Route Of Exposure

Allergen Exposure

The fig tree is believed to be indigenous to western Asia, and to have been distributed by man throughout the Mediterranean area. It has been cultivated for thousands of years, remnants of figs having been found in excavations of Neolithic sites dating back to at least 5 000 B.C. European types were eventually taken to China, Japan, India, South Africa, Australia, and North and South America. Some members of the fig family are ornamental plants (e.g. the weeping fig, or Ficus benjamina), and some produce rubber. Over 700 varieties of fig exist.

The fruit (usually pear-shaped, and up to 5 cm in diameter) is actually a swollen flower stalk; female flowers are borne on the inside of a fleshy structure called a receptacle, which expands greatly as the fruit matures. In some varieties, a female fig wasp crawls through the ostiole (a small hole at the end of the fig) to pollinate the flowers. Some varieties can bear fruit without pollination. Fermentation of the fruit can occur if there is too much rain during maturation, since rain can seep into fruit.

The tree grows among rocks and in woods and scrub, or in cultivated groves. In warm, humid climates, figs are generally eaten fresh and raw without peeling. Peeled or unpeeled, fresh, canned or dried, the fruits may be stewed or cooked in various ways, in pies, puddings, cakes, bread or other bakery products, or they may be added to ice cream mix. The fruits are sometimes preserved in sugar syrup or prepared as jam, marmalade, or paste. In Europe, western Asia, northern Africa and California, commercial canning and drying of figs are industries of great importance. Figs have been roasted and ground up as a coffee substitute. In Mediterranean countries, low-grade figs are converted into alcohol, which is sometimes used as a flavouring for liqueurs and tobacco. The seed yields an edible oil that can also be a lubricant. The leaves can be an animal fodder. The latex is dried and powdered for coagulating plant and animal milk. From it can be isolated the protein-digesting enzyme ficin, which is used for tenderising meat, rendering fat, and clarifying beverages.

The latex is widely applied on warts, corns, skin ulcers, insect bites, and piles, and taken as a purgative and vermifuge, but with considerable risk. (See under Other Rreactions.) In Latin America, figs are often employed as folk remedies. A decoction of the fruits is gargled to relieve sore throat and diseases of the chest; figs boiled in milk are packed against swollen gums; the fruits are often used as poultices on tumours and other abnormal growths. The unripe green fruits are cooked with other foods as a galactagogue and tonic. A leaf decoction is taken as a remedy for stomach complaints, diabetes and calcifications in the kidneys and liver, and is used as a steam bath for swollen piles. The young branches are also a pectoral remedy. Fresh and dried figs have long been appreciated for their laxative action.

Also, some members of this tree family produce rubber. Fig wood, though of low quality, may be used for hoops, garlands, emery boards, etc.

In southern France, there is some use of Fig leaves as the source of a perfume material called ‘Fig-leaf absolute’ – a dark-green to brownish-green, semi-solid mass or thick liquid of herbaceous-woody-mossy odour, employed in creating woodland scents.

Clinical Relevance

Allergen Description

In an early report of 8 patients with allergic symptoms after fig ingestion, an immunoblot revealed the presence of IgE-binding proteins with molecular weights ranging between 14 and 90 kDa; the more salient IgE-binding bands corresponded to approximately 61, 42, 33, 25 and 17 kDa.

In an investigation of the serum of 2 individuals who experienced oral allergy syndrome (OAS) to fig, a major band of about 20 kDa and a minor band with a lower molecular weight were recognised in the serum of 1, while 3 proteins of about 10, 22 and 24 kDa were detected using the serum of the second patient. However, immunoblotting experiments confirmed the presence of IgE-binding proteins in the phosphate-buffered saline (PBS)-soluble fractions of the skin of the fig, whereas the PBS extract of the pulp did not show any potential allergens. Though the 2 patients examined had similar clinical features, they did not show IgE binding to the same protein bands, which suggested that OAS symptoms can be induced by different allergens present in the PBS-soluble fraction of the fig skin. The authors pointed out that in 1 patient, IgE recognised 2 protein bands of the pulp that were insoluble in PBS, and that these proteins, therefore, are unlikely to act in the aqueous environment of the mouth, but may be involved in allergic responses (eg anaphylaxis) at the gastrointestinal level.

Indeed, in the assessment of the serum of a 35-year-old woman who experienced anaphylaxis to dried fig and symptoms to weeping fig (Ficus benjamina), specific IgE directed at a protein of 35 kDa, found in dry fig and fresh fig, was demonstrated in her serum. The F. benjamina extract contained 2 allergens of 35 and 19 kDa that were totally and partially inhibited by fresh and dried fig, respectively.

The following allergens have been characterised.

Fic c 4, a profilin.

Fic c Ficin, a protease.

Fig c LTP, a lipid transfer protein.

A 17 kDa protein, a Bet v 1 homologue, has also been isolated.

In jelly fig (Ficus awkeotsang), a related family member, 2 thaumatin-like protein isoforms were isolated, as well as a pectin methylesterase and a chitinase in the jelly fig curd. Whether similar allergens are present in fig has not been determined to date.

Fig extracts lost most of their allergenicity when denatured by heat (95°C), but allergic reactions to fresh or dried figs are possible.

Potential Cross Reactivity

An extensive cross-reactivity among the different individual species of the genus could be expected, but this has not been fully investigated to date. An early report of 8 individuals allergic to fig stated that skin tests with related allergens (Ficus benjamina, mulberry pollen, latex, kiwi, papain and bromelin) were positive with Ficus benjamina in all eight patients, with kiwi in 3, and with latex and papain in one patient each. Sensitisation to fig with cross-sensitisation to weeping fig and natural rubber latex has been reported.

In a fig-allergic individual, detection of serum-specific IgE to weeping fig tree pollen (F. benjamina) indicated sensitisation. Further investigation revealed that these 2 species of Ficus share some allergens. Where cross-reactivity between F. benjamina and fig occurs, authors have suggested that it is likely that allergy to fig is a consequence of initial sensitisation to F. benjamina pollen. Therefore, in a patient with asthma and conjunctivitis caused by an immediate-type allergy to weeping fig pollen, who was shown to have serum-specific IgE to fig, the patient tolerated fig in an oral provocation test. Sensitisation to latex protein, a possible cross-reaction allergen (see below) was not found.

The Fig has also been included among those plant foods responsible for ‘latex-fruit syndrome”, an allergic disease resulting from cross-sensitisation to latex (Hevea brasiliensis) and several types of fruits. Studies have reported and confirmed cross-sensitisation among fig, weeping fig, and natural rubber latex, and among latex, papaya, avocado, banana, chestnut, passion fruit, fig, melon, mango, kiwi, pineapple, peach, and tomato. Fruit-specific IgE antibodies were detected in only 32.1% of the 136 patients investigated.

Hypersensitivity to weeping fig latex may cause IgE-mediated respiratory allergy. In a report, the authors conclude that an allergic association between fig and papain is likely, due to the existence of cross-reactive allergen structures.

Recently, it was reported that sensitisation to Ficus benjamina latex usually occurs independently of latex (H. brasiliensis) allergy, but that the Ficus sensitisation is commonly associated with allergic reactions to fig and other tropical fruits (‘Ficus-fruit syndrome’). In a study of 54 F. benjamina-allergic individuals, sensitisation to F. benjamina 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%). Fig-specific IgE was inhibited 87% by F. benjamina, 89% by fresh fig, 80% by dried fig, 38% by kiwi, and 59 and 44% by the thiolproteases ficin and papain respectively. The authors concluded that this cross-reactivity was mediated at least in part by the thiolproteases ficin and papain.

Serum from 4 patients with known allergy to F benjamina leaves, fig and kiwi, and from 1 patient allergic to F benjamina leaves and kiwi, were studied for cross-reactivity patterns. Inhibition studies showed a high degree of cross-reactivity between F benjamina leaves and fig extracts, and a lower level between these and kiwi extract.

A study reported on 3 individuals with associated fig and mulberry (Morus nigra and Morus alba) allergy. They were also sensitised to multiple other food allergens (mostly fruits) and airborne allergens. The authors speculated that as Ficus and Morus are closely related genera of the Moraceae family, concomitant hypersensitivity to fig and mulberry might be the result of allergen cross-reactivity rather than mere coincidence.

In an evaluation of the clinical characteristics of melon allergy in 66 melon-allergic patients, 48% self-reported allergy to fig. Skin-specific IgE was most frequently demonstrated (after pollen) to peach, fig, and kiwi. About 82% of the patients were shown to have skin-specific IgE to fig.

As a result of allergy to fig fruit having been described in patients allergic to Ficus benjamina or rubber latex and also in pollen-allergic patients, researchers evaluated the potential cross-reactivity between fig and taxonomically related fruits with the major birch pollen allergen Bet v 1. One hundred and eighty-eight patients with or without birch pollen allergy were prick-to-prick tested with fig, mulberry (Morus alba), jackfruit (Artocarpus heterophyllus; all family Moraceae) and other pollen-associated foods. Among 85 patients with isolated birch pollen allergy, 78% had a positive skin test to fresh fig, 10% to dried fig, 91% to mulberry, 91% to jackfruit, 77% to Rosaceae fruits and 83% to hazelnut. Sixty-six per cent of birch pollen-allergic patients positive for fig reported symptoms after consumption of fresh figs, whereas dried figs were mostly well-tolerated. In 60 patients with isolated Ficus benjamina sensitisation, the reactivity rates to the same foods were 83-40-0-0-0-0%. None of 32 mugwort pollen-allergic patients reacted to Moraceae fruits. Anti-Mal d 1 and patient sera reacted to a 17 kDa band in all Moraceae extracts and IgE binding to these proteins was completely inhibited by birch pollen and rBet v 1. Several peptides from the 17 kDa fig, mulberry and jackfruit allergen were identified with (respectively) 60%, 56% and 76% homology to Bet v 1. Therefore fig and other Moraceae fruits contain allergens homologous to Bet v 1 and represent clinically relevant birch pollen-associated foods.

The presence of a profilin may result in cross-reactivity with other plants containing this panallergen, e.g. melon, but this has not been adequately evaluated.

Clinical Experience

IgE-mediated reactions

Fig may induce symptoms of food allergy in sensitised individuals. Symptoms include pruritis, generalised urticaria, facial angioedema, asthma, gastrointestinal symptoms, oral allergy syndrome, and anaphylaxis.

An early study of 8 patients with allergic symptoms after fig ingestion reported that symptoms included conjunctivitis, palpebral oedema oral allergy syndrome, facial angioedema, labial oedema, and anaphylaxis in one. Skin tests performed by prick-by-prick with the fresh fruit were positive in all eight patients, and all were negative to the commercial extract. The skin tests with related allergens (Ficus benjamina, mulberry pollen, latex, kiwi, papain and bromelin) were positive with Ficus benjamina in all eight patients, with kiwi in 3, and with latex and papain in one patient each. Serum-specific IgE levels were positive in 6 patients, and levels ranged from 0.36 to 7.14 kU/L for fig flesh and 0.36 to 13.55 kU/L for fig skin. The oral challenge test was positive in the five cases in which it was performed.

A study was conducted at 17 clinics in 15 European cities to evaluate the differences among some Northern countries regarding what foods, according to the patients, elicit hypersensitivity symptoms. Questionnaires concerning 86 different foods were administered to food-allergic individuals. The foods most often reported as eliciting symptoms in Russia, Estonia, and Lithuania were citrus fruits, chocolate, honey, apple, hazelnut, strawberry, fish, tomato, egg, and milk; which differed from the situation in Sweden and Denmark, where birch pollen-related foods such as nuts, apple, pear, kiwi, stone fruits, and carrot were the most commonly reported culprits. The most common symptoms reported were oral allergy syndrome and urticaria. Birch pollen-related foods dominated as reported allergens in Scandinavia, whereas some mugwort-related foods appeared to be of more importance in Russia and the Baltic states. Among 1 139 individuals, fig was the 68th-most reported food resulting in adverse effects, in 6.7%.

A number of case reports have recorded the diverse range of adverse clinical effects reported as a result of fig allergy.

A report was made on 3 individuals with associated fig and mulberry allergy, who were sensitised to multiple other food allergens (mostly fruits), along with airborne allergens. A 12-year-old girl developed lip and oropharyngeal angioedema and pruritis a few minutes after eating white mulberry; she also experienced shortness of breath, a sense of suffocation, and lip, tongue and oropharyngeal swelling and pruritis after eating a fig. The second patient, a 43-year-old female, developed acute generalised urticaria with pruritis, flushing, a sensation of heat, conjunctival injection, colic and drowsiness, 2 hours after eating fig. The third patient, a 47-year-old male, reported several episodes of generalised pruritis, acute urticaria, and attacks of severe abdominal pain, after eating fresh fig. Similar reactions had occurred after eating white and black mulberries. The authors suggested that cross-reactivity occurred between mulberry and fig as a result of the family relationship between Ficus and Morus.

The unusual characteristics of fig allergy were further elucidated in a report of 2 cases of oral allergy syndrome (OAS) to fig. Patient 1 was a 27-year-old woman with seasonal allergic rhinitis and asthma resulting from grass and birch pollens, and OAS to apple, peach and kiwi. She reported oral symptoms after the ingestion of fig, which she had previously tolerated. Her most recent episode had resulted in OAS, followed by rhinoconjunctivitis, mild oedema of the eyelids and lips, and burning of the throat. Patient 2 was a 34-year-old woman with seasonal rhinitis and asthma from grass and birch pollens. She experienced OAS after eating apple, pear, peach and hazelnut. Similarly, she had tolerated fig until a recent episode in which, while chewing a fig, she experienced marked itching of the mouth, followed by severe conjunctivitis and rhinitis, sore throat, wheezing, dyspnoea and oedema of the lips and face. Skin-specific IgE evaluation with a skin fraction of green fig was markedly positive in both patients, while only a minimal reaction occurred to fig pulp. Phosphate-buffered saline (PBS) extracts of both fig skin and pulp resulted in similar responses. No skin-specific IgE was detected for latex (Hevea brasiliensis) and weeping fig pollen, among others, and serum-specific IgE to weeping fig and fig was negative. The oral challenge tests with fig were positive in both patients. Symptoms appeared approximately 10 minutes after the challenge. For patient 1, the oral mucosal symptoms were followed by conjunctivitis, eyelid and lip oedema, and slight rhinitis with nasal obstruction. For patient 2, the oral symptoms were followed by rhinoconjunctivitis and asthma, with significant nasal obstruction and bronchospasm. The authors state that although the 2 patients had similar clinical features, they did not show IgE binding to the same protein bands in immunoblotting, which indicates that OAS symptoms can be induced by different allergens.

Further, the authors point out that fig is an unusual multiple fruit, consisting of a hollow receptacle with hundreds of small fleshy flowers facing each other on the inside (a syconium); and that in these patients the allergic symptoms appeared to be due to components present in the skin (receptacle), whereas the flowers (the internal red part of the Fig) do not appear to be allergenic. This is relevant, as figs are sometimes eaten with the skin. If not, the skin is only partly removed by peeling. In any case, eating a peeled fig may result in different symptoms of hypersensitivity than eating an unpeeled one.

Five patients were described with oral allergy syndrome (OAS) or anaphylaxis after the ingestion of fig. The authors concluded that allergic reactions to fresh or dried fig can present as a consequence of primary sensitisation to airborne F. benjamina allergens, independent of sensitisation to natural rubber latex allergens.

Anaphylaxis has also been reported in a 35-year-old woman following contact with fig. Immediately after eating a dried fig, she experienced pruritus of the palate, sneezing, nasal obstruction, hydrorrhoea, sore throat, dyspnoea, cough, and bilateral palpebral angioedema that required urgent treatment. She had previously had no adverse effects to fig. She had previously reacted to F. benjamina: after touching its leaves – she experienced severe bilateral palpebral angioedema, watery eyes, ocular pruritus, and dry cough. She also described a blocked nose, hydrorrhoea, watery eyes, and dry cough in her domestic environment, the symptoms disappearing when she left the house. Skin-specific IgE was demonstrated to dried fig, to the skin and pulp of green fig, and to the leaf and latex of F. benjamina, as well as to commercial extract of fig. Serum-specific IgE for fig was 4.2 kU/l, and 0.35 kU/l for latex (H. brasiliensis). No skin-specific IgE was demonstrated for kiwi, banana, hops, chestnut, or Hevea brasiliensis latex; i.e. there was no evidence for ‘latex-fruit syndrome’.

A case report described a patient who developed a first episode of facial angioedema and urticaria, following exercise and preceded by the ingestion of figs. The patient was shown to be sensitised to fig. The authors suggested that in this particular case, concomitant treatment with a non-steroid anti-inflammatory for lumbago may have been implicated as a factor favouring the reaction. A provocation test reproduced the initial symptoms.

A multi-food allergy was described in a 4-year-old child, who had a skin-specific IgE reaction resulting in a 4 mm wheal, and serum-specific IgE to fig.

Few studies of the prevalence of fig allergy have been conducted.

In 2002, 107 cases were reported to the French Allergy Vigilance Network, of which 59.8% were cases of anaphylactic shock (1 being fatal). The most frequent causal allergens were peanut (n=14), nuts, shellfish, and fruits of the latex group; occurring most often in patients allergic to latex were allergies to the following: avocado (n=4), kiwi (n=2), fig (n=2), and banana (n=1).

Studies evaluating the main foods/food allergens causing anaphylaxis in over 1 000 adult patients with food allergy, diagnosed by common criteria at 19 allergy centres scattered throughout Italy, reported only 1 patient with allergy to fig. The predominant symptom was urticaria.

Other reaction

The latex of the unripe fruits and of any part of the tree may be severely irritating to the skin and eyes if not removed promptly. It is an occupational hazard not only to fig harvesters and packers, but also to workers in food industries, and to those who employ the latex to treat skin diseases. In tropical America, the latex was an ingredient in some of the early commercial detergents for household use, but was abandoned after many reports of irritated or inflamed hands in housewives.

Contact with sap from fig leaves and stems can result in contact dermatitis, phototoxicity or phytophotodermatitis. Phytophotodermatitis is an acute skin reaction that may be easily confused with other causes of contact dermatitis. It is characterised by sunburn, blisters, and/or hyperpigmentation. The reaction takes place when certain plant substances known as psoralens, after being activated by ultraviolet light from the sun, come into contact with the skin. Psoralen and bergapten appear to be the only significant photoactive compounds in fig; they are present in appreciable quantities in the leaf and shoot sap, but are not detected in the fruit or its sap. Lower concentrations of both compounds are present in autumn, compared to spring and summer. The higher content of both photoactive compounds in spring and summer is partly responsible for the increased incidence of fig dermatitis during these seasons.

A 55 year old male presented with a 3-day history of generalised erythematous and oedematous rash with vesicles and bullae, especially on the trunk and extremities. These symptoms emerged several hours after the patient had pruned the branches of a fig tree while working in his garden without wearing a shirt.

A study demonstrated that phytophoto-allergic contact dermatitis resulting from furocoumarins (present in fig sap) is not an exceptional finding, and should be suspected in subjects with diffuse clinical manifestations in photo-exposed (but also non-exposed) sites.

Cutaneous reactions may be severe. Two arborists presented with acute blistering eruptions on their forearms, hands, and fingers a day after both men had pruned branches from a large fig tree that had sustained damage during a storm. The initial symptom was burning discomfort, which rapidly evolved into erythema and bullae on the skin that had been in direct contact with the tree branches. Symptoms resolved gradually over 4 to 6 weeks.

Cutaneous reactions may mimic a burn injury.