by Evan Li, MD
Over the last several decades allergic conditions have experienced unprecedented spikes in incidence amongst the general population. At no point in the documented history of medicine has atopic diseases, such as asthma, food allergies and eczema garnered such attention from the medical community and the public at large. There have been various proposed hypotheses for this phenomenon, including changes in diet, genetics, over utilization of antibiotics, ubiquitous nature of plasticizers, pollution, loss of farming communities, even vaccines. Though compelling they may be most explanations are far from conclusive. Perhaps one such condition encapsulates this genre of diseases better than any. It is a condition whose rise was accidental yet wholly inexorable. It baffles with its sometime sudden and devastating presentation. It frustrates with its difficult to diagnose nature and lack of therapeutic options. It came to prominence in tandem with the signature epidemic of the 1980s and threatened the lives of healthcare professionals and patients alike. Its story spans the scopes of chemistry, immunology, botany, occupational medicine, public health, and personalized medicine. And through more precise diagnostic measures, stricter regulatory standards, improved manufacturing quality and increased awareness its outbreak was contained as quickly as its meteoric rise. This is a brief but fascinating story of latex allergy.
A History of Latex Allergy
When one hears of latex allergy the image of the rubber glove naturally comes to mind. While the eventual widespread utilization of latex examination gloves no doubt contributed to the emergence of latex allergy the circumstances surrounding the initial adoption of rubber gloves was somewhat ironic. During the 1840s contemporary physicians Hungarian obstetrician Ignaz Semmelweis and Harvard Professor Oliver Wendell Holmes independently came to the conclusion that disinfecting hands and instruments lead to dramatically improved outcomes for the mother after childbirth. Later on in the 1870s the Irish surgeon Joseph Lister advocated for the use of phenol to disinfect surgical instruments and the washing of hands by surgeons. While on a lecturing tour in the United States, Lister presented his findings to famed surgeon William Halsted who adopted Dr. Lister’s practice of cleaning surgical instruments with phenol. However Dr. Halsted’s most trusted nurse at the time, Caroline Hampton, who would later become his wife, suffered terrible allergic dermatitis from constant exposure to the caustic cleaning agents. As a response to this Dr. Halsted in 1889 requested a pair of rubber gauntlets from the Goodyear Rubber Company. Satisfied with the initial trial more gloves were ordered and soon all his surgical assistants began wearing them exclusively rather than operating with their bare hands. And so it was allergic contact dermatitis, not infection control, that ushered in the popular use of rubber gloves in medicine. It would not be another year before Robert Koch’s famous postulates proved the causative effect of microorganisms on the pathogenesis of disease.
The first described cases of rubber glove hypersensitivity published in English medical literature came from the New England Journal of Medicine in 1933. By this time no operating theater in the US performed surgeries without gloves and its use had spread to other industries. Dr. John G. Downing noted three curious cases of what he perceived to be dermatitis from rubber gloves. And having been unable to find literature of this condition anywhere else he decided to publish his findings. The three men that sought out his consultation were linemen that had worked for the same company for many years and had no previous history of skin conditions or sensitivity to materials. Dr. Downing observed a red, blistering rash that was most severe in the webbings of the men’s fingers and back of their hands. The rash started at the level of the wrist, and gradually shaded to a lighter pink towards the palmar surfaces. The rash steadily worsened over the two weeks prior to examination and came with it severe itching and swelling. Dr. Downing noted that the men wore heavy rubber gloves up to 8 hours per day. And despite a protective layer of cotton worn beneath the gloves, the men’s hands were never-the-less affected on the dorsal surfaces where the cotton did not cover. When one of the men’s symptoms resolved after avoidance of glove use for a month put the glove back on for only five minutes, the rash promptly returned the next day. Decades before we would understand the immunologic basis of this phenomenon, Dr. Downing described in perfect detail all he features of classic contact hypersensitivity to latex: a delayed, pruritic, blistering rash that develops in a previously unsensitized individual after prolonged and repeated exposure that improves with avoidance and recurs with re-exposure.
With greater recognition of latex contact dermatitis as a distinct entity separate from hand eczema or detergent dermatitis it became apparent the importance of proper diagnosis as avoidance would become the only effective palliation. This proved to be challenging as not only can contact dermatitis arise from a variety of household products, even if the clinician were to narrow in on the glove as the culprit the diagnosis may still be in question. The problem lay not only with the latex but also with the extraction and manufacturing process. The fundamental particle that makes up commercial rubber is a colorless, volatile organic liquid compound called isoprene. Isoprene is produced by many plants and these backbone units polymerizes to form polyisoprene. Polyisoprene is then coated with a layer of protein and lipids and becomes the rubber particle which forms the basis of milky sap known as latex. Latex is mainly cultivated from the rubber tree, Havea brasiliensis, mostly from southeast Asia and some parts of south and central America. After latex is tapped ammonia is added as a primary preservative and secondary preservatives are often added. During the processing of natural rubber latex it undergoes a process called vulcanization, in which it is heated with sulfur and other accelerants to improve its elasticity and thermal stability. Because of the various agents involved in the manufacturing process of commercial rubber the diagnosis of latex allergy is made difficult not only due to its clinical similarity to other entities but also the complexities of the rubber molecule and synthetic additives that end up in the finished product. One series published by English dermatologist Harold Wilson, MD clearly demonstrated these challenges. In this case series Dr. Wilson utilized a diagnostic technique invented at the turn of the 20th century known as the patch test. This method is currently still in use today with somewhat more sophistication but the principle behind it has not changed. It tests for delayed hypersensitivity reaction by the application of an adhesive tape laced with a diluted solution of the agent in question. The tape is left in place for 2-3 days for the reaction to develop. An interpreter then assesses the reaction based on the redness of the skin where the adhesive was in contact with skin. Dr. Wilson performed patch testing on 42 patients with suspected glove dermatitis to five common accelerants used in rubber vulcanization (dipentametyhlene thiuram disulphide, tetramethyl thiuram disulphide, mercaptobenzthiazole, zinc diethyl dithiocarbamate, 2,4-dimethyl-6-tert-butylphenol) along with unprocessed latex. High incidences of positivity were found to the accelerants with 37 of 42 testing positive to at least one of these agents. Surprisingly, of the 25 patients patch tested to untreated latex none had a positive result. Dr. Wilson mistakenly concluded that latex itself seemed to be an inert and did not contribute to glove dermatitis, which he concluded was due to accelerants. This case series demonstrates the challenge posed to clinicians when confronted with a patient with suspected latex allergy as one always must question if it is the latex, an impurity or both that is responsible for the reaction.
In order to better understand the clinical manifestations of latex allergy one has to understand that there are two fundamental types of allergic reactions. The more dramatic of the two is called immediate hypersensitivity where a patient develops rapid onset symptoms of hives, itching, swelling of the lips, tongue, throat, and/or genitals, shortness of breath, wheezing, abdominal pain from swelling of the intestines, diarrhea and dangerous drop in blood pressure. This reaction usually occurs within minutes of exposure to the inciting agent. The second type of allergic reaction, known as delayed hypersensitivity. This type of allergic reaction is characterized by a chronic, itchy, blistering rash that typically manifests about 48 hours after the initial contact with the inciting agent. This type of reaction is a more chronic condition that typically is not life threatening as it does not present with the dramatic intestinal and throat swelling, drop in blood pressure and respiratory distress associated with immediate hypersensitivity. Up until the 1980s the only documented cases of latex allergy was of the delayed type. This changed in 1979 with the first case report of an apparent immediate hypersensitivity reaction to latex. In a report published by Dr. A.F. Nutter, the patient, a 34 year old woman with long standing history of hand eczema, who one day developed intense itching several minutes after trying on a new pair of rubber gloves. An attempted patch test to a piece of latex glove lead to flaring of her skin within 15 minutes rather than the expected 48 hours. An extract solution made from the glove and applied to her skin via needle prick test elicited an immediate reaction and subsequent prick testing with leaf extract from the Havea brasiliensis had the same reaction. Throughout the 1980s more case reports were published indicating a growing phenomenon of dangerous immediate hypersensitivity to latex. Many of these cases involved health care workers such as nurses or young patients with spina bifida, a congenital defect that leads to exposed nerves of the spine due to incomplete closure. Spina bifida patients often have disorders or urination that requires frequent use of latex containing urinary catheters and often undergo a number of surgical operations at a young age exposing them to high amounts of latex. Many times the initial manifestations of the allergy occurred during surgery where the patients would suffer unexplained respiratory distress, low blood pressure and racing heart rates. These initial cases baffled clinicians and invariably the patients would test negative to the anesthetic agents or antibiotics given before and during surgery. It was not until 1989 that the anesthesia literature would definitively recognize latex as the causal agent in these cases of anaphylaxis. Latex allergy reached epidemic proportions during the 1980s and early 1990s and a systemic review of the literature known as a meta-analysis as conducted by the French National Regulatory Authority that compiled the data from several studies from 1990 to 2003 involving over 16,000 individuals showed prevalence of latex allergy in the general population to be 1.37% but amongst health care workers it was 4.32%. There is no one explanation as to the increased incidence of latex allergy, especially in health care workers, but likely a combination of increased presence of latex containing materials, increased incidence of allergy in the general population and increased awareness of latex allergy as a disease entity. One large contributing factor that likely lead to the high prevalence of latex allergy in health care workers was the emergence of the human immunodeficiency virus. HIV not only ravaged the general population but many health care workers unwittingly fell victim to the infection due to lack of awareness and lack personal protective standards amongst the medical employees prior to HIV becoming an epidemic. As a response to the growing awareness of transmissible diseases such as HIV and hepatitis in 1987 the Centers for Disease Control published a document titled Recommendations for Prevention of HIV Transmission in Health-Care Settings. This document recommended that the bodily fluids of all individuals rather than just ones suspected of having a transmissible agent be considered as potentially infectious. The result of these recommendations was the increased utilization of barrier protection including latex containing gloves.
One of the most surprising aspects of latex allergy is the idiosyncratic ways it can manifest. Probably the most common clinical manifestation is no symptom at all. From the French meta-analysis that showed 4.32% prevalence of clinical allergy to latex the same study also showed a 7.8% prevalence of skin test positivity to latex. This means that a large proportion of latex sensitive individuals carry the antibody to latex but for some reason is able to tolerate at least some minimal level of exposure without developing symptoms. These individuals may have higher threshold of tolerance to latex molecules than truly allergic individuals or have not yet had the necessary amount of exposure to latex to mount physical symptoms. It is likely that with repeated exposure to the right amount of latex antigen this subset of individuals will eventually develop clinical symptoms. Like patients with true latex allergy the risk groups that develop sensitivity prior to symptoms are individuals with spina bifida or other congenital urogenital abnormalities, healthcare workers, rubber industry workers, patients with other types of allergies (hay fever, eczema, asthma), and patients who have undergone multiple procedures. As mentioned previously latex allergy can be divided into immediate and delayed reactions. The immediate reactions are due to the presence of what are known as IgE antibodies to latex that are produced over a long period of time in a genetically susceptible individual after years of exposure to latex particles. This type of antibody is akin to the antibodies we make after an infection. As more and more of these antibodies accumulate at first they do not cause any outward manifestations. They may be detectable on skin testing or blood testing in a sensitized person that does not have symptoms of latex allergy. However like a volcano building up lava with enough exposure these antibodies will eventually lead to an initial clinical event. The trigger is always exposure to latex particles via either skin, blood, gastrointestinal or the respiratory tract. The latex molecule binds to the antibodies, which in turn causes the release of histamine from the body’s immune cells. Histamine then acts on a variety of tissues to cause itching, hives, swelling of the throat, tongue, lips and intestines. Histamine causes the fluid in our blood to leak out into the soft tissue which causes the swelling which clinicians term angioedema. The two most dreaded complications from angioedema are a dangerous drop in blood pressure due to fluid leaving the circulatory system and asphyxiation due to swelling of the throat. Both are potentially fatal manifestations of immediate sensitivity reaction to latex. Swelling of the intestines can also lead to profound diarrhea and abdominal pain. Histamine can also act on the lungs to induce shortness of breath, coughing, wheezing and potentially fatal respiratory failure. When the reactions are localized to the skin, such as when a person is exposed to gloves or condoms, the symptoms are typically limited to the skin in the forms of hives and itching and are typically not life threatening.
However when the latex gets past the skin barrier the potential for a deadly reaction is high. Such circumstances usually occur during a surgical operation where latex gets into the circulation either via an infused product, from the gloves of the surgeon working on an open cavity or from a urinary catheter. Outside of the surgical setting systemic exposure that lead to immediate reactions are either through respiration or ingestion. Aerosolization of latex particles which once inspired by a sensitized individual can lead to symptoms of hay fever such as nasal congestion, sneezing, itching, runny nose or asthma like symptoms of chest pressure, coughing, shortness of breath and wheezing. This typically occurs with the use of powdered latex gloves where the allergic individual breaths in the powder that sloughs off the glove. When ingested the patient may experience severe abdominal pain and diarrhea, along with swelling of the tongue, throat and lips, as well as asthma symptoms. This scenario typically happens when an allergic individual eats food prepared by someone using latex gloves. A very peculiar type of reaction called oral allergy syndrome (or oral pollen syndrome or latex fruit syndrome) can occur when a latex allergic individual develops a reaction after eating certain foods such as bananas, avocado, chestnuts or kiwi.
This reaction manifests as numbness, tingling or itching of the tongue and lips without overt angioedema and thus is not usually life threatening. The reason for this is the protein in these foods are structurally similar to latex, confusing the immune system and thereby eliciting a response. Interestingly this reaction can be prevented by cooking these foods which structurally alters the proteins in a way the immune system cannot recognize. Testing for immediate sensitivity to latex involves skin prick testing or blood testing. Skin testing entails scratching the surface of either the back or the forearm with a sharp plastic prick or needle that is dipped in a liquid latex solution that is available commercially available. If the site of the prick turns red and raised and causes itching it is considered a positive test. Blood testing involves the detection of the latex specific IgE antibodies and can be done using several different methods and are readily available through major vendors such as Quest or LabCorp. Both tests are highly accurate and sometimes allergists employ both tests simultaneously if the result of one is borderline. The treatment of localized skin reaction to latex typically involves oral antihistamines like Benadryl, Allegra, Zyrtec or Claritin until the signs and symptoms resolve. For the more dangerous systemic reactions, immediate use of epinephrine (adrenaline), which constricts the blood vessels and prevents or reverse the angioedema and low blood pressure is indicated as a life saving measure. Clinicians often times will use intravenous antihistamine and steroids as an adjunct to epinephrine in these cases. The other major form of latex allergy is the delayed type sensitivity that was the first to be recognized almost 100 years ago. This reaction is called delayed because it typically requires 2-3 days for a part of the body’s immune system called T-cells to mount this type of reaction. In this type of reaction the immune system can react to either the latex itself, the additives contained within the latex product or both. The additives can also cause an irritant reaction that is not immune mediated but more akin to a chemical burn. Whether it be delayed reaction to the additives or latex (termed allergic contact dermatitis) or irritant reaction to the additives (termed irritant contact dermatitis) the clinical manifestations are similar and typically is characterized by redness, itching, blistering and a degree of swelling that is not as severe as angioedema. This type of rash is distinct from the hives seen in immediate sensitivity reactions. Testing invariably involves patch test to the additives and latex and treatment involves avoidance and topical steroids and sometimes oral steroids in an effort to shut off the T-cells responsible for the reaction. Management for latex allergy of all kinds comes down to treatment with either antihistamines or steroids for the acute episodes and avoidance for long term care. Luckily synthetic alternatives exist for pretty much all rubber products (eg balloons, condoms, gloves). Many hospitals have drastically reduced the use of latex containing gloves and some have outright banned them. All glove vendors now offer fully synthetic gloves such a nitrile or neoprene. Many office clinics are now stocked exclusively with synthetic gloves. However latex is prized for its superior elasticity, strength, durability and tactile sensation. These properties and the fact that it is biodegradable makes them still the preferred gloves for many surgeons. For many providers the middle ground is powder free, low latex protein content gloves that provides many of the benefits of latex gloves while minimizing its risks.
Though the 80s and 90s brought latex allergy to epidemic levels since the turn of the 21st century there is evidence of either a decline or stabilization of its prevalence in the population. This is happening despite the overall rise in allergic disease and lack of effective treatment for latex allergy. What has contained this former public health crisis? The keys to combating latex allergy still is and has always been recognition and avoidance. Standardized and accurate skin test reagents are highly reliable in determining sensitivity and blood protein assays have been developed to such sophistication that antibodies to not one, but fifteen different allergenic latex proteins can be commercially assayed for in humans. The cooperative efforts of clinicians, healthcare facilities, regulators and manufacturers has amounted to drastically increased recognition and awareness of latex allergy, massive reduction in the use of powdered gloves and natural latex rubber containing gloves, reduction in latex content of gloves, adoption of synthetic alternatives and willingness of healthcare facilities and other workplaces in adopting standardized measures to protect latex sensitive employees. These successes have largely come from affluent Western nations and not necessarily translate to developing states where the incidence of latex sensitivity is higher relative to their wealthier counterparts. Thus despite tremendous progress latex allergy still poses a worldwide threat. However with persistent vigilance in instituting avoidance measures latex allergy should continue to remain an afterthought rather than the menacing specter that it used to be.
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