Route Of Exposure

Allergen Exposure

Papaya trees, which originated in West India, Mexico or Central America, are widely cultivated in tropical and subtropical areas worldwide. There are 2 types of papaya fruit: Hawaiian and Mexican. The Hawaiian varieties are the papayas commonly found in supermarkets. These pear-shaped fruits generally weigh about half a kilogram. Mexican papayas are oblong and may weigh up to 5 kg. Papaya skin is generally yellow to green. The flesh is bright orange, yellow or pinkish, depending on the variety, and small black seeds cluster in the centre. A properly ripened papaya is juicy, sweetish and somewhat like a cantaloupe in flavour.

The fruit can be used to make drinks, salads, marmalade and sweets. Papain, a protease enzyme weighing 23 kDa, is obtained from the latex of the full-grown but unripe papaya fruit; it is also present in the leaves and trunk. It has many industrial and consumer uses, including as a meat tenderiser, a clearing agent in the production of beer, a contact-lens cleaner, and a reagent in the biochemical and pharmaceutical industries. (See Papain.) The edible seeds have a spicy flavour, somewhat reminiscent of black pepper.

Unusually for a fruit, Papaya contains butyric or butanoic acid (1.2 mg/kg). This is a fatty acid also found in butter and used in the manufacture of plastics.

Clinical Relevance

Allergen Description

The following allergens have been characterised:

Car p 1 was previously known as Car p 3.

The latex is present in both the fruit and the plant, and is evident during various stages of ripening, after incision of the unripe fruit. The plant proteinases are present mainly in the unripe fruit of the papaya tree.

A class II chitinase is said to be present in the latex of Carica papaya, but not in the fruit. It is completely free of any proteolytic and bacteriolytic activities. The allergenicity of this protein was not investigated. Although the protein described in the study has properties similar to those of basic class I chitinases with lysozyme activity, it lacks an N-terminal hevein domain, and it has been suggested that it should be classified as a class II chitinase. Its allergenicity was not assessed.

The latex of the unripe fruit, from which Chymopapain is purified, contains another 3 immunologically distinct cysteine proteinases: 1) caricain, 2) glycyl endopeptidase, and 3) Papain. In a study, all 4 papaya cysteine proteinases were demonstrated to be present in Chymodiactin, a pharmaceutical preparation of Chymopapain which is used in chemonucleolysis for the treatment of sciatica, and which may result in allergic reactions. The contribution that each of the 4 proteinases makes to the allergic response that occasionally occurs during injection of a damaged intervertebral disc with Chymopapain preparations was evaluated. Specific IgE antibody levels to each of the 4 papaya cysteine proteinases were assayed by an enzyme-linked immunoassay in 12 sera containing IgE antibodies to Chymodiactin. Chymodiactin contained 70% Chymopapain, 20% caricain, 4% glycyl endopeptidase, and 0.1% Papain. IgE antibodies to all 4 proteinases were found 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. See Chymopapain.

In another study of the cysteine proteinases, it was found that papaya latex also contains other enzymes as minor constituents: a class-II and a class-III chitinase, an inhibitor of serine proteinases, and a glutaminyl cyclotransferase. The presence of a beta-1,3-glucanase and of a cystatin is also suspected, but they have not yet been isolated. Some of these substances are allergens in their own right, e.g. Chymopapain and Papain.

A profilin, probably with little clinical significance, has been demonstrated in papaya.

Potential Cross Reactivity

Extensive cross-reactivity between the different individual species of the genus could be expected, but in fact has not been reported.

Among patients with kiwi allergy, a group of researchers found strong reactions to apple and hazelnut; moderate reactions to carrot, potato, and avocado; and weak reactions to wheat and rye flour, pineapple and papaya, and their enzymes Bromelain and Papain.

It is clearly recognised that natural rubber latex allergy can be associated with serological cross-reactivity to plant allergens, especially in tropical fruits and Ficus. In contrast, data on the frequency and clinical value of specific IgE antibodies against these allergens remain rare. The purpose of one study was to investigate the prevalence, the sensitivity, and the specificity of these different specific IgE antibodies in patients suffering from NRL allergy. Serum samples of 42 NRL-allergic adults were investigated. A plant food-specific IgE antibody was observed in 88% of the serum samples, most frequently to papaya (71%) and least frequently to kiwi (17%). According to the questionnaire and the threshold of 0.35 kUa/L, sensitivity of the plant food IgE antibodies varied between 0% for papaya and 73% for avocado. Specificity varied between 28% for papaya and 91% for kiwi.

In 82 patients (43 men and 39 women, aged between 18 and 45 years) with latex allergy, 39 (47.5%) were found to have positive skin tests to fruit. Prick tests with fruit extracts were positive in 28 patients (kiwi, 21 patients; banana, 17 patients; avocado, 8 patients; and papaya, 3 patients); and the prick-by-prick test had positive results in 11 patients (kiwi, 7 patients; banana, 4 patients; and avocado, 3 patients).

Among 25 patients with latex allergy, including 9 greenhouse and 6 hospital workers, 42 food allergies were diagnosed in 13 patients (52%), and 23 of these allergies involved systemic anaphylaxis. The most frequent food hypersensitivities were to avocado (n=9), chestnut (n=9), banana (n=7), kiwi (n=5), and papaya (n=3).

In a study of latex allergy, cross-reacting IgE antibodies recognising latex and fruit allergens (papaya, avocado, banana, chestnut, passion fruit, fig, melon, mango, kiwi, pineapple, peach, and tomato) were demonstrated by RAST-inhibition tests. Putative class I chitinases seem to be relevant cross-reactive components in foods associated with latex-fruit syndrome, and to play a specific role in allergy to latex, but not to fruit.

A study concluded that allergic reactions to fresh or dried figs can present as a consequence of primary sensitisation to airborne Ficus benjamina allergens, independent of sensitisation to rubber latex allergens. Kiwi fruit, papaya, and avocado, as well as pineapple and banana, may be other fruits associated with sensitisation to Ficus allergens.

In RAST inhibition studies using Carica papaya pollen extract in solid phase, significant cross-reactivity was found between papaya pollen, papaya fruit, and Papain.

Clinical Experience

IgE-mediated reactions

Anecdotal evidence suggests that papaya may occasionally induce symptoms of food allergy in sensitised individuals; however, few studies have been reported to date. Reactions may occur to individual commercially-extracted components of papaya, e.g. Papain or Chymopapain. Reactions include urticaria, colitis, and anaphylaxis (sometimes to Papain). Papaya allergy is thought to be mainly due to cross-reactivity to latex, but may occur on its own.

A 23-year-old female presented with classical features of an immediate hypersensitivity reaction after contact with papaya. Skin-specific IgE to papaya extracts was positive.

A 28-year-old atopic patient was described who had experienced angioedema after ingestion of papaya cake during a party. A year before, he had also experienced angioedema, urticaria, and acute dyspnoea after contact with rubber gloves. Serum-specific IgE was positive to Papain. Two other latex-allergic patients tested with papaya latex were positive to this substance.

In 142 adult patients sensitised to foods (from among 7 698 patients visiting an outpatient clinic), 120 experienced clinical symptoms after consumption of 1 or more foods. The most frequent recorded symptoms were the following: urticaria/angioedema, in 84 patients (70%), oral allergy syndrome in 65 (54%), asthma in 48 (37%), and anaphylaxis in 33 (27.5%). Shellfish sensitisation occurred in 50 patients, fresh fruit sensitisation in 33, and nut sensitisation in 29. The most frequent causes of food hypersensitivity were shrimp (n=48 patients), squid (n=33), kiwi (n=14), papaya (n=14), avocado (n=13), and banana (n=12).

A 55-year-old woman without a history of atopic disease or drug allergy developed a maculopapular symmetric exanthematous rash about 2 days after taking throat lozenges containing papaya juice.

Other reactions

Carotenemia has been associated with papaya ingestion.

Atmospheric surveys carried out in different parts of India reveal that Caraica papaya is one of the allergenically important pollens of the country.

Asthma and hayfever to pollen from the tree have been recorded elsewhere. Among 6 patients with clinical histories of seasonal rhinoconjunctivitis or bronchial asthma in relation to Carica papaya tree exposure (suggestive of IgE-mediated respiratory allergy), commercial SPT and specific serum IgE to papaya fruit and Papain were positive in 4. IgE-mediated hypersensitivity to a papaya pollen extract was demonstrated in all patients by means of SPTs, specific serum IgE determinations, and conjunctival challenge tests.

Five hundred allergy clinic patients were skin-prick tested with Papain. Five of 475 subjects with seasonal allergic disease had positive skin tests to both Papain and local pollens. The 5 subjects with positive skin tests to Papain underwent double-blind placebo-Papain challenges: all the challenges were positive. Papain-induced symptoms included palatal itching, watery, itchy eyes, sneezing, rhinorrhea, abdominal cramps, diarrhoea, and diaphoresis. Circulating Papain-specific IgE was detected in all of the Papain-sensitive individuals.