|
Author(s)
Pete Phillips Deputy Director
|
Contents
|
|
Published:
October 2001
Last updated: October 2001 Revision: 1.0 |
Keywords: latex allergy; latex gloves.
Medical devices, such as latex gloves, made from natural rubber latex (NRL) can cause allergic reactions, and have the potential to provoke life-threatening (type 1) reactions in sensitised individuals.
Risk groups for latex allergy are individuals predisposed to allergy and those frequently in contact with latex gloves, such as the medical profession and patients needing multiple surgery.
To avoid latex allergy or latex allergic contact dermatitis, products with low amounts of allergenic proteins and sensitising chemicals should be used.
Latex-sensitised individuals must avoid direct contact with NRL products. Information on the package, including ingredient information may help prevent allergic responses.
Most woundcare practitioners wear gloves during routine clinical procedures, but latex allergy has led many practitioners to question the place of latex gloves in wound care, and to look for alternative materials. This paper summarises the opinion of a group of European experts on the role of Natural Rubber Latex (NRL)in latex allergy.
On the 27th June 2000, a report entitled 'Opinion on Natural Rubber Latex Allergy' was adopted by the Scientific Committee on Medicinal Products and Medical Devices (SCMPMD) [1]. The report had been requested by DG Enterprise (DG III) of the European Commission, who posed a series of 16 questions on latex allergy and related issues to the SCMPMD. The opinion is based mainly on literature related to the use of medical gloves and the associated risk of developing a latex allergy.
Latex allergy became a topic of intense interest in the late 1980s when 15 patients in the USA died after latex balloons on rectal catheters caused anaphylaxis. Unfortunately for the patients concerned, it was a while before the proteins in the latex balloon were identified as the cause of these incidents. Latex gloves are one of the most widely used medical devices in medicine, and although it had been recognised as early as 1979 that latex itself could cause sensitisation, it was not until the late 1980s and early 1990s when it became apparent that a significant problem was developing in the USA and Europe, with both healthcare workers and patients experiencing a range of latex-associated reactions. Such reactions can range from local wheal and flare in its mildest forms, through rhinitis and wheeze, and finally to anaphylaxis in its most severe form.
Distinguishing between latex sensitisation and latex allergic disease is important. Sensitisation can be diagnosed in vivo by skin prick tests or in vitro by immunoglobulin E (IgE) analyses of blood, which show that the individual has been exposed to natural rubber latex (NRL). The NRL proteins act as an antigen, stimulating antibody production. Subsequent contact with these proteins causes an antigen-antibody reaction, with release of histamine and other substances into the bloodstream. Latex allergic disease is usually diagnosed using challenge (provocation) tests, whereby a person experiences symptoms after secondary contact with latex products. It is possible to have a diagnosis of latex sensitivity and yet be asymptomatic.
The questions to which the committee were asked to respond, were intended to put into context the published literature from the last decade. The experts were asked to provide advice on ways to enhance the detection of chemical and protein allergens in medical devices, methods of diagnosis, the role of powder, and techniques for controlling the risk of latex allergy.
The experts were asked whether it was possible to identify populations at risk from latex allergy. Whilst it is possible to identify certain groups at risk (such as atopics, patients with multiple operations (such as spina bifida children), and health professionals), the committee acknowledge that it is not possible to determine whether any particular person who has a latex sensitivity will experience a serious reaction when undergoing surgery or after close mucosal contact.
Publications are cited where patients have had a positive skin prick test (SPT) and experienced an anaphylactic reaction during surgery, but who have a negative IgE to latex. Whilst noting that the SPT is superior to IgE detection in diagnosing sensitisation, the committee criticise the quality of many of the published papers dealing with sensitisation diagnosis, as having a paucity of information on the methodology used and the quality of the test materials. The committee conclude that the lack of standardised materials makes comparisons difficult and hampers diagnosis. Essentially, this means that the tests will sometimes indicate sensitivity where none exists, or may not detect a truly sensitive patient.
When diagnosing latex allergic disease, the committee note that the techniques used for challenge testing are adequate for the majority of subjects, but there is lack of consistency in the materials used. With latex gloves, in particular, it is becoming increasingly difficult to find gloves with sufficiently high allergenicity and false negatives may occur.
Whilst most studies have demonstrated a relationship between leachable proteins and allergic reaction and/or sensitisation, attention has also been drawn to those studies which do not support this relationship. However, the committee have no reservations about implicating leachable proteins in latex gloves with sensitisation and the risk of allergic reaction.
The effect of reducing leachable protein levels does not appear to be as clear cut. Although the committee agree that reducing protein levels is of benefit to many, they also note that current analytical methods cannot rule out the possibility of a small amount of residual protein remaining in latex products. Leaching may not reduce allergenic proteins in the same proportion as total protein and therefore there will always be a small minority who will react to these low levels of allergens. Despite their reservations, the committee conclude that measurement of total protein is the best method at present to monitor the allergenic properties of latex products, and that the risk of sensitisation and allergic reaction can be reduced by minimising leachable protein levels.
Because, in the opinion of the committee, there is at present no reliable method for routinely measuring the allergen content of NRL, they concentrate on two methods used to measure leachable protein levels. These are:
The committee chose these methods because they have been shown to correlate well with SPT, although the superiority of the amino acid analysis technique is highlighted because it is less susceptible to interference from chemicals used during glove production.They conclude that the modified Lowry is useful to distinguish between gloves containing low, moderate and high protein levels, is simple to perform, and can be used as a routine method for monitoring production. However, they believe that because the limit of elicitation/sensitisation is likely to be close to, or below the quantification limit of the assay, there are concerns about whether it can be used to define a safe protein level.
In contrast, the amino acid analysis method is known to be more sensitive, and can probably measure proteins in the range where exposure limits for sensitisation and allergic reactions are likely to occur. The method is, however, time consuming and expensive and is not suitable for routine analysis.
Methods for assaying leachable allergen levels were also considered, such as RAST-inhibition and IgE ELISA inhibition. These methods measure allergens, the proteins which specifically cause the allergic reactions. They rely on a solution of pooled sera from patients with a pre-existing latex allergy. However, these solutions of allergenic proteins have not been standardised between different manufacturers and laboratories, and their availability is limited.
The committee therefore conclude that validated assays for determining allergenic content are not yet widely available, and those that are available have not been standardised. They anticipate that monoclonal antibodies to individual allergens will become available in the near future and overcome the problems of limited availability.
To establish safe levels of exposure to leachable proteins and/or allergens for sensitisation, the committee state that it would be unethical to perform the studies required (exposing subjects to increasing doses until they developed a Type I sensitivity). However, because a dose response relationship has been established for gloves, they believe that a threshold level will be established for which less than 5% of the sensitised population will show a positive reaction.
When questioned on the possibility of determining a threshold level of protein which is needed for sensitisation, the committee responded by noting that these levels are not yet known, and that a low level of protein exposure will reduce the risk for sensitisation and elicitation of symptoms.
Dipped latex is naturally a very 'grippy' material and powder (hydrolysed cornstarch) has been used in gloves for decades to facilitate donning. It is also used during the manufacturing process to help remove gloves from the hand-shaped formers on which they are dipped. Hence, even gloves claiming to be 'powder-free' will contain a low level of powder.
The committee state that there is little evidence to suggest that powder plays a significant role in the sensitisation to latex proteins. In studies comparing powdered and non-powdered gloves, levels of latex allergens were higher in powdered than non-powdered gloves. Therefore the differences observed in the study population may have been due to the differences in latex allergen levels.
Similarly, in studies which have attempted to correlate airborne allergen levels with sensitisation, it was not possible to determine whether the airborne powder or direct skin-contact with the allergens in the glove were responsible for the sensitisation.
The committee conclude that: "No study has been published, in which patients have been exposed to powdered and powder-free gloves respectively, with similar contents of protein. The influence of powder-bound allergens versus direct skin exposure to the same amount of proteins/allergens, on induction of sensitisation, cannot therefore be assessed."
The committee criticise the quality of some studies purporting to show elicitation of symptoms in latex-allergic individuals when exposed to powder from latex gloves via their airways. Although vinyl gloves were used as a control, many of the studies do not state whether these were powdered. In addition, none of the provocation studies were blinded for the patient, nor were any double-blind, placebo-controlled experiments performed.
Interestingly, the committee could not find any provocation studies with airborne, powder-bound latex particles in patients with both a negative skin prick test and allergic asthma which would have provided good evidence of a role for powder in sensitisation.
Although the committee conclude that exposure to powder from latex gloves can provoke allergic symptoms in sensitised patients, they state that: "The reaction to glove powder is not dependent on the powder but on the protein carried by the powder. In one study, powder from low protein containing gloves did not provoke symptomatic reactivity. It has not been demonstrated that powdered gloves are more likely to induce sensitisation than powder free gloves, provided the protein content of the gloves is identical."
Although it has been postulated that factors such as pH and endotoxin may act to potentiate the sensitising effect of powder from latex gloves, the committee question this, stating that it is not possible to evaluate the effects of these factors because the core role of powder in sensitisation has not itself been established.
Latex gloves have a range of chemicals added to them during processing. Leaching of the gloves removes most of these additives, but a few remain in the final product at low levels. Some of these chemicals cause a Type 4 (delayed) hyper-sensitivity reaction.
The committee looked at methods of detection before addressing questions on the risks posed by chemicals; a more logical method would have been to first look for evidence that the chemicals in NRL pose a risk to individuals. The fact that chemicals used in the manufacture of NRL are well known as contact allergens is not at issue. These chemicals have been documented to cause delayed hyper-sensitivity (Type 4), resulting in allergic contact dermatitis. Many of the chemicals are used by the manufacturers as antioxidants,vulcanising agents or accelerators, but some of the chemicals detected are not added directly and are the result of a chemical reaction in the presence of zinc oxide.
The committee conclude that the chemicals are bioavailable, may penetrate into the skin, and can induce delayed hyper-sensitivity. However, they caution that: "The risk is not confined to NRL, but may also be presented by most synthetic rubber products containing the same or similar chemicals."
The committee draw a distinction between being able to detect and assay residual chemical levels in gloves and whether those chemicals are bioavailable or clinically relevant. Although patch testing the products demonstrates the bioavailability of the chemicals, it is only possible to identify the chemical responsible for the reaction by patch tests using the pure chemical. When asked whether there were any reliable test methods available to estimate the bioavailable and allergologically relevant chemicals in NRL, the committee agreed that several techniques are available which allow identification of the chemicals present in the glove. These are:
Gas chromatography (GC)
Gas chromatography-mass spectrometry (GC-MS)
High performance liquid chromatography (HPLC)
High performance thin layer chromatography (HPTLC).
Finally, with regard to the best way to manage the risk of these chemicals, the committee considered two main techniques: substitution or reduction in exposure. Although the risk can be managed by substituting sensitisers with non-sensitisers, they state that this is not currently possible for NRL products (but do not clarify whether this is because no suitable alternatives are presently available).
The committee state that substituting strong allergens with weaker allergens is a "reasonable possibility", but report that this is not simple, as it is difficult to determine which chemicals are less potent sensitisers than others in-vivo. The problems are compounded by the fact that the chemicals may react to produce different by-products in the final latex product, and the potency and bio-availability of these products may be significantly different from the originals.
Although no in-vitro tests are presently available to measure clinically relevant, bioavailable chemical residues in NRL products, the committee agree that it is logical to reduce the level of chemical residues and thereby reduce the sensitising capacity of the products. Ingredient information would also be useful so that individuals already sensitised can avoid products likely to produce a reaction.
Chlorination has become the most common manufacturing method for producing powder-free gloves. The committee agree that, although it is known that chlorine and hypochlorite can cause adverse or allergic reactions, there is no published data on such reactions to chlorinated gloves.
With regard to the environmental concerns of chlorination, they note that although the chlorination process uses vast quantities of water, processing non-chlorinated gloves to attain the same low protein levels consumes similar amounts.
The committee also state that chlorination may lead to a decrease in the tensile or tear strength of NRL over time, but do not cite any evidence for this.
Many latex-free alternatives are now available, including PVC, neoprene, polyurethane, and various copolymer gloves, which the committee believe to show "good to moderate performance". However, many of the chemicals used in these gloves are the same as those used in latex glove production, and therefore pose the same types of contact dermatitis risks as latex gloves. The committee conclude that there is only limited data available on the risks associated with these new materials, and note the high price for some of these products.
In addressing the various questions, the expert scientific committee reached the following conclusions:
A relationship between leachable protein levels and risk of allergic reaction has been demonstrated.
The measurement of total leachable protein is currently a useful method to estimate the allergenic potential of a latex glove.
The modified Lowry and amino acid analysis method both have advantages, although amino acid analysis is more sensitive.
The threshold level for inducing sensitisation has not yet been established.
It has not been demonstrated that powdered gloves are more likely to induce sensitisation then powder-free gloves, provided the protein content is identical.
Various methods can be used to detect chemicals in NRL known to induce Type 4 reactions, but quantification in medical devices is still a problem, and there is currently no agreement on the best applicable method.
Type 4 reactions due to chemicals in NRL have been well demonstrated, but alternative synthetic materials may pose a similar risk to NRL.
The main groups at risk for latex allergy are atopics and subjects frequently in contact with latex medical gloves, such as healthcare workers and those patients who require multiple surgery. To control these risks, products with low levels of residual allergenic proteins should be used. Latex sensitised individuals should avoid contact with NRL products.
The expert committee report is a valuable and balanced contribution to the latex allergy debate. In particular, it dispels many of the myths regarding latex allergy, and provides a sound platform on which users of latex goves can base their purchasing strategy.
Accelerators are used to increase the rate of the vulcanisation process in latex manufacture.
An allergen is an antigen, usually protein, that elicits an allergic reaction in a previously sensitised person.
A HPLC laboratory assay, which is used to measure total amino acid levels in gloves, and thereby total protein levels. Less susceptible to interfering substances than the modified Lowry assay, but more expensive and time-consuming.
A substance that can trigger an immune response, resulting in antibody production. All allergens are antigens, but all antigens are not allergens.
Proteins produced by lymphocytes which neutralise antigens or foreign proteins. Formation of IgE antibodies (immunoglobulin E) may result in asthma, rhinitis or other Type 1 reactions when the individual is again exposed to the allergen which caused the initial IgE antibody formation.
Chemicals added to latex to prevent degradation of the latex through contact with air.
An atopic is an individual with a pre-disposition, usually genetic, to developing IgE mediated responses to common allergens.
Performed either as a provocation test, where the patient is exposed to an extract from a latex product, or a use test, where the patient uses the product itself.
Enzyme linked immunoabsorbant assay, based on inhibition of the binding of human latex specific IgE antibodies to allergenic proteins after incubation of the serum with extracts of latex products.
Leachable proteins are proteins which can be extracted from NRL by aqueous methods, such as exposing the surface of samples of NRL to water.
A laboratory assay used to measure the total amount of protein in latex products. The method is detailed in European Standard EN-455, Part 3.
Antibodies which have been cloned artifically from a culture of cells in which all the cells derive from a single cloned cell. They produce antibodies with a single specificity that are, therefore, known as monoclonal antibodies.
Radioallergosorbent test, based on inhibition of the binding of human latex specific IgE antibodies to allergenic proteins after incubation of the serum with extracts of latex products.
The skin prick test (SPT) is usually thought of as the gold standard in diagnosing latex allergy. A drop of latex exudate or extract is placed on the skin and a lancet or needle is used to puncture the skin at the site of the exudate. As a control, a drop of normal saline is also placed on the skin and the skin punctured. The reaction from both is compared.
Type 1 sensitivity is an immediate reaction that happens within minutes to 2 hours, depending on the route of absorption and dose of allergen. The reaction leads to a release of histamine and other chemicals, resulting in local and systemic changes, including vasodilatation, smooth muscle contraction (bronchospasm) and increased vascular permeability. In the most serious of cases, anaphylaxis may result. It is predominantly caused by protein which occurs naturally in NRL.
Type 4 sensitivity is a delayed response. It occurs 6-48 hours after contact and includes erythema, itching, oedema, cracking of the skin and red swollen rashes that appear only on skin areas that have been in contact with the latex. It is predominantly caused by an allergy to the residues of accelerating agents used during latex manufacture.
The process of treating raw latex by subjecting it to heat and sulphur to cross-link the rubber particles, producing a latex film which has excellent elastic properties.
1. Scientific Committee on Medicinal Products and Medical Devices. Opinion on natural rubber latex allergy. European Commission, June 2000.