Management of Latex Allergy

OVERVIEW: What every practitioner needs to know

Are you sure your patient has latex allergy? What are the typical findings for this disease?

Latex allergy is an IgE mediated immediate hypersensitivity disease caused by contact with proteins retained in finished rubber products derived from Natural Rubber Latex (NRL) from the plant species Hevea Brasiliensis.The most common symptoms of latex allergy include:

• urticaria (hives)*

• angioedema*

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• rhinitis*

• conjunctivitis*

• wheezing (asthma)

• anaphylaxis**

*most common

**most severe and may be life-threatening

These signs and symptoms occur shortly after direct or indirect contact with latex products. The proteins easily elute from finished rubber products and may become airborne when a rubber product is lubricated with cornstarch donning powder. Such reactions may be frequently seen with gloves and balloons. Cornstarch powder may act as a carrier and transfer the proteins into the air for inhalation or to other materials where the powder has been deposited by contact (e.g. glove contact with a telephone or food). Thus, allergic reactions may occur from direct contact with a rubber product or unique indirect forms of contact.

The practitioner must have a high index of suspicion and take a comprehensive medical history since the patient, their family, or others may not recognize that the reaction was caused by contact with latex. This certainly was the case in the first allergic reactions identified in the 1980’s associated with latex allergy when anaphylaxis occurred after air contrast barium enemas. In these circumstances, a latex balloon tip was inflated during retrograde contrast and was administered in the lumen of the colon where mucosal contact with the balloon likely caused anaphylaxis.

Most allergic reactions to NRL occur within 15 minutes to 2 hours after contact with rubber proteins and almost certainly within 6-12 hours of exposure. If a patient has had a delayed type of reaction (e.g. 24-48 hours after exposure) it is less likely that this is due to contact with proteins from latex but may be due to other exposures or even delayed hypersensitivity reactions to chemicals retained in finished rubber products such as thiurams and mercaptothiobenzole chemicals. Typically those reactions result in skin reactions and not systemic reactions.

What are the usual circumstances when a practitioner should suspect the clinical reaction is due to latex allergy?

The clinical circumstances when a practitioner should suspect latex allergy include the following:

• Anaphylaxis in the operating room.Published reports suggest that there are two unique times when a patient may experience anaphylaxis in the operating room from latex allergen contact. Anaphylaxis within 30 minutes of arrival to the operating suite usually occurs prior to surgery starting. These may be due to airborne inhalation (most often from airborne latex that came from powdered latex gloves) or by direct contact, especially children, when the intravenous buretrol or intravenous tubing contains valves made of latex. These DO NOT refer to the injection ports frequently found on such tubing but rather in-line valves that contain latex. Anaphylaxis may occur between 40 and 220 minutes into a surgical procedure. These reactions are most commonly associated with mucosal surface contact with rubber products (e.g. surgical glove contact with the peritoneum during abdominal surgery).

• Allergic reactions after latex contact with mucosal surfaces. There are numerous medical reports of allergic reactions to rubber after mucosal contact. These include reactions to latex bladder catheters, latex condoms, rectal catheters, and oral mucosa from balloons or dental work when latex gloves are used.

• Asthma symptoms and wheezing after contact with latex or in circumstances where airborne latex is possible.Clinical concerns about indirect inhalation have occurred in hospital settings and other medical settings where powdered latex products have been present. This was so prevalent in the 1990’s that no patient known to have latex allergy underwent surgery except as the first case of the day.

• Urticaria after use of rubber products that are worn in direct contact with the skin. Many industries wear gloves to prevent the spread of infection and are the most prominent example of such reactions. Some children who volunteer/work in hospitals or similar jobs where latex gloves and other latex materials are worn appear to be at risk.

• Children who have undergone multiple operations. Medical literature suggests that sensitization increases with multiple surgical operations. This is especially concerning in subjects who have cloacal anomalies or spina bifida. Patients with spina bifida will be considered separately.

• Latex allergy reactions in patients with urologic or neurologic defects. As noted above, patients who have urogenital defects and spina bifida (especially those who require primary closure of the spinal defect and subsequent placement of ventriculo-peritoneal shunts) were found to be at high risk of developing latex allergy in the 1990s. This risk was so pronounced, with as many as 72% of patients with spina bifida developing latex allergy, a recommendation to avoid use of all products containing latex was adopted in that decade. Subsequently, the prevalence of sensitization appears to have declined in this group. Whether the introduction of fetal surgery in this special group of subjects will further reduce this risk is unclear but avoidance of latex remains the standard for this group of patients.

• Allergic reactions (either locally or systemically) after vaccine administration. A number of vaccine vials contain natural rubber latex in the top of a multiple or single dose vial or the syringe itself.

• Allergic reactions after injection of insulin in children with diabetes mellitus. Case reports of the development of allergic reactions during insulin administration have been reported in the medical literature. Although rarely systemic reactions occur, most reactions appear as hives at the site of injection. These patients fail to test positive for specific IgE directed against insulin epitopes.

• Unexpected patient populations with allergic reactions to latex. Although anyone may become sensitized to latex proteins, it appears that individuals that receive prolonged medical care in the hospital or home setting requiring use of latex gloves may develop this allergy. Examples of these populations include premature infants, patients who require bladder catheterization, patients who require chronic mechanical ventilation or tracheostomy, and atopic subjects.

• Clinical allergic reactions to foods known to cross-react with latex. The major foods that have been identified to have cross-reactive proteins with latex include the following: banana, kiwi, avocado, chestnut, bell pepper, pear, tomato, pitted fruits (cherry, peach, etc.), potato. As many as 50% of patients whose primary allergy develops due to latex, may have clinical cross-reactive allergies. The opposite is not true although still of concern. In contrast, patients with primary allergy to the foods listed above may develop symptoms from latex contact less than 10% of the time.

• Latex allergy in the general population of children. Two large prevalence studies of children performed in Europe suggest that 1.0 % or less of children in the general population become sensitized to latex. The route and timing of this sensitization is not known but still places one of every 100 children at risk of developing this allergy.

• Immediate Hypersensitivity response after vaccine administration. Similar to patients with insulin dependent diabetes, injection with a vaccine (as opposed to insulin) has the theoretic chance of inducing a reaction to latex. There are usually two plausible sources of such contact with latex: (a) The rubber stopper to a multiple dose vial transferring allergen to the vaccine and/or surface of the needle that drew up the vaccine or (b) Latex extracted during contact of vaccine with a soft natural rubber plunger in a single dose vaccine. A list of at risk files has been uploaded into this document as of May, 2011. However, the following website link is kept up to date by the Centers for Disease Control. http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/B/latex-table.pdf

See Figure 1 for Food allergy cross reactions in latex allergic patients.

Figure 1.n

See Figure 2 for vaccine preparations that may contain latex.

Figure 2.n

Who else appears to be at risk for developing latex allergy?

One of the most common circumstances surrounding development of latex allergy symptoms is in health care workers (HCW). Although children are rarely employed in such circumstances, understanding the circumstances surrounding HCW signs and symptoms give clues to the pediatric practitioner when to suspect latex allergy in their patients.

Many of the presenting signs and symptoms were initially recognized in adults with the constellation of allergic symptoms shortly after contact with latex rubber products, especially latex gloves that were lubricated with cornstarch donning powder. Approximately 50% of health care workers who develop latex allergy also develop occupational asthma. This has been presumed to be due to sensitization through the respiratory system from inhalation of latex allergy carried on cornstarch powder. This also gave clues to allergic reactions that occurred after ingestion of foods that had been handled by workers wearing latex gloves.

In Germany, a public health initiative banning the use of powdered latex gloves (not latex gloves themselves) has resulted in a marked decline in cases of occupational asthma from latex in HCW.

What other disease/condition shares some of these symptoms?

All IgE mediated allergic reactions share the similar signs and symptoms of latex allergy. Most common conditions confused with latex allergy include the following:

• IgE mediated drug allergy.

• Anesthesia related allergic reactions. These reactions occur most commonly with quaternary amine compounds, barbiturates, succinylcholine, and non-depolarizing muscle relaxants.

• Narcotic induced histamine release. In general, narcotic reagents release histamine from mast cells in a non-IgE mediated mechanism. Symptoms of urticaria, pruritis or hypotension may mimic the timing seen in latex allergic reactions seen in the operating room suite or intensive care unit.

• Idiopathic anaphylaxis.

What caused this disease to develop at this time?

Epidemiology: The first modern case of latex allergy was described in the medical literature as urticaria from contact with rubber gloves in 1979. No prior cases were described except in the German literature in the 1930’s. After those initial reports, the full spectrum of IgE mediated disease (urticaria, angioedema, rhinitis, conjunctivitis, asthma, and anaphylaxis) was reported in the next decade.

In the 1980’s the advent of universal precautions (now referred to as standard precautions) were implemented for the prevention of viral infection transmission of hepatitis, human immunodeficiency virus (HIV), and other infections when handling bodily fluids. The regular use of latex powdered examination gloves rapidly increased as a result. Prior to 1987, the medical use of latex gloves was approximately 30 million/year in the United States while that number exceeded 30 billion gloves in 2011. The use of surgical latex gloves changed minimally when compared to the use of latex exam gloves. This unprecedented 100 fold increased use of latex exam gloves paralleled the rise in reported allergic reactions to latex. In fact, the number of reports in the medical literature explodes during the same time period.

Shortly after this recommended standard, numerous reports heralded the beginning of an unprecedented epidemic of a new allergy. The initial reports of anaphylaxis occurred predominantly in patients with spina bifida as well as workers who increased their use of natural rubber gloves such as HCW. By the early 1990’s, the prevalence of latex allergy was found to be as high as 68% in patients with spina bifida and 17% of selected health care workers. One study showed that as many as one of every eight surgeries in pediatric patients with spina bifida resulted in severe untoward allergic reactions, which was a 500 fold increase compared to other children undergoing surgery. Elective surgery in subjects with spina bifida was stopped in 1993 throughout the United States until a safe method to deliver anesthesia and medical care could be instituted.

The exact reason that patients with spina bifida were so predisposed to development of latex sensitivity has never been determined. It has been speculated that the requirement for two early surgeries (closure of the meningocoele and subsequent placement of the ventriculo-peritoneal shunt), >8 surgeries, atopy (increased total IgE), bladder catheterization for neurogenic bladder, paraplegia with need for manual rectal disimpaction, and possibly epigenetic factors all contributed to this marked prevalence of disease. Although a definitive genetic cause of spina bifida in a subset of patients has been linked in part to three mutations in the VANGL 1 gene, the contribution of these genetic alterations to development of latex allergy is unknown.

Interestingly, multiple cases of anaphylaxis, with some resulting in death, were recognized from use of the EZM balloon catheter used for air contrast barium enema studies. Initially, these clinical reactions were thought to be due to allergic sensitization to barium but in retrospect were likely due to latex allergy. Lack of a standard test to confirm this relationship was not available at that time. Also, these subjects did not appear to have risk factors for development of these allergic reactions.

The unique high prevalence of latex allergy in patients with spina bifida led to evaluation of patients with similar clinical syndromes such as infants with multiple surgeries and cloacal anomalies. Indeed, those individuals appear to have significant risk of developing latex allergy as well. However, adult patients with acquired paraplegia, who may have similar medical needs as patients with spina bifida, appear to have a low risk of developing latex allergy.

The unique circumstance of occupational latex allergy in health care workers is important to recap despite the focus of this writing on children. HCW developed latex allergy at a rate exceeding the general population. However, a large proportion of these HCW (as many as 90%) appear to develop dermatitis simultaneously or prior to the development of IgE symptoms. Much of the dermatitis described is an irritant form of dermatitis on the hands from numerous reasons (e.g., powder irritation, multiple hand washing). However, contact dermatitis from thiuram leached from latex gloves may also occur. Regardless, the disruption of the skin barrier appears to be an important factor in developing latex allergy.

Early on in the recognition of latex causing allergic reactions, numerous additional reports of latex allergic individuals developing systemic reactions after ingestion of fruit and some vegetables were reported. Eventually, this phenomena was termed the latex fruit syndrome. Common foods inducing allergic reactions in latex allergic individuals are listed in the accompanying
Figure 1. As many as 50% of latex allergic subjects develop symptoms when ingesting one or more of the foods listed in the table. The most common fruits include banana, kiwi, avocado, chestnut, and stone fruits (e.g., cherries or peaches).

Interestingly, some individuals (<10%) with primary food allergies to these fruits may develop symptoms to latex contact. Multiple allergenic proteins in latex share conformational or linear epitopes with these proteins since they derive from a similar family of proteins (e.g., defense proteins) causing clinical cross-reactions. Some of the cross-reactions occur only in the laboratory and are uncommon causes of clinical reactions.

Ultimately, a medical history of immediate symptoms of allergy shortly after contact with latex, medical diagnoses (e.g., spina bifida), recurrent exposures of skin or mucosa to latex by multiple routes, are all important in making a clinical diagnosis of latex allergy.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Confirming a diagnosis of latex allergy requires a trained medical professional to perform a medical history, physical examination, and ordering of appropriate tests. The testing available depends on the country where the patient resides. Currently a standard skin test reagent is available in Europe but not in the United States or Canada. Skin testing in the 1990’s during clinical investigations, found a higher rate of systemic reactions than with other standardized reagents on the market. As a result, FDA did not clear a latex allergy reagent for testing. Published work suggests that medical history alone may have a false positive rate of 15%.

Thus, trained allergy specialists are limited to extracting latex proteins from a finished product such as a latex glove when necessary to perform a skin prick test, rely on serologic tests, and/or perform clinical use tests. General physicians practicing family medicine or pediatrics should only consider skin testing measures with proper training, appropriate medication, and emergency equipment to reverse a severe untoward reaction. As a result, the clinician must resort to ordering serologic tests to detect the presence of anti-latex IgE antibody in the patient.

Skin Testing: Skin prick testing is the most sensitive and specific method of confirming the presence of sensitization to latex proteins. Achieving the highest sensitivity has required the use of more than one source of latex material (non-ammoniated latex and extract of a latex glove). The use of two source materials achieved 100% sensitivity, 99% specificity. A negative skin test achieved 100% predictive value in concluding that a patient was not allergic to latex. A standardized reagent for skin testing was developed by Greer® with a non-ammoniated reagent from clone 600 of the Hevea Brasiliensis tree. At a concentration of 100 µg/ml, clone 600 had a diagnostic sensitivity of 95% and specificity of 99%. An adverse reaction rate, although minor, occurred in nearly 16% of subjects in the multi-centered skin test study.

Serologic Testing: There are three FDA cleared serologic tests available in the United States as well as an ELISA performed in the laboratory at the Medical College of Wisconsin (MCW) to detect anti-latex IgE antibody. The ELISA was available prior to clearance of the commercial serologic tests in the early 1990’s. In general, serologic assays have inferior testing metrics when compared to skin testing. This is due to many more false positive and false negative tests when using this method. Thus, these tests have a tendency to over and under call the presence of specific IgE.

Diagnostic performance of the three cleared serologic assays are as follows:

• ImmunoCAP (Baltimore, Maryland) (Sensitivity – 76.3%; Specificity – 96.7%)

• AlaSTAT (Cincinnati, Ohio) (Sensitivity – 73.3%; Specificity – 97.2%)

• HYTEC (Irvine, California) (Sensitivity – 91.6%; Specificity – 73.3%)

See Figure 3 for Performancy characteristics of serologic assays in the detection of anti-latex IgE antibody.

Figure 3.n

Since the negative and positive predictive values of medical tests are dependent upon the prevalence of disease in the population studied, it is not wise to predict the performance of these tests on patients from low prevalence populations. The prevalence of latex allergy in the multi-centered study was 40% and not representative of the clinical situation found in the day to day practice of clinicians. In general, one would expect a higher false positive and false negative rate in the general population where the prevalence of latex allergy appears to be approximately 1%.

The serologic test is most helpful when a clear clinical history and physical exam indicates there is no clinical evidence of latex allergy and the test does not detect latex specific IgE. It is also very helpful when there is clear clinical evidence of latex allergy and the test detects latex specific IgE.

Discordance of the clinical history and serologic assay may be due to false negative or false positive tests. When this is the case, higher levels of specific IgE in the ImmunoCAP assay [>0.65 kUa/L] (D Accetta – master’s thesis on file at Medical College of Wisconsin) are likely to be more specific and indicative of actual sensitization to latex.

Use tests: The utility of “use tests” was demonstrated in the multi-center skin test study when there was discordance between the clinical history and skin test. Placement of the subjects wet hand inside a latex glove followed by pricking the skin through the glove and massaging the skin over the prick sites increased the sensitivity of identifying a latex sensitized individual. There are numerous explanations for this observation. First, the proteins from a latex glove have been ammoniated and vulcanized. Both procedures may expose epitopes that bind specific IgE of latex sensitized subjects that are otherwise unrecognized in the non-ammoniated preparation used in skin testing. Second, it is possible that the content of specific latex allergen causing the reaction is higher in the glove material used in the test that elicits a positive response. The data from the study suggests this is unlikely since the sensitivity of a use test alone is lower than the skin test.

Use tests present some interpretation problems for the clinician. A positive test is quite helpful but a negative test leaves the same dilemma as a discordant history and test. Because of the variable allergen content of latex gloves on the commercial market, the clinician may also be confused by discordant results. In addition, the risk of an adverse reaction with a use test is like a challenge test and subject to adverse reactions. We recommend that “use testing” be performed by a trained allergist.

Confirming the diagnosis

Clinical algorithms for confirming the diagnosis of latex allergy have been described for allergy/immunology specialists. This latex allergy algorithm (Figure 4) has been modified for primary care physicians involved in the diagnostic work up patients suspected of latex allergy. In the United States there is an almost exclusive reliance on medical history and serologic tests. This algorithm goes beyond that level of testing and may be best handled by a specialist with training in allergic disease diagnosis and management (see Figure 4).

Figure 4.n

If you are able to confirm that the patient has a latex allergy, what treatment should be initiated?

See Figure 5 for Latex allergy precautions.

Confirming that an acute allergic reaction is due to latex contact can be a daunting task. It requires a high index of suspicion. However, the first line of therapy is to follow the basic life support measures of evaluating and protecting the airway (A = airway); assessing that adequate air exchange is present (B = breathing); and evaluating that perfusion, blood pressure, and adequate oxygen delivery to the tissues is present.

Airway – Patients with allergic reactions to latex may have nasal, eye, and facial edema or erythema often accompanied by urticaria.

Breathing – Most importantly, acute bronchospasm may occur (especially after inhalation) leading to hypoxemia from ventilation – perfusion mismatch and hypercarbia from insufficient ventilation.

Circulation – Hypotension, poor perfusion, and shock may be part of the symptom pattern manifested during acute allergic reactions to latex. By definition, shock is the delivery of inadequate quantities of oxygen to the tissues in order to maintain aerobic metabolism. End organ dysfunction may be manifested as altered mental status with or without lactic acidosis.

Latex avoidance – Acute allergic reactions to latex require an immediate assessment of the potential source of continued latex exposure. Descriptions in the medical literature suggest that direct mucosal contact with a latex product made by a dipping method may lead to the most significant reactions (oral, vaginal, rectal, and intraperitoneal). Rarely, intravenous administration, or even intramuscular injection can be frought with hazard. For example, vaccine preparations or containers may contain traces of latex that can lead to an allergic response in susceptible individuals. Some intravenous lines may have check valves cut from latex that can allow proteins to be extracted into the intravenous solution and subsequently injected. Although less frequent today than in the past, use of powdered latex gloves led to risk of inhalation of latex allergen resulting in acute asthma and airway compromise.

Pharmacologic Therapy – Any systemic reaction to latex should receive intramuscular epinephrine. The dose for a child under 30 kg is 0.15 mg of the 1:1000 concentration. A child or adult over 30 kg should receive a full dose of 0.3 mg of epinephrine. Although intravenous use is possible as a continuous drip, this route of delivery may lead to cardiac ischemia and therefore epinephrine is generally given by intramuscular injection.

Latex Allergy Avoidance Measures: Ideally, latex allergen avoidance is the treatment of choice for prevention of latex allergic reactions. The most important concepts of approaching this task are to be reasonable while maintaining safety. Since there are over 40,000 commercial products made with natural rubber latex, avoidance can be impractical.

The practitioner should know that nearly 88% of these products are made as dried rubber with extremely high heat vulcanization for prolonged time. This leads to near complete destruction and denaturation of protein polypeptide allergens in the finished rubber product. These products rarely cause systemic allergic reactions from contact by a latex allergic patient.

In contrast, latex products made by a dipping method (e.g., gloves, condoms, bladder catheters, gastrostomy tubes, surgical drains, balloons, and many more) are heat vulcanized at low temperature for a short duration. Usually, a porcelain or other inert form has a coagulant placed on its surface. The form then is dipped in a slurry of latex to form a film on the surface of the form after which heat vulcanization takes place.

In the 1980’s to 1990’s, most dipped rubber products did not undergo extensive washing to remove protein allergens. Today, many of these products are extensively washed or coated with a synthetic material that prevents significant leaching of remaining latex protein out of the products. One example of this has been the use of chlorination leading to a significant reduction in latex protein extraction.

It is now exceptionally clear that latex precautions means stopping the use of powdered latex dipped products. In order to facilitate donning of rubber products that are worn (e.g., examination gloves), highly cross-linked cornstarch powder was used to coat the surface of the material. That cornstarch powder was able to carry latex allergen into the air and even into the Heating Ventilation and Air Conditioning (HVAC) system which may have contributed to persistent aeroallergen exposure especially in health care settings. This may lead to allergic reactions despite no obvious direct skin or mucous membrane contact with a latex product. Typical latex products are listed in Figure 6.

Immunotherapy: Allergen desensitization to latex via injection or via the oral route has been complicated by systemic reactions in patients with latex. Very few groups have undertaken this approach and have favored avoidance as the primary treatment of latex allergy.

Anti-IgE therapy: The use of omalizumab, a monoclonal antibody that binds IgE molecules, has been safely used for severe asthma. The theoretic use of this therapy offers the potential for an improved quality of life and reduction in the number of life threatening events a patient may suffer from. No controlled trials of efficacy have been performed with a large enough patient population to assess the risk and benefit of this approach to therapy.

Figure 5.n

Figure 6.n

See
Figure 6 for common products to avoid.

What are the possible outcomes of latex allergy?

Current knowledge suggests that sensitization to latex may be persistent and lifelong. Thus, patients already sensitized should avoid direct contact with latex and avoid situations where inhalation of latex proteins could result in either allergic reactions or heightened sensitization. Because of this, patients with high risk of developing latex allergy, especially those individuals with spina bifida, should be managed in a latex safe environment.

A latex safe environment includes no personal skin, mucosal surface, or mucous membrane contact. Seemingly innocuous situations such as a visit to the dentist office could result in major complications. Counseling the family on future employment opportunities should include avoiding professions where latex is unavoidable. Fortunately, the medical field has become safer but is not 100% free of latex contact.

Patients who are sensitized by occupational exposure may exhibit evidence of diminished sensitivity over time. However, they may never return to using latex or work in an environment where latex is used. Such exposure may induce further production of IgE against the allergenic proteins in latex and exacerbation of allergy symptoms.

The improvement in manufacturing of products made from natural rubber latex with greatly diminished latex allergen content of finished products has promised a safer environment with infrequent reports of anaphylaxis.

For those individuals who develop asthma associated with latex allergy, small studies suggest that as many as 50% of those subjects may continue to have asthma despite exposure being controlled.

Immunotherapy has been disappointing currently but may be available in the future especially with the availability of anti-IgE therapy. Clinical anecdotal case experience suggests that this may reduce the number of reactions and severity. There is insufficient evidence to recommend this for all latex allergic subjects and be reserved for selected individuals with recurrent life-threatening episodes.

Are additional laboratory studies available; even some that are not widely available?

Skin Testing with source of latex that caused a clinical reaction: Virtually all commercial skin test reagents and serologic reagents use non-ammoniated latex as the source material of proteins. However, almost all latex finished products have been ammoniated in the process leading to alteration of allergens and even formation of neo-allergens not seen in the native source.

Researchers in Finland were the first to show the presence of neo-allergens in finished latex gloves. Thus, extracting protein from a finished product, creating serial dilutions of the skin test reagent, and applying prick puncture skin tests may be the only method of detecting sensitization to latex. Because of either severe untoward reactions to skin test from the Medical College of Wisconsin or an increased frequency of adverse reactions than usually seen with skin prick testing at Mayo clinic, such testing should be left to experience allergy/immunology trained physicians.

How canlatex allergy be prevented?

Patients with high risk of developing latex allergy, especially thoseindividuals with spina bifida, should be managed in a latex-safeenvironment.

What is the evidence?

Alenius, H, Mäkinen-Kiljunen, S, Alroth, M, Turjanmaa, K, Reunala, T, Palosuo, T. “Crossreactivity between allergens in natural rubber latex and banana studied by immunoblot inhibition”. Clin Exp Allergy. vol. 26. 1996. pp. 341-348. (This study characterizes the molecular mechanism for cross reactions between latex and bananas by Hev b 6 allergen retained in natural latex.)

Allmers, H, Schmengler, J, Skudlik, C. “Primary prevention of natural rubber latex allergy in the German health care system through education and intervention”. J Allergy Clin Immunol. vol. 110. 2002. pp. 318-323. (Dr. Allmers epidemiology and government wide mandates to eliminate powdered latex gloves in healthcare have led to a marked reduction in occupational asthma from latex. Although indirect, this work was sentinel in outlining appropriate avoidance measures of airborne latex.)

Alroth, M, Alenius, H, Turjanmaa, K. “Cross-reacting allergens in natural rubber latex and avocado”. J Allergy Clin Immunol. vol. 96. 1995. pp. 167-173. (Dr. Alroth and colleagues further characterized the cross-reactions of another frequent cross-reacting food (avocado) with natural latex.)

Beezhold, DH, Reschke, JE, Allen, JH, Kostyal, DA, Sussman, GL. “Latex protein: a hidden “food” allergen”. Allergy and Asthma Proc. vol. 21. 2000. pp. 301-306. (This work by Beezhold and colleagues is one of the clearest demonstrations that latex gloves worn by food handlers will transfer allergen from the glove to the surface of foods which could result in an allergic reaction to latex without the patient knowing the source of the latex protein. Most likely, this has led many treating physicians to search for irrelevant allergies.)

Bernardini, R, Novembre, E, Ingargiola, A, Veltroni, M, Mugnaini, L, Cianferoni, A. “Prevalence and risk factors of latex sensitization in an unselected pediatric population”. J Allergy Clin Immun. vol. 101. 1998. pp. 621-5. (Study from Italy in a very large cohort of children demonstrated a very low risk of sensitization to latex in the general population.)

Biagini, R, Deitchman, S, Esswein, E. “NIOSH Alert, Preventing Allergic Reactions to Natural Rubber Latex in the Workplace. Cincinnati, OH: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health”. DHHS (NIOSH) Publication. 1997. pp. 97-135. (This is one of the most important publications to have ever come out on latex allergy. The Department of Health and Human Services from the National Institute of Occupational Safety and Health provided guidelines that are valid today in 2011. Most importantly, this office took a very proactive response to prevention of this disease when only a small amount of evidence was available.)

Biagini, R, Krieg, E, Pinkerton, L, Hamilton, R. “Receiver Operating Characteristics Analyses of Food and Drug Administration-Cleared Serological Assays for Natural Rubber Latex-Specific Immunoglobulin E Antibody”. Clin Diagn Lab Immunol. vol. 8. 2001. pp. 1145-1149. (Dr. Biagini updated the performance characteristics of serologic assays cleared by the United States Food and Drug Administration.)

Blanco, C, Carrillo, T, Castillo, R. “Latex allergy: Clinical features and cross reactivity with fruits”. Ann Allergy. vol. 73. 1994. pp. 309-314. (Dr. Blanco is one of the early investigators who reported the marked percentage of latex allergic subjects with clinical reactions to foods.)

Bousquet, J, Flahault, A, Vandenplas, O. “Natural rubber latex allergy among health care workers: a systematic review of the evidence”. J Allergy Clin Immunol. vol. 118. 2006. pp. 447-454. (Dr. Bousquet from France provided one of the finest reviews of the evidence of latex allergy and the association of natural rubber exposure in the healthcare workplace.)

Breiteneder, H, Ebner, C. “Molecular and biochemical classification of plant-derived food allergens”. J Allergy Clin Immun. vol. 106. 2000. pp. 27-36. (Dr. Breiteneder is one of the world's experts on plant-derived food allergens and their cross reactions with multiple exposures including latex.)

Gelfand, DW. “Barium enemas, latex balloons, and anaphylactic reactions”. Am J Radiology. vol. 156. 1991. pp. 1-2. (One of the first accounts documenting that it is the exposure of the colonic mucosa to latex balloons that contain the barium, rather than the barium itself, that cause allergic reactions during barium enema radiologic examinations.)

Gold, M, Swartz, J, Braude, B, Dolovich, J, Shandling, B, Gilmour, R. “Intraoperative anaphylaxis: An association with latex sensitivity”. J Allergy Clin Immuno. vol. 87. 1991. pp. 662-666. (Dr. Gold in Canada and Kelly (MMWR) in the US reported nearly simultaneously the risk of intraoperative anaphylaxis from latex allergy.)

Grzybowski, M, Ownby, DR, Rivers, EP, Ander, D, Nowak, RM. “The prevalence of latex-specific IgE in patients presenting to an urban emergency department”. Ann Emerg Med. vol. 40. 2002. pp. 411-419. (One of the screening studies that shows a high prevalence of detectable anti-latex IgE antibody detected by serologic studies. This paper led to controversy and ultimately to most allergy experts reminding clinicians that a medical history of latex allergy should be obtained prior to testing for latex allergy. Further work continues on why such high prevalence of specific IgE to latex is detectable. It is speculated that cross-reactions of Hev b 8 (a profilin found in many pollens such as grass or other plant derived allergen) may have some relation to this.)

Hamilton, RG, Adkinson, F. “Diagnosis of natural rubber latex allergy: Multicenter latex skin testing efficacy study”. J Allergy Clin Immunol. vol. 102. 1998. pp. 482-90. (Dr. Hamilton and Adkinson at Johns Hopkins University organized one of the most important latex skin test studies in the United States. Twelve centers (authors in paper) contributed to this work.)

Hamilton, RG, Biagini, RE, Krieg, EF. “Diagnostic performance of FDA-cleared serological assays for natural rubber latex-specific IgE antibody”. J Allergy Clin Immunol. vol. 103. 1999. pp. 925-30. (Dr. Hamilton and Adkinson at Johns Hopkins University organized one of the most important latex serologic test studies in the United States on latex allergy as part of the skin test study referenced above. Twelve centers (authors in paper) contributed to this work.)

Kelly, KJ, Leung, Sampson, Geha, Szefler. Pediatric Allergy. October 2010. pp. 631-639. (This review is the latest comprehensive pediatric review on latex allergy in the literature.)

Kelly, KJ, Kelly, B, Pawankar, R, Holgate, S, Rosenwasser, L. “Diagnosis and Treatment of Latex Allergy”. Allergy Frontiers: From Epigenetics to Future Perspectives; Therapy and prevention of allergies and Special Considerations in Children, Elderly and Pregnancy. 2010. pp. 653-674. (This review is one of the latest comprehensive pediatric and adult reviews on latex allergy in the literature. It was paired with a second chapter in a 5 volume textbook published internationally (next reference).)

Kelly, KJ, Kelly, B, Pawankar, R, Holgate, S, Rosenwasser, L. “Clinical Manifestations”. Allergy Frontiers: From Epigenetics to Future Perspectives; Clinical manifestation of allergic diseases. March 2009. pp. 487-508. (This review is one of the latest comprehensive pediatric and adult reviews on latex allergy in the literature. It was paired with a second chapter in a 5 volume textbook published internationally (previous reference).)

Kelly, KJ, Kurup, V, Zacharisen, M, Resnick, A, Fink, JN. “Skin and serologic testing in the diagnosis of latex allergy”. J Allergy Clin Immunology. vol. 91. 1993. pp. 1140-5. (An important article on skin and serologic testing in the United States.)

Kelly, KJ, Pearson, ML, Kurup, VP, Havens, PL, Byrd, RS, Setlock, MA. “A cluster of anaphylactic reactions in children with spina bifida during general anesthesia: Epidemiologic features, risk factors, and latex hypersensitivity”. J Allergy Clin Immunol. vol. 94. 1994. pp. 53-61. (This is the comprehensive prospective study on the epidemic outbreak of operating room anaphylaxis to latex allergy that identified latex as the cause in the 1991 Morbidity Mortality Weekly Report in 1991 by the Centers for Disease Control and Prevention in the US.)

Kelly, KJ, Setlock, M, Davis, JP. “Anaphylactic reactions during general anesthesia among pediatric patients”. MMWR. vol. 40. 1991. pp. 437(This report followed by a survey of children's hospitals in the USA led to the halt of all elective surgical procedures in patients with Spina Bifida in the United States until the cause and avoidance of reactions could safely be implemented.)

Kurup, VP, Kelly, T, Elms, N, Kelly, KJ, Fink, JN. “Cross reactivity of food allergens in latex allergy”. Allergy Proceedings. vol. 15. 1994. pp. 211-6. (This is one of the very early publications on cross-reactive food with latex allergens.)

Liss, GM, Sussman, GL, Deal, K, Brown, S, Cividino, M, Siu, S. “Latex allergy: epidemiological study of 1351 hospital workers”. Occup Environ Med. vol. 54. 1997. pp. 335-342. (One of the early intervention trials attempting to link prevention of latex allergy in health care workers to avoidance of latex gloves.)

Nettis, E, Colanardi, M, Soccio, A, Marcandrea, M, Pinto, L, Ferrannini, A, Tursi, A, Vacca, A. “Double-blind, placebo-controlled study of sublingual immunotherapy in patients with latex-induced urticaria: a 12-month study”. Br J Dermatol. vol. 156. 2007. pp. 674-681. (One of the trials on immunotherapy for latex allergy. Unfortunately, this therapy has not proven to be safe and effective on a wide scale.)

Nutter, AF. “Contact urticaria to rubber”. Br J Dermatology. vol. 101. 1979. pp. 597-8. (The initial modern case report on latex causing IgE mediated disease.)

Roest, MA, Shaw, S, Orton, DI. “Insulin-injection-site reactions associated with type I latex allergy”. N Engl J Med. vol. 348. 2003. pp. 265-6. (A short case report on the risk of developing latex allergy in diabetic patients presumably from contamination of the vial or needle from the latex top on multiple dose vials of insulin.)

Slater, J. “Rubber Anaphylaxis”. N Eng Jour Medicine. vol. 320. 1989. pp. 1126-30. (The first US case report of latex allergy in Spina Bifida patients but not in the operating room. This case brought to light the risk of mucosal contact with latex allergen. Dr. Slater goes on to publish numerous scientific papers on the molecular basis of latex allergy.)

Vassallo, SA, Thurston, TA, Kim, SH, Todres, ID. “Allergic Reaction to latex from stopper of a medication vial”. Anesth Analg. vol. 80. 1995. pp. 1057-8. (Dr. Vassallo reports an early concern about latex contamination of multiple dose vials with latex allergen.)

Yagami, T, Sato, M, Nakamura, A, Komiyama, T, Kitagawa, K, Akasawa, A. “Plant defense-related enzymes as latex antigens”. J Allergy Clin Immunol. vol. 101. 1998. pp. 379-385. (Dr. Yagami and colleagues in Japan have been some of the most active investigators of the latex-fruit and latex-vegetable syndromes. This details the beginning of some of their tremendous additions to the world's medical literature on the subject.)

Ylitalo, L, Turjanmaa, K, Palosuo, T, Reunala, T. “Natural rubber latex allergy in children who had not undergone surgery and children who had undergone multiple operations”. J Allergy Clin Immunol. vol. 100. 1997. pp. 606-12. (Dr. Ylitalo in Finland enlightened us about other children at risk of latex allergy.)

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