Summary

The commercial natural rubber latex (NRL) is the milky intracellular sap (with 2-3% in proteins content) produced by the rubber tree, Hevea brasiliensis and collected by the method of rubber tapping. It is applied in the production of several daily used products, such as catheters, cannulas, gloves, endotracheal tubes, bottles having pierceable septum, bandages, anaesthesia masks, condoms, balloons, swim caps, gum boots etc. Latex allergy is one of the significant allergies associated with occupational exposure and groups at higher risk may include health care workers (HCW), children with spina bifida and individuals with multiple surgeries. Additionally, persons using latex products such as cleaners, food service providers, hairdressers, person using condoms and workers in the rubber industry are also at higher risk of latex allergy. The prevention of contact with NRL remains the gold standard of the treatment of latex allergy which could be achieved by the shift from the use of powdered gloves to powder-free gloves or synthetic gloves. The main route of exposure to latex is through direct skin or mucosal membrane contact or via inhalation. The clinical manifestations of IgE-mediated type I immediate hypersensitivity to latex may differ considerably among individuals and mostly depend on the exposure route, allergen quantity and personal factors. These manifestations mainly include urticaria or itchy skin and can also lead to angioedema, asthma, or even systemic reactions, including anaphylaxis, while patients in operation theatres mostly present with rashes or bronchoconstriction or even cardiovascular collapse due to direct contact with latex proteins. Till date, 15 allergenic components (Hev b 1-15) have been identified and officially published by the World Health Organization (WHO) and International Union of Immunological Societies’ (IUIS) Allergen Nomenclature Subcommittee for latex. Hev b 1 and Hev b 3 are reported to be major allergens in spina bifida children while Hev b 5 and Hev b 6 are reported to be major allergens in HCW. “Latex-food” syndrome is cross-reactivity syndrome observed between latex proteins and wide range of fruits, vegetables, nuts as well as grains which has been reported in approximately 30% to 50% of latex-allergic patients.

Epidemiology

Worldwide distribution

Latex allergy is one of the significant allergies associated with occupational exposure and is found to be more prevalent among health care workers (HCW) who frequently come in contact with latex gloves and the susceptible patients undergoing repeated surgeries. It is reported that the prevalence rate varies among different populations.

The HCW (physicians, dentists, nurses, pathologists etc.) were more exposed to rubber products like corn-starch powdered gloves in the early 1980’s, which made them as the most affected occupational group for the latex allergy. However, the prevalence of latex allergy reduced with the use of the powder-free latex gloves or synthetic gloves. Based on a recent review of articles published from 2009 to 2015, the prevalence of latex allergy and sensitization among HCW (n=19,233) across the globe (especially parts of Asia, Europe and the United States) was found to be between 9.7% and 12.4%, respectively.

Further, another review analyzing the articles for prevalence of latex allergy from 2006 to 2015 reported a pooled prevalence of about 5.1% (n=5884) among the HCW. A study conducted in Japan among 497 asthmatic nurses found latex allergy to be prevalent in 33.5% (166 out of 497). Another study conducted in Denmark reported that clinical allergy to latex significantly reduced (p<0.004) from 1.3% between the year 2002 and 2005 to 0.5-0.6% between the year 2006-2009 and 2010-2013.

In addition to the HCW, patients undergoing certain surgeries, especially spina bifida (children), cesarean delivery, or patients with catheterization like urinary tract abnormalities, diabetics taking insulin injections or even patients under anesthesia have high exposure to latex allergens and hence increased probability to develop latex allergy. The prevalence of latex allergy and sensitization among such patients with high latex exposure (n=1515) was reported to be 7.2% and 30.4%, respectively as per a review analyzing studies from 2009 to 2014 across the globe. The prevalence of latex allergy among children with spina bifida was observed to range from 8.2% (n=73) in Iran (myelomeningocele, a type of spina bifida), 16% (n=88) in Turkey, 20% (n=55) in Brazil (myelomeningocele children), to about 46% (n=35) in Singapore. Besides, a study conducted in Egypt reported positive skin prick test (SPT) to latex in 4% of infants and children with allergic diseases (6 out of 400).

Additionally, elderly patients were not considered to be the group at high risk. However, a study conducted in Italy among 88 elderly subjects (≥65 years) found positive SPT to latex in 11.4%. Further, another study in Turkey reported latex sensitization in 3.4% of patients undergoing hemodialysis.

Other occupational groups that may be at higher risk of latex allergy may include individuals working in rubber industry, laboratory personnel, hairdressers, or even gardeners as well as housekeeping personnel. However, extensive studies in such occupational groups are still lacking. A cross-sectional study conducted in Thailand among 795 workers with latex exposure (glove factories or latex tappers) reported a prevalence rate of 1.5% for positive SPT to latex. Further, certain studies conducted on general population were reviewed and reported a prevalence of 4.3% and 2.1% of latex allergy and sensitization, respectively.

Risk factors

Latex allergy is commonly associated with occupation, and occupational groups at higher risk may include HCW, children with spina bifida and individuals with multiple surgeries. Besides these, patients having an atopic history, allergic to certain foods like banana, avocado or kiwi, or even showing delayed reactions to chemicals used in rubber processing are susceptible to latex allergy.

The regular use of powdered NRL gloves were identified as the main cause of latex allergy in HCW. Therefore, characteristics of the gloves can have an impact on the extent of risk for developing NRL allergy. Gloves with high protein content or highly-powdered gloves carry greater risk in comparison to non-powdered, low-powdered or low protein NRL gloves, carrying lesser risk. Further, it has been shown that changing the same gloves several times, sweaty hands or broken skin as well as use of oily lotions could increase the allergy risk through skin contact. Additionally, studies have also documented increased risk in HCW with functional polymorphisms, involving genes for interleukin-13 (IL-13) and IL-18.

Furthermore, the risk is also present in non-HCW which are exposed to latex, such as cleaners, food service, hairdressers and workers in the rubber industry. Individuals coming in contact with latex products that are frequently used, such as balloons, condoms, masks or even medical examination tools (e.g., obstetric patients) are at higher risk.

Pediatric issues

Children with spina bifida are particularly at higher risk of developing latex allergy and thus, special care has to be taken for these children. A recent guideline has been published that mentions about the precautions needed for these children. It suggests the avoidance of latex products while dealing with infants or children with latex allergy, not only in hospitals but also at schools and at home, including the toys, balloons, pacifiers, bottle nipples as well as other medical supplies. Also, keeping adrenaline injections with them all the time may also be suggested.

Route Of Exposure

Main

The main route of exposure to latex is through direct skin or mucosal membrane contact or via inhalation. The exposure can either be occupational or non-occupational.

The inhalational exposure could occur when the powder that the gloves contain comes in contact with mucosal membrane in the respiratory system.

Clinical Relevance

Reactions to latex can be classified as immunogenic and non-immunogenic. Immunogenic reactions include immediate type I immunoglobulin (Ig)E-mediated or delayed type IV- hypersensitivity reactions. However, type IV hypersensitivity reactions are mainly due to other chemicals added during the rubber processing like antioxidants or accelerators, while latex proteins are associated with type I reactions. Clinical manifestations of IgE-mediated type I immediate hypersensitivity to latex may differ considerably among individuals and mostly depend on the exposure route, allergen quantity and personal factors. These manifestations mainly include urticaria or itchy skin and can also lead to angioedema, asthma, or even systemic reactions, including anaphylaxis, while patients in operation theaters mostly present with rashes or bronchoconstriction or even cardiovascular collapse due to direct contact.

Contact Dermatitis/Urticaria

Contact urticaria can be observed as immediate type I hypersensitivity reaction to NRL. Latex is said to be the most common cause of occupational contact urticaria. It may be manifested as flare and wheal reaction or itchy skin at the site of contact within 10-15 min. This reaction usually precedes systemic reactions. Mucosal contact of NRL may also induce angioedema. Rather than pruritis, contact urticaria is more correlated with latex sensitization.

A 10-year follow-up Italian study among nurses concluded that the incidence of allergic contact dermatitis ranged from 0-5.7 per 1000 cases, with 24 cases being reported among 1013 nurses after the year 2000. However, among these 24 cases, only 5 cases were found to have latex sensitization. Additionally, 7 cases of urticaria were reported, among which only three of them showed latex sensitization. Another study conducted in Denmark reported prevalence of 46.4% for atopic dermatitis among a total of 235 NRL-sensitized patients between the period from 2002 to 2013.

Allergic rhinitis and Asthma

Health care workers or other occupational workers using NRL gloves or exposed to latex at their workplace, generally show allergic rhinitis (AR) or asthma due to inhalational exposure to latex. The allergic individuals may show frequent sneezing, rhinorrhea, blocked nose along with rhino-conjunctivitis. The prevalence of asthma was found to be lower as compared to rhino-conjunctivitis among HCW exposed to NRL as per a review compiling data from 7 different studies. The rate of pooled prevalence (n=3567) of rhino-conjunctivitis was reported to be 7.6%, while that of asthma was reported to be 1.4%.

Latex is found to be an important cause of occupational asthma with a prevalence of 2.5-10% among different occupations, like hairdressers, housekeeping professionals or factory workers.

Further, a 10-year follow-up study among nurses concluded that the incidence of respiratory allergic reactions has greatly reduced with only 2 cases, each of asthma and AR being reported after the year 2000 among 1013 nurses. Also, the study reported no new case of respiratory symptoms after the year 2004 till 2009. This low symptom burden was attributed to the use of non-powdered gloves or NRL alternative gloves, like vinyl or nitrile gloves after 2000.

However, a study conducted in Japan for the prevalence of AR among asthmatic nurses found a significant association between latex allergy and AR. Another study conducted in Denmark reported prevalence of 71.9% and 38.7% for rhino-conjunctivitis and asthma among a total of 235 NRL-sensitized patients between the period from 2002 to 2013.

Systemic reactions and Anaphylaxis

Latex has been considered as the second-most prevalent cause of anaphylaxis in adult perioperative patients under anaesthesia, after neuromuscular blocking agents; while it is considered to be the main cause in children undergoing anaesthesia. The prevalence of anaphylaxis in surgical French patients during anaesthesia due to latex was reported to be 0.5% in early 1984-1989, which increased gradually to about 20% in the year 2005-2007. However, this prevalence had seen a reduction of about 5.2% during the year 2011-2012, according to French studies. Latex-induced anaphylaxis have been reported to be severe in patients with unmanageable asthma. However, with the increased use of latex-free gloves or latex-safe environment, the rate of latex-induced anaphylaxis has been reduced. Additionally, latex allergy could lead to cardiovascular collapse in addition to skin rashes or bronchoconstriction in children under anaesthesia. Of interest, the allergenic latex proteins could be transferred from gloves to food in cases where food is handled using gloves. This could generate an anaphylactic response in sensitive individuals consuming such food.

Other topics

Certain other non-allergic reactions related to exposure of latex, include irritant contact dermatitis and type IV hypersensitivity, which may be either immediate or delayed within a range of 24 to 96 hours.

Diagnostics

Challenge tests

Diagnosis for type I latex allergy is mostly determined by IgE test, SPT or challenge test with powdered gloves.

Prevention And Therapy

Allergen immunotherapy

Several studies have been reported in literature evaluating percutaneous, subcutaneous and sublingual immunotherapy in patients with latex allergy. Currently, application of SLIT as treatment for latex allergy is not supported by strong evidence but could be used for individuals with latex allergy, who could not avoid latex exposure at the workplace. A systematic review and meta-analysis including 5 studies (n=116) evaluated SLIT efficacy in patients with latex allergy as compared to placebo. It reported statistically significant improvement in the glove provocation test score, but not in other outcomes in patients undergoing SLIT for latex allergy. However, the therapy was reported to be safe if continued for prolonged duration (3-8 years). Thus, SLIT could be proposed as a potential therapy for latex-allergic individuals who cannot avoid exposure to latex.

Prevention strategies

Prevention of contact with NRL remains the gold standard of the treatment of latex allergy. Prevention mainly includes the avoidance of latex by using non-NRL gloves or low-protein/low-powdered NRL gloves, which could decrease the prevalence of the allergy. This measure has been highly effective in reducing the exposure of allergic individuals in healthcare, allowing them to continue working. Several studies have shown a reduction in the prevalence of latex sensitization or allergy due to shift from the use of powdered gloves to powder-free gloves. An expert review has evaluated these studies and has shown that latex sensitization among HCW has reduced from 14.1% to 4.5% in the Netherlands and from 6% to 3.6% in Italy due to implementation of such preventive measures. Also, the incidences of skin allergy (0.21 to 0.14 per 1000 cases), asthma (0.09 to 0.05 per 1000 cases) and contact urticaria (0.30 to 0.07 per 1000 cases) were reduced among HCW in Germany.

However, the prevalence of latex allergy in Asia still remains high at present. In a study on 229 HCW in India in 2018 reported the latex allergy prevalence of 10.91% which may be attributed to still existent use of powdered latex gloves in medical system. Prevention of latex gloves and use of powder free gloves may be helpful in reducing the prevalence in Asia as compared to Europe or North America.

Furthermore, instead of NRL gloves, its alternative source i.e., guayule gloves may be used (Hevea latex free), which has been approved by US Food and Drug Administration. Also, it is suggested to develop a latex allergy task force and required facilities for the HCW. If possible, a latex-free environment should be developed in all the health care facilities.

Children with spina bifida should be avoided with the exposure of latex since birth as a primary preventive measure to avoid allergic reactions. Avoidance of latex exposure should also be implemented at other places, like dentists, primary care or even schools in addition to the hospitals. Furthermore, identification of cross-reacting foods like banana, avocado, kiwi or pear should also be done and avoided as much as possible.

Secondary preventive measures may include premedication before surgical procedures.

Cross-Reactivity

It has been reported that 30% to 50% of latex-allergic patients present with syndrome derived as “Latex-fruit”, which basically is a cross-reactivity observed between latex and fresh fruits. However, recently it has been referred to as latex-food syndrome, since the cross-reactivity has extended from tropical fruits to wide range of fruits, vegetables, nuts as well as grains. This cross-reactive syndrome may be as a result of sensitization to ubiquitous structural and defense proteins in the latex-allergic patients. The fruits and vegetables most commonly associated with this syndrome include avocado, banana, chestnut, and kiwi. Other foods which may also be involved to a lesser extent include fruits like apple, citrus fruits, grapefruit, figs, peach, pear, strawberry, cherry, coconut, lychee, plum, watermelon, passion fruit, papaya and pineapple; vegetables like beet, carrot, lettuce, spinach, tomato, potato, celery, zucchini and sweet pepper; nuts like apricots, hazelnuts, and walnuts; grains like buckwheat and wheat; sunflower seeds as well as shellfish.

The allergens that have been identified as causing latex-fruit syndrome are Hev b 2, 5, 6, 7, 8, 11 and 12. Hev b 2 shares sequence similarity with fruits like olive, bell pepper, peach or cherry. Hev b 5 has shown homology to the acidic protein of kiwi, Hev b 6 has shown >50% identity with chitinases of banana, avocado and chestnut, Hev b 7 was found to share >50% homology to patatin (a protein found in Solanaceae), and thus found to cross-react with tomato and potato. Hev b 8 may also be involved with fruits like kiwi and avocado, however it was found to mostly cross-react with pollens like Ambrosia artemisiifolia, birch or olive pollens. Hev b 11 and 12 are said to be involved with cross-reactivity to fruits, however it is yet not known.

Of interest, in a recent cross-sectional study, latex-papaya syndrome was displayed in 11 patients with latex allergy and having history of anaphylaxis due to papaya. The cross-reactivity was attributed due to similarity in the IgE epitopes noted between hevein protein of latex and class I chitinases of papaya.

Hev b 9 and 10 have been found to be associated with cross-reactivity to fungi, such as Cladosporium, Alternaria and Aspergillus, while Hev b 6 and 11 have been found to be cross-reactive to Ficus species.

Furthermore, sequence homology has been reported between the protein sequences of latex antigens Hev b 7.01/Hev b 7.02, and oxytocin and vasopressin, with reports of patients being allergic to both latex and oxytocin depicting cross-sensitization. Thus, oxytocin or vasopressin administration could enhance the antigen recognition, generating a faster anaphylactic reaction to latex.