent study of 500 allergy clinic patients tested for the presence of skin-specific IgE to Papain, found that 5 of 475 subjects with seasonal allergic disease had positive skin tests to both Papain and local pollens. All 5 Papain-sensitised subjects were positive to double-blind placebo-controlled challenges with Papain. Papain-induced symptoms included palatal itching, watering, itchy eyes, sneezing, rhinorrhea, abdominal cramps, diarrhoea, and diaphoresis. Serum-specific IgE to Papain was found in all 5 patients, as well as cross-reacting antibodies with chymopapain (27). Latent sensitisation also occurs in the general population as a result of eating Papaya. The prevalence of sensitisation has been estimated to be between 1-2% (28, 29), but a study reported that in a particular group of patients, IgE antibodies to Papain were probably present in 2% - 6% (3). In communities where Papaya is more frequently consumed, latent sensitisation will be more prevalent.
 
In a French study, 700 patients were investigated prospectively before undergoing chemonucleolysis; they were chosen because of a history of allergy and/or previous exposure to Papain, either in food, beverages or drugs. They were tested for skin-specific IgE to chymopapain, and based on the results, the subjects were classified into 4 groups: Group I, 225 non-atopic, non-Papain-exposed subjects; Group II, 285 non-atopic, Papain-exposed subjects; Group III, 69 atopic, non-Papain-exposed subjects; and Group IV, 121 atopic, Papain-exposed subjects. Latent sensitisation to Papain was observed in 0.4% of subjects in Group I, 3.16% in Group II, 5.8% in Group III and 7.4% in Group IV (30). Other studies have reported that chymopapain used in intradiscal injections for the treatment of patients with chemonucleolysis may induce IgE-mediated anaphylaxis in approximately 1% of the patients treated (15).
 
Papain was used in early versions of soft contact lens solutions; this was thought to be the cause of contact urticaria in an individual user (31).
 
Papain is a very important and common occupational allergen, resulting in occupational asthma, rhinitis or both (21-22). A number of studies attest to this fact.
 
An early study reported that 17 of 33 workers who were regularly exposed to airborne Papain developed asthmatic symptoms such as shortness of breath, wheezing, coughing, sneezing, rhinorrhoea and contact conjunctival irritation. Skin- and serum-specific IgE and bronchial provocation tests proved IgE-mediated hypersensitivity to Papain in 14 of these workers. Bronchial provocation was positive to as little as 0.001--0.5 mg of Papain, and immediate or immediate and delayed asthmatic reactions were recorded in all 8 workers with serum-specific IgE to Papain greater than 3 u/ml. Non-IgE-mediated reactions included blood-stained nasal secretions and/or cutaneous flare reactions in 4 heavily-exposed Papain workers, suggesting a direct effect of the proteolytically active enzyme on human tissue. Of these 4, 3 had no evidence of skin- or serum-specific IgE to Papain (32).
 
Early studies suggested that airborne Papain is a highly immunogenic agent in humans, which results in immediate hypersensitivity reactions in a large percentage of the exposed subjects (33). In a study of 11 workers occupationally exposed to airborne Papain, 7 developed immediate hypersensitivity reactions, predominantly asthma and rhinitis. Skin- and serum-specific IgE determination for Papain was positive in all symptomatic workers, but not in the 4 asymptomatic workers. Bronchial provocation tests with 0.15-0.5 mg Papain performed in 5 patients with positive case histories showed in each case an immediate asthmatic reaction; in addition to that, 1 patient developed signs of a dual asthmatic reaction (33). Similarly, late-onset asthma occurred in a non-atopic worker in a factory where Papain powder was packed. The patient had had 3 attacks of asthma since first being exposed to atmospheric Papain dust. Skin-specific IgE to Papain was detected. The same study reported that a worker in another factory died following the precipitation of severe asthma shortly after re-exposure to Papain (34).
 
Similarly, occupational sensitisation to Papain powder with life-threatening anaphylaxis was reported in a 40-year-old male, who experienced urticaria, angioedema and glottic symptoms, as well as intermittant symptoms mimicking rheumatoid, gastrointestinal, cardiac and pulmonary disease following contact with Papain. He experienced a painful swelling of the inside of his knees, occasional swelling of the soles of his feet, increasing flatus, nausea, vomiting, mid-sternal pain, “thumping of the heart”, and general malaise (3).
 
As Papain is used in the pharmaceutical industry, it is not surprising to find reports of hypersensitivity reactions in this occupational setting (35). An early study, of 23 employees at a pharmaceutical plant manufacturing a new product containing Papain, found that 12 had cough, wheezing, dyspnoea or chest pain following exposure to Papain. The presence of specific IgE antibodies to Papain correlated significantly with decreases in lung function (36). Early reports document hypersensitivity reactions to caroid, a commercial Papain, in druggists. Rhinitis was described in a druggist following exposure to this product (37); rhinitis and asthma were reported in a druggist handling caroid; and in a third subject, angioedema and dyspnoea occurred after ingestion of caroid (38). In a study of 10 sensitised workers from a pharmaceutical factory who had been exposed to powdered trypsin, chymotrypsin, bromelain, Papain, amylase, and lipase, skin-specific IgE determination demonstrated sensitisation to multiple proteolytic enzymes, i.e., Papain (9/10), trypsin (8/10), chymotrypsin (8/10), and bromelain (7/10). These instances appeared to be more frequent and more pronounced than sensitisations to amylase (3/10) or lipase (3/10) (20).
 
Hypersensitivity reactions, including rhinoconjunctivitis, have also been described in cosmeticians and cosmetologists (39, 40). Two cases illustrate the risks. A 22-year-old woman was described who had worked in a beauty salon for 5 years and progressively developed contact urticaria, rhinoconjunctivitis, and asthma when she used Papain tablets dissolved in water for removing adhesives. She had never eaten Papaya and was asymptomatic with Pineapple, Kiwi, meat, beer, Latex and toothpaste. A 31-year-old woman who had worked in a beauty salon for 10 years reported rhinitis, asthma, and contact urticaria when she used Papain tablets for removing adhesives. She had never eaten Papaya and was asymptomatic with meat and Pineapple, but developed mouth itching after eating Kiwi. She did not drink beer. She tolerated Latex and toothpaste. Skin- and serum-specific IgE to Papain was present in both. Although cross-reactivity among Papain, bromelain, Latex, latex from Wheeping fig, and certain fruits occurs, in these 2 individuals this was not found (23).
 
A number of reports have recorded allergic reactions to Papain used as a tenderiser. Asthma was reported in an individual working in a meat tenderiser factory, after long-term contact with Papain dust. His symptoms were worse at work and better on weekends and vacations. Bronchial inhalation challenges resulted in both immediate and late asthma. Skin- and serum-specific IgE to Papain was detected (41). A worker using Papain as a tenderising agent for Squid/Calamari presented with contact urticaria, rhinoconjunctivitis and bronchial asthma to Papain. The routes of exposure to Papain were cutaneous and airborne. Skin- and serum-specific IgE to Papain was detected. Nasal challenge with Papain was positive (23).
 
An early report described 4 food technologists occupationally exposed to heavy concentrations of Papain dust in the air; 2 were reported to have developed immediate acute asthma. The symptoms of obstructive airways disease persisted for some months while both remained in the same working environment, presumably exposed to small, gradually diminishing amounts of residual Papain dust (42).
 
Importantly, individuals may be hypersensitive to Papaya alone, without being hypersensitive to Papain. A patient with systemic contact dermatitis to Papaya but without Papain hypersensitivity was described (43).
 
Compiled by Dr Harris Steinman, harris@zingsolutions.com

References

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