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Natural Rubber Latex Allergy
A Problem of Interdisciplinary Concern in Medicine
Randolf Brehler, MD;
Birgitta Kütting, MD
Arch Intern Med. 2001;161:1057-1064.
ABSTRACT
In the past 10 years, IgE-mediated allergy to natural rubber latex has
become a significant health problem in industrialized countries, especially
among health care workers, patients with congenital malformations, and children
with a history of multiple surgical interventions. Curative treatment inducing
immunological tolerance in formerly sensitized patients is experimental and
not yet generally available. Therefore, it is important to be aware of the
seriousness of latex allergy and to understand the risk factors leading to
this allergy. Preventive measures are needed to decrease the incidence of
natural rubber latex sensitization. This article gives a brief review of the
current state of knowledge concerning latex allergy, including a definition
of latex, epidemiological data, identified allergens,
the clinical spectrum, diagnostic procedures, cross-reactions, preventive
measures, the legislative background, and economics.
INTRODUCTION
In today's health care practice, the use of gloves is indispensable.
Because of their low price, high comfort, and tactile properties, natural
rubber latex (NRL) gloves are preferred over synthetic ones. Contact dermatitis
(allergic and nonallergic) is a well-known problem related to the use of NRL
gloves, but during the last 20 years, the immediate reactions to NRL have
been the focus. Between 1989 and 1992, the Food and Drug Administration received
reports of more than 1000 serious allergic reactions and 15 deaths due to
NRL allergy.1
Immediate allergic reaction to NRL is a significant occupational problem
for employees wearing NRL gloves; about 10% of health care workers are sensitized
to NRL. On another level, patients are at risk of anaphylactic reactions due
to contact with NRL during medical treatments, especially surgical procedures;
about 19% of the anaphylactic reactions associated with anesthesia are caused
by NRL allergy.2 Gloves are not the sole source
of contact with NRL in sensitized patients. Natural rubber latex is found
in more than 40 000 medical devices and other nonmedical products (Table 1). To avoid exposure in daily life,
sensitive patients must be able to identify products containing NRL, but the
labeling of these products is not regulated in most countries.
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Table 1. Natural Rubber Latex in Medical and Privately Used Products
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Recent reviews3-13
focus on different aspects of NRL allergy, such as epidemiology, diagnostic
procedures, allergen identification, prevention, and therapy, but despite
the increasing awareness and prevention programs, NRL allergy is still a problem.
Therefore, the current state of NRL allergy is examined in this review.
DEFINITION OF LATEX
To avoid confusion when discussing NRL allergy, clear definitions of
the terms latex and rubber
are needed because, depending on the context, they can have multiple meanings:
- Natural rubber latex refers to the milky
sap produced by more than 2000 species of plants from about 300 genera.14 Industrial use of NRL is almost exclusively from
the rubber tree Hevea brasiliensis.
- Synthetic rubber is produced by synthesis
of polyisoprene or other polymers. The term latex
is used in referring to NRL and synthetic rubber.
- A technical definition of latex is common
in some countries, where the term refers to a suspension of different kinds
of particles (such as latex wall paint) and does not necessarily indicate
the presence of rubber latex in these products.
EPIDEMIOLOGY
Since the first epidemiological study among medical personnel by Turjanmaa,15 the prevalence of NRL allergy has increased. Today,
between 10% and 17% of medical personnel in Europe and the US are believed
to be sensitive to NRL.16-26
Children with congenital malformations, especially those associated with spina
bifida, are another well-identified risk group. The prevalence of NRL allergy
in patients with spina bifida is about 50% in industrialized countries27-34
and about 5% in less industrialized countries, such as Venezuela.35 This is believed to be related to contact with NRL
during medical treatments, especially surgical interventions in early childhood.
A history of multiple surgical interventions has also been reported in the
general population of children with sensitivity to NRL.36
Sensitivity was found in 34.1% of children with a history of 3 or more interventions.36 Surgical interventions are a risk factor for the
development of NRL allergy in children28, 34, 36
but not in adults.37
Higher prevalence of NRL allergy was also found among hairdressers,38 housekeeping personnel,24
latex doll manufacturers,39 latex glove manufacturers,40-41 textile workers,42
and greenhouse workers.43 The prevalence in
the general population is unknown but has been estimated to be less than 1%.44-45
CLINICAL REACTIONS
Clinical reactions to contact with latex gloves can be divided into
3 groups (Table 2): nonimmunological
and delayed- and immediate-type allergy.
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Table 2. Natural Rubber Latex (NRL) GloveRelated Skin Problems
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Nonimmunological irritant contact dermatitis is manifested as irritative
eczema with redness, scaling, and itching, predominantly on the back of the
hands and interphalangeal. In contrast to the others, this type of clinical
reaction is not based on an immunological mechanism. It is a general problem
of glove wearing that is independent of the chemical composition of the gloves.
Gloves can induce skin irritation "mechanically" or by an alkaline pH:
- "Mechanical" irritation can be avoided by use of powder-free gloves.
In tests of glove wearing on powdered vs unpowdered hands, laser profilometry
demonstrated increased skin roughness after wearing the same glove on prepowdered
hands.46
- The alkaline pH of most powdered gloves is believed to be responsible
for irritative skin reactions.47 Powder-free
gloves offer a lower surface pH that is in the range of normal skin pH. The
presence of a long-lasting alkaline skin surface pH after removal of powdered
gloves has been reported.47
The second type of clinical reaction is manifested by a delayed-type
allergic contact eczema caused by glove contact, usually on the back of the
hands. Rubber chemicals, mostly accelerators, used for manufacturing latex
products are responsible for such reactions.48
Thiurams have been identified as the predominant contact sensitizers in NRL
gloves. Because most manufacturers no longer use thiurams, the delayed-type
reactions play a minor role.
Immediate-type reaction to NRL is IgE-mediated, and the term latex allergy is usually used to describe this. Localized itching,
erythema, or contact urticaria within minutes after NRL exposure are initial
symptoms. Progressive sensitization can also lead to generalized urticaria,
angioedema, rhinitis, conjunctivitis, asthma, and anaphylactic shock minutes
after dermal or mucosal contact with NRL proteins. An increasing number of
individuals allergic to NRL report severe reactions to latex, including generalized
urticaria, bronchospasm, and hypotension.49
The severity of clinical reactions can be classified according to the
system of von Krogh and Maibach.50 Stage 1
of contact urticaria syndrome indicates localized urticaria; stage 2 denotes
generalized urticaria with or without angioedema; stage 3 includes bronchial
asthma, rhinoconjunctivitis, orolaryngeal, and gastrointestinal symptoms;
and stage 4 is severe anaphylactic shock.
Glove powder is believed to play a central role in reactions to NRL
products. Natural rubber latex proteins on gloves bind to the glove powder
(usually cornstarch powder) and become aeroallergens. Therefore, respiratory
tract reactions induced by aeroallergens may occur concomitantly with dermal
reactions caused by local dermal contact.51-52
In this case, a clear distinction between a systemic reaction produced by
localized dermal contact and reactions caused by allergen inhalation is impossible.
Parenteral latex exposure can also trigger reactions.53-54
Because of resorption of NRL allergens through mucous membranes, NRL
allergy is not only a problem for employees who wear latex gloves but also
an increasing problem for sensitized patients undergoing medical treatment
by persons wearing gloves. Fatal cases have been reported in the literature,2, 31 especially during surgical interventions.
About 19% of all anaphylactic reactions during surgery (anesthesia "accidents")
are related to NRL allergy,2 and the percentage
is higher in children.55 The risk of anaphylaxis
to NRL in children with spina bifida has been estimated to be 500 times greater
than that in the general population.56-57
ALLERGENS
Natural rubber latex derived from H brasiliensis
contains more than 200 polypeptides, 56 of which have been identified as allergens
associated with IgE-mediated reactions. Their molecular weight ranges from
4 to 200 kd. Some of the allergens have been characterized,58-61
some as general major allergens and others as major allergens only for patients
of defined risk groups. Hev b 1, for example, is a major allergen for children
with spina bifida but not for health care workers.62-68
Different routes of NRL exposure and subsequent sensitization may explain
this. Hev b 1 and Hev b 3, which are major allergens in children with congenital
malformations, are particle-bound proteins and less soluble than other latex
allergens, and sensitization to these allergens may result from repeated mucosal
contacts.65 It has been speculated that the
aerogen NRL protein exposure associated with the use of powdered gloves in
delivery rooms may be responsible for the development of NRL allergy in neonates.69 Further variation has been identified in mice that
have been subcutaneously sensitized to NRL, leading to the development of
IgE antibodies recognizing 14-kd and 27-kd proteins. Intratracheally and topically
sensitized animals produced IgE antibodies to 14-, 35-, and 92-kd proteins.70
Some latex allergens are a part of a plant's defense system (Hev b 2
and class 1 endochitinases). This may explain the increasing prevalence of
sensitivity to NRL. It is hypothesized that the amount of NRL obtained from
an H brasiliensis tree increased in the last few
years. There may be a correlation between the production of defense proteins
in relation to the frequency and intensity of hurting the trees.58
Further complicating the issue, Mäkinen-Kiljunen and colleagues59 identified an allergen in a surgical glove extract
that is not found in natural rubber, suggesting that rubber proteins may be
altered during glove manufacture.
DIAGNOSIS
In Vitro
The quantitative measurement of serum-specific IgE antibodies to NRL
is generally accepted as a diagnostic tool for latex allergy. However, the
sensitivity of specific-IgE analysis ranges from 8% to 100%. For the widely
used Pharmacia CAP (Pharmacia AB, Uppsala, Sweden) radioallergosorbent test
method, the sensitivity is reported to range from 50% to 80%.71-73
Data about the specificity of in vitro diagnosis are rare.71, 74-75
Using different assay systems (CAP-FEIA [fluoroimmunoassay; Pharmacia AB]
and AlaSTAT [Diagnostic Products Corp, Los Angeles, Calif]), NRL-specific
IgE was detected in the serum samples of patients despite negative findings
on skin tests and no history of NRL allergy.74-75
Cross-reacting IgE antibodies binding to plant proteins and NRL are believed
to be responsible for this. Mäkinen-Kiljunen and Turjanmaa74
found IgE specific to banana in the serum of most patients with a false-positive
radioallergosorbent test for NRL. Also, IgE antibodies to Ficus benjamina (weeping fig) may account for the frequent false-positive
finding of specific IgE to NRL.75 On the other
hand, IgE antibodies against carbohydrates were shown to be the cause of IgE
reactivity against a broad range of foods, from plant to invertebrate animal
origin. These IgE antibodies have been shown to be responsible for positive
results in in vitrospecific IgE assays, despite negative skin-prick
test (SPT) results and an absence of clinically relevant sensitization.76-77
In Vivo
Diagnosis of immediate-type NRL allergy should be based on positive
SPT results. Because SPTs with single latex extracts have a sensitivity below
100%, it is necessary to use a panel of different allergen extracts.71, 78-81
In Germany, extracts that are available from allergen manufacturers are generally
unstandardized. High-ammoniated NRL milk, available from glove manufacturers,
can be used exactly as received; glove extracts can be prepared by a short
extraction in isotonic sodium chloride solution.82-83
Because of the potential risk for anaphylactic reactions associated with SPTs
in patients allergic to NRL,30, 81, 84
it is recommended that diluted solutions be used initially. Recombinant NRL
proteins can be used for SPTs, but a panel of allergens is necessary to get
a sufficient sensitivity.85
The reliability of NRL glove wearing test results depends on the test
protocol and the protein concentration of the gloves used.86
Increased sensitivity of exposure tests has been obtained by Hamilton and
Adkinson86 by puncturing the skin before contact
with the NRL glove. A potential risk for anaphylaxis can be reduced by exposing
only 1 finger to a glove finger before exposing the hand to the whole glove.57
CROSS-REACTIVE ALLERGENS
Cross-reactions between proteins in NRL and several foods have been
demonstrated, and a "latex-food" syndrome has been postulated.87-89
In one study, 43% of patients with NRL allergy reported reactions caused by
the ingestion of foods, particularly tropical fruits. Fruit-specific IgE antibodies
are present in about 70% of serum samples of patients allergic to NRL. However,
their presence is of limited significance given the low sensitivity and specificity
of in vitro tests relative to a patient's self-reported allergic reaction
after fruit ingestion.89 The relevance of fruit
sensitization varies considerably, based on a patient's diet and cultural
background. On Spain's Grand Canary island, sensitization to avocado was found
to be the predominant food allergen in patients with latex allergy,87, 90 whereas in Germany, reactions to
kiwi, banana, and tomato were much more frequent.89
Patatin,91-94
profilin,95-96 chitinases,97-98 plant endo-1,3-ß-glucosidases,99 glucanases,59, 94, 99-100
and hevein101 are allergens believed to be
responsible for cross-reactions.
Ortiz et al102 found IgE antibodies to
NRL proteins in 85.9% of patients allergic to fruits. Only 10.5% of them had
clinically relevant latex allergy. This indicates that patients sensitized
primarily by food allergans may also react to NRL.
THERAPY AND PREVENTION
Desensitization
Several recent case reports103-106
of NRL-specific immunotherapy have been published. Administering oral103 and subcutaneous 104-106
allergens was demonstrated to be effective in reducing allergic symptoms from
NRL contact; SPT sensitivity decreased during specific immunotherapy. In the
first randomized, double-blind, placebo-controlled study107
on 17 patients with NRL allergy, significantly lower rhinitis, conjunctivitis,
and cutaneous scores were reported in the patient group, but asthma symptoms
were not significantly different in patients vs controls. Therefore, NRL-specific
immunotherapy remains an experimental treatment of NRL allergy, and avoidance
of exposure remains the mainstay of therapy and prevention.
Protein Concentration of Gloves and Powder
The modified Lowry test is the current standard method for determination
of protein content in gloves.108 A protocol
for protein analysis has been issued by the European Union, but there are
no guidelines about how many gloves from each batch need to be tested. Therefore,
data from manufacturers can be based on the analysis of only a few gloves,
with no guarantee that all the gloves, especially if they are from different
batches, have the same protein content. Standardized protocols for the quantitative
analysis of allergens in gloves are not available. A correlation between the
protein concentration and the allergen concentration of gloves has been demonstrated
by enzyme-linked immunosorbent assay and radioallergosorbent test inhibition
methods and SPT.109
Significant variation in the NRL protein concentrations in different
types of gloves has been observed by several investigators.49, 109-112
Powder-free gloves normally have low protein concentrations because of special
leaching procedures used in their production. The protein concentration of
powdered gloves varies between 45 and 1640 µg/g.109
Heese et al49 have reported decreasing protein
concentrations in gloves manufactured using newer technology.
A correlation between glove wearing and the development of NRL allergy
has been demonstrated in other studies:
- Heese et al20 compared the prevalence
of NRL allergy in a group of dental students at 2 time points 3 semesters
apart. After the first time point, students regularly wore latex gloves. The
prevalence of NRL allergy increased from 2% before glove use to 10.4% 3 semesters
later.
- Brehler et al19 demonstrated that
the use of powder-free gloves results in low rates of NRL sensitization. The
finding of minimal NRL allergy in 2 English hospitals was attributed to the
use of powder-free gloves with a low protein level, whereas the prevalence
was much higher in a German hospital where only powdered gloves with high
protein contents were worn.
Moreover, powder is an allergen carrier. The air in rooms where powdered
NRL gloves are used has high concentrations of allergen,113
with much lower concentrations where powder-free gloves are used.114-115 Sensitized persons may have asthmatic
and systemic reactions to airborne NRL proteins associated with the use of
powder. A hospital's changing from powdered, high-protein content gloves to
powder-free or synthetic ones results in a decrease of airborne allergen levels
to below the limit of detection within a few days.116
Strict avoidance of NRL products decreases the risk of latex allergy development
even in identified risk groups. After construction of a special NRL-free operating
room for children with spina bifida, none of 12 patients studied became sensitized
to NRL allergens.117
Powdered gloves with a low protein content have become available in
Germany, but a reduced risk for the development of NRL sensitization has not
been demonstrated with the use of these gloves.
Prevention Guidelines
The primary prevention of NRL allergy is the avoidance of NRL exposure,
but because of the ubiquity of NRL in products, this is nearly impossible.
Threshold allergen exposure levels to avoid NRL sensitization are not defined.
These levels may vary for individuals with atopic vs nonatopic predisposition.
Natural rubber latex protein levels should be reduced to the lowest technically
possible minimum. Individuals at high risk to develop sensitization should
not be exposed to any NRL. These include children with congenital malformations
and those with diseases bearing the risk of repeated surgical interventions.
Persons who regularly wear gloves in their professions should use NRL-free
gloves if eczema of the hand develops, especially if they have an atopic predisposition.
Eczema lesions of the hand are opportunisitic for the development of NRL sensitization
by allowing protein to penetrate the skin. Less than 1% of NRL proteins penetrate
intact skin, whereas 23% penetrate abraded skin.118
To identify patients who are sensitized to NRL, screening questionnaires
may be used (Table 3). In sensitized
individuals, NRL avoidance is the cardinal rule of NRL allergy control and
to avoid life-threatening anaphylactic reactions. Aerogen exposure from powdered
gloves and other NRL products must be avoided. Contamination of foods with
NRL allergens from kitchen personnel wearing powdered gloves can also lead
to anaphylaxis.119 Finally, indirect contact
with NRL proteins on surfaces contaminated with NRL, such as clothing,120 can cause a life-threatening reaction.
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Table 3. Screening Questionnaires to Determine Latex Allergy in Children
and Adults*
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Latex-safe environments for patients with NRL allergy should be provided
in all medical and dental facilities. Medical procedures in high-risk patients
should be performed in a latex-free setting. Substitute products without NRL
are available for nearly all products containing NRL.
LEGISLATION
In 1997, a joint statement121 from the
American Academy of Allergy, Asthma, and Immunology and the American College
of Allergy, Asthma, and Immunology formulated new guidelines that only powder-free
latex gloves should be purchased and used to reduce aeroallergen levels and
exposure.
The Food and Drug Administration has begun requiring manufacturers to
put allergy warnings on products or packaging containing latex and is regulating
the mislabeling of these products as "hypoallergenic."122
Labels for NRL gloves must include the statement "Caution: This product contains
natural rubber latex, which may cause allergic reactions."
In 1995, the American Society for Testing and Materials published standard
test method D5712-95 for analyzing protein in natural rubber and NRL products.
The Food and Drug Administration is proposing that the recommended limit on
water-extractable protein per glove and the actual protein level appear on
the label of NRL gloves. The proposed guidance document also recommends that
manufacturers of NRL gloves used for surgery or examination limit the amount
of water-extractable protein in the gloves to no more than 1200 µg of
protein per glove, regardless of glove size. The lowest acceptable amount
of water-extractable protein will be limited by the sensitivity of the current
American Society for Testing and Materials D5712 test method to 50 µg
of protein per gram of NRL product (300 µg of protein per glove for
a 6-g glove). The Food and Drug Administration believes that without a more
sensitive standard method lower claims would be misleading.
In Europe, no consensus exists for a recommendation to use powder-free
gloves only. In Germany, guidelines for the use of NRL gloves were established
by the Department of Labor and Social Affairs (Bundesministerium für
Arbeit und Sozialordnung) in the Technical Regulations on Dangerous Substances
(Technische Regeln für Gefahrstoffe, or TRGS) in December 1997. The TRGS
describe the requirements for marketing and use of dangerous substances with
regard to safety, occupational medicine, hygiene, and industrial science.
TRGS 540 recommends replacing use of powdered NRL gloves with powder-free,
low-allergen NRL ones or other suitable gloves. The protein level is required
to be less than 30 µg per gram of glove. The standard test method is
given in the European Standard EN 455-3 set by the European Committee for
Standardization. However, the labeling of NRL protein concentrations on gloves
is not required.
ECONOMICS
The issue of NRL allergy bears economic consequences. Addressing occupational
latex allergy has direct costs, including the purchase of NRL-free and powder-free
gloves, substitution of other hospital equipment, and the cost of installing
air filtration and laminar flow changing stations. The costs of implementing
a dust-free and NRL-free working environment have been estimated at between
$75 000 and $200 000 per year.123
Indirect costs are worker-related and include job relocation to other areas
in the hospital, job change with or without retraining, and additional education
for other nonclinical employment.123 It has
been reported that in Canada the employer's cost will be more than Can $200 000
for a registered nurse who has to stop work because of NRL allergy.124 In Germany, the Employers Liability Insurance Association
estimated costs of about $83 000 for each individual with a legally ascertained
occupational disease related to NRL allergy (Employers Liability Insurance
Association, oral communication, 1997). At present, about 20% of occupational
skin diseases and 33% of occupational asthma cases registered by the Berufsgenossenschaft
für Gesundheitsdienst und Wohlfahrtspflege (the Employers Liability Insurance
Association for many health care workers in Germany) are attributed to NRL
allergy.
In a recent analysis of 3 health care institutions of different types,
the costs of disability due to NRL allergy from continued latex use were compared
with the costs of converting the facilities to be latex-safe. It was found
that all facilities were likely to benefit economically from becoming latex-safe.125
CONCLUSIONS
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