Diagnosing allergies depends not only on immunology, but also on skilled skills and experience.
撰文 | 特雷莎 · 麦克费尔（Theresa MacPhail）
Translation | Qin Qikai
Parik has been practicing allergy treatment for over 10 years and is a clinical assistant professor in the Department of Pediatrics at NYU Grossman School of Medicine. She specializes in asthma care and conducts research on childhood asthma, but her clinic in Midtown sees patients with different types of allergies.
Allergy is a medical subspecialty that relies as much on clinician experience and intuition as it does on modern diagnostic tools and the patient's biomedical history. That's why Parrick likens her day-to-day job to that of a detective. Diagnosing allergies is never easy. In a way, it's like solving a medical mystery.
Like Tolstoy's unhappy family, every allergy sufferer has its own misfortunes. No two allergy cases are the same, and a formal allergy diagnosis can take hours, days, weeks, months, or even years. This is because allergies are biologically complex, test results can be uncertain, and the most common symptoms of allergies are very similar to those of other diseases.
Parikh was puzzled that I hadn't seen an allergist because I had allergies and my father had died from a bee sting. She looked at me with a friendly smile and said, "I really think you should make an appointment with me, get tested, we should fix this." ”
Like many allergists, I was hesitant to see an allergist. Since my symptoms are generally mild and easily controlled with over-the-counter antihistamines, it's easy for me to procrastinate in seeking more specialized treatment. But I knew Parik was right, so I ended up taking her advice.
Typical atypical diagnosis
When I came to her office again, a full year had passed and my sinuses were really uncomfortable. As instructed at the appointment, I haven't taken antihistamines for a week. After a brief consultation, Parrick called her nurse into the exam room and gave me a standard skin prick test to test my response to specific allergens and a quick breath test to check if I had mild asthma in addition to allergies. After 3 measurements, the nurse told me that the indicators were completely within the normal range: no asthma at all.
The nurse returned to the room with 3 small blue plastic trays. The tray contains a white plastic applicator that looks like an 8-legged insect. There is a pointed tip at the end of each leg, and by pressing it lightly on the upper arm or back, it is able to slightly cut through the skin and release trace amounts of allergen extract under the first dermis layer. Allergists prefer to do the test on their arm so that the patient can see the reaction on their own, as seeing their own skin reaction is often the first step for the patient to understand their own condition.
In total, I was tested for reactions to more than 50 different allergens, including pollen from trees and grasses, as well as common food allergens like eggs and wheat. The test also includes a negative control (normal saline) to which normal skin should not react and a positive control (histamine) to which it should respond to ensure that the test is normal and the results are accurate. The nurse marked the corresponding number on my arm so that Parik could easily see the results, and she carefully pressed the applicator against my forearm and upper arm, gently rocking it back and forth. I felt the plastic head of the applicator sink in. Subsequently, the nurse left the room, leaving me to stare at my skin for the next 20 minutes, which is the average time it takes for skin cells to respond to each allergen.
I immediately felt histamine as a positive control starting to work. The skin under the small scratches begins to itch – at first it is mild, then it becomes uncontrollable. I managed to resist scratching it. I stared at my arm and saw a raised pink rash where histamine was, like a mosquito bite. Sensitive people's skin reacts immediately to allergens, creating an inflammatory reaction at the injection site, which is what allergists call a "rash and flush reaction." The release of histamine from the patient's mast cells is the main driving force behind this response. In general, a rash greater than 3 mm and erythema greater than 10 mm in diameter is considered positive for sensitivity. However, if the positive control produces a rash and erythema less than 3 mm, this size may be the basis for evaluating other rashes. A rash of any size is considered evidence of allergic sensitization, although a smaller rash may not represent a true allergy.
I observed the reactions at the other numbers, but all I saw were dry marks of the allergen extract dripping on my pale skin. After the allotted time, Parrick knocked on the door and looked inside. She scrutinized my arms, gave me an "um", and then told me that my skin was not reacting to any allergens. "It doesn't necessarily mean you're not allergic to these things," she explained, "and it just means we have to dig deeper, pardon my pun." ”
Typically, an intradermal test is performed after a failed skin prick test. Intradermal testing uses a conventional syringe to deliver a small amount of allergen extract deep into the skin. Parrick's nurse returned with a metal tray filled with 20 different syringes. She wiped my upper arm with an alcohol swab, wiped off the handwriting and any remaining extract, and gently pinched my skin for the injection. Needles were piercing my skin one by one. After the nurse was done, my skin looked terrible. At the point of the needle prick, small droplets of blood and raised bumps are formed. Then, I waited another 20 minutes. This time, as I stared at my arm, I remembered that there was an aunt among my relatives who had severe allergies. I want to know to what extent my immune response will be like a loved one or not. However, nothing happened except for a pinprick wound and itching of the skin from the injection of histamine.
After the allotted time, Parikh returned to the room, examined my arm carefully, and sat down. "First of all," she said, "I want to emphasize that I believe in you. I think you have clinical signs of allergies. The problem is that your skin is 100% non-responsive. This kind of thing happens all the time. ”
Parikh explained that in a small percentage of patients with significant respiratory allergy symptoms, skin cells are much more tolerant to allergens than sinus cells. In other words, I may indeed have a plausible, convincing seasonal episode of hay fever or perennial respiratory allergies, but it will never show up on any skin test. The cells on the skin and the cells that make up the mucous membranes react very differently when exposed to the same allergen.
Parikh decided to give me a serological allergen test. In a serological allergen test, the person's serum will be mixed with the allergen, and then the doctor will check the resulting antibody response. IgE antibodies are associated with atopy and are predictors of anaphylaxis, and if they are activated upon exposure to an allergen, the patient is considered sensitive to the allergen (complicating matters is that standard diagnostic tools can only test sensitivity and cannot always accurately predict whether a patient has developed or will develop an allergy).
It was only a few months later that I got my antibody test results, but the follow-up was online. When Parrick and I spoke again in May of that year, it was a particularly bad spring pollen season, and I was dealing with full-blown hay fever symptoms. My eyes were itchy and hot, and sometimes I would cry spontaneously, as if I was crying. Even though I have to take allergy medication every day, my nose seems to be blocked forever. I was anxious to know which trees or grasses might be the cause of these discomforts.
"You're special!" Parik announced at the beginning of the call, as if she was telling me that I had won a coveted prize, "and based on these results, your blood doesn't react at all." You're completely unresponsive. In fact, your IgE antibody levels are low. If I had just looked at these test results, I would have said that you are not allergic to anything. ”
In that brief moment of silence, I felt a little crazy. If the results of every test I do (skin prick test, intradermal test, blood antibody test) are 100% negative, then do I really have allergies? Or do I have itchy eyes and blocked nose that I have always imagined? What is the cause of the obvious nasal irritation that the otolaryngologist diagnosed many years ago and that I experience every spring, summer and autumn?
"I believe you have clinical signs," Parrick said, as if reading my mind, "I definitely think you're allergic." It's just that for some patients, their allergies are not mediated by IgE, and there is no easy way to detect them. It's obvious that your body is responding to something, but it's not responding through the IgE pathway. You have local allergic rhinitis, that's my diagnosis. ”
Basically, this means that the immune cells on the mucous membranes of my nose and eyes react when they come into contact with allergens. For me, allergic reactions are targeted or "localized" rather than systemic or "systemic". My skin cells and their antibodies may not respond to pollen flowing in the spring air, but the cells in my nose and inside my eyes do. Unfortunately, this also means that there is no way to know which specific allergen is causing my symptoms. Strictly speaking, we could try another method, but it would require placing each of the 50 allergens one after the other, in small amounts, directly on my eyes or nasal mucosa, and waiting for the body to respond. Unsurprisingly, neither Parrick nor I were willing to do that.
Parrick exhausted all available methods and still couldn't solve the case: what triggered my allergies remained a mystery. She prescribed me daily antihistamine nasal sprays and eye drops and advised me to stop taking oral antihistamines because of their side effects and the fact that my allergies were topical. If my allergies weren't systemic, there was no need to risk the side effects of anti-allergy medications circulating throughout my body. She suggests that it is much better to treat the symptoms at the source.
At the end of this months-long, very personal, but not uncommon, complex allergy diagnosis story (filled with multiple negative allergy test results, and medical history based on patient reports and clinical observations), I want to ask you the question: Am I diagnosed with respiratory allergies?
The answer to this question depends on two things: the first is how we define what an allergy is, and how we can distinguish it from similar symptoms and medical conditions. Because my IgE levels are low and there is no evidence of a systemic immune system response, but the immune cells in my nose, eyes, and throat are activated, then I have allergies or type I hypersensitivity, but I am not atopic allergies.
The second is that we can accept different types of evidence that can be used to substantiate an overactive immune response. If we only refer to the results of clinical IgE skin and blood tests, there is no scientific "evidence" that I am allergic. However, if we had done further testing and had clear evidence of inflammation and irritation after exposure to pollen, it would have confirmed my local allergic reaction.
My own story illustrates well (and perhaps too well) that allergy diagnosis in the 21st century is a perplexing mystery. From the invention of the dermatography allergy test in 1865 to the recent development of fluorescent immunoassays for specific IgE antibodies, it has never been easier to diagnose or medically confirm an allergic reaction without actually observing symptoms. The milder or less obvious the reaction, the more difficult it is to detect, diagnose, or "prove" an allergy. Diagnosing allergies depends not only on immunology, but also on skilled skills and experience.
Why are skin tests not as accurate?
In the early 80s of the 20th century, allergies were considered a backward field of medicine. In fact, medical students have little to no training in allergies. (This is still the case, and most interns only spend about two weeks studying allergic diseases.) "People don't even think it's a science," explains Sampson, Kurt Hirschhorn Professor of Pediatrics at Icahn School of Medicine at Mount Sinai and director emeritus of the Elliott and Roslyn Jaffe Institute for Food Allergy in New York City, "and they don't really think there's any point in skin testing." "There's a reason behind this lack of belief: getting accurate results from an ordinary skin prick test is often a difficult thing to do.
First of all, the skin test must be done correctly, with positive and negative controls. The negative control is the thinner used in the mixture, to which normal skin should not react, and the positive control is histamine, which normal skin reacts to, forming a rash. Second, skin tests and intradermal tests must be performed precisely. For skin prick testing for respiratory and food allergies, the applicator puncture must be deep enough to deliver the allergen to the correct location on the skin. If the puncture is too deep and causes the patient to bleed, it may be considered a false positive (especially if the intradermal puncture is too deep). If the scratches or injections are too close, the results can be difficult to identify, as it may not be clear which specific allergen is causing the reaction. The results are much better if you use high-quality, standardized allergen extracts, but it's much more difficult than it seems.
Part of the problem with the accuracy of skin testing is that there are several different companies that currently produce extracts for skin prick testing and intradermal testing, and these extracts can vary significantly in allergen concentration (how many allergens are in each dose) and composition (the type of solution in which the allergens are mixed). Due to the lack of standardized regulations for the commercial preparation of allergens in skin prick testing, the amount of allergen actually injected can vary, making it difficult to know how much of the allergen has penetrated the skin. Not enough or too much can affect the results. Sometimes, the inactive ingredients used in different extracts themselves cause reactions, resulting in false positives. There is a high risk of injecting too many allergens in an intradermal test, which can lead to false positives or more severe reactions. (In fact, all skin allergy testing must be done in a clinical setting in case the patient has a severe allergic reaction to one of the allergens.) ）
Today, the allergen extracts used in most skin tests are either single allergens or mixtures of similar allergens (for example, in tests for allergies to "grasses", the extracts used may contain allergens from multiple grasses). This makes it difficult to interpret the results accurately, especially if a certain vegetated allergen common to the patient's geographic region is absent from the extract. The results of skin tests are collected, averaged, and then used to standardize allergen extracts (which may seem like circular logic, but that's okay), and for epidemiological and pharmacological studies, which is one of the reasons why it's difficult to get an accurate number of allergy patients.
Even if everything is done correctly to produce high-quality allergen extracts, the reliability of skin prick and intradermal test results can be influenced by "the skill of the person, the testing instrument, the skin color, and the potency of the extract," as well as "the location of the test, age, body mass index (BMI), medications, allergen immunotherapy, circadian rhythms and seasonal changes, menstrual cycles, stress, and anxiety." Taking antihistamines, steroids, antidepressants, sedatives, and other medications that affect the function of the immune system can also affect skin test results. Because of this, allergists often ask patients to stop using these medications from a few days to a week before the test. If a skin test is to be done anyway, such as in a patient who cannot interrupt medication for medical reasons, all negative results must be considered likely to be false negatives, although a positive test result is still considered positive.
It is also difficult for babies to undergo skin testing. Their skin doesn't show reactivity until around 3 months, and even after that, their results can be harder to read than adults and considered more uncertain. That's why early 20th-century physicians often defaulted to the P–K test to detect allergen susceptibility in infants.
Finally, and perhaps most importantly, there is currently no standardized or universally accepted system for interpreting skin tests or recording and collecting results. There are some general recommendations for clinicians, but each allergist can decide for himself how best to interpret the results of skin prick and intradermal allergen testing. That's why it's important to have a trained allergist, rather than a GP, manage and interpret skin tests. A more accurate reading of skin test results may require years of experience.
In addition, skin tests can only be performed on "normal" or currently unresponsive skin, otherwise allergy results are almost impossible to interpret. As you can imagine, this makes it difficult for people with skin allergies to get accurate results.
You can only do what you can
When I spoke with Dr. Peter Leo, one of the top experts on atopic dermatitis (eczema), he explained that common skin prick tests are usually not suitable for patients with skin allergies. In his clinic, skin testing is time-consuming. Leo will put 80~120 stickers containing various allergens on the patient's back and leave it for 48 hours.
"It's kind of a drag," Leo said, "and on Monday, you put stickers on patients." On Wednesday, we'll take them off. Then, on Friday, the patient came back and we observed the results of the skin in the last 96 hours. It's more invasive for the patient, but it does give us important information. Once the final result reading process is complete, and on the basis of any positive reactions, Leo will give his patients a list of things to avoid in various products. Sometimes triggers are hidden in shampoo, soap, or other items of everyday use. It can take a while to determine which allergens are actually causing an allergic reaction, as it can take up to two months for a patient's skin to "calm down" after they stop being exposed to these substances.
For a patient to be diagnosed with atopic dermatitis rather than a positive skin test alone, three criteria must be met. First, the patient must have eczema, rashes, or skin inflammation that is not just blisters or bumps. Second, the patient must have symptoms of itching. Third, the rash and itching must be chronic, or recurrent, not occasional. Atopic dermatitis is mostly diagnosed in the pediatric population and usually goes away as they reach adulthood, but it can also get worse in adult patients. Leo explained to me that the current research could lead to the development of a new diagnostic test for the subtype of atopic dermatitis based on immunophenotyping, a test used to study the different proteins expressed by each cell. But for now, patch testing is the only way he can determine possible allergy triggers for eczema.
For respiratory allergies and food allergies, there is an option to test for specific IgE antibody responses to allergens when the results of skin tests are inconclusive or inconsistent. When Sampson first started his career, allergists were also using the radioallergen adsorption test (RAST) to check the IgE responsiveness of a patient's blood to different allergens. This test is a radioimmunoassay that uses a small amount of radioactive antigen mixed with the patient's serum. If the patient is allergic to the antigen, then the patient's IgE antibodies bind to the antigen, and the free-floating antigen is measured by a gamma counter (the less free-floating antigen, the more active the IgE is, and therefore the more sensitive the patient is to the antigen).
Today, RAST has essentially been replaced by new immunoassay methods, but in common parlance, the term "RAST" is used to refer to other blood tests, even by allergists. If you're like me and need a blood test, your allergist will usually prescribe you an enzyme-linked immunosorbent assay (ELISA) or the more popular and accurate fluorescent enzyme immunoassay (FEIA).
In an ELISA test, antigens and enzyme-labeled antibodies are mixed with the patient's serum to detect antibody responses to specific allergens. ELISA tests are rapid and inexpensive, but require allergists to test for individual allergens or groups of allergens. They also require manual operation. FEIA is a test that uses a similar method to RAST and ELISA, except that the antibody label used to measure the response of an antibody to a specific antigen is a luciferase. FEIA is fully automated, error-prone, and can screen for multiple allergens at once. The advantage of standard FEIA (trade name ImmunoCAP) is that it measures allergen-specific IgE (sIgE) rather than total serum IgE levels. It can also reduce (but not completely eliminate) the chance of false positives due to accidental cross-reactivity or genetic similarity of antigens (e.g., different nuts from the same family).
However, even if a serum test is "valid" and shows positive sIgE activity, it does not necessarily mean that the patient is allergic to a specific allergen, only that they are reactive to that antigen. Sampson reminded me that relying on blood tests to diagnose food allergies was a very bad idea. He noted that when people with positive blood test results undergo an oral food challenge, "the proportion of positive tests far exceeds the number of people who actually have a clinical response." In fact, the false positive rate of skin and blood tests for food allergies can reach 50%~60%.
Decades have passed, and allergy researchers have finally been able to demonstrate a strong correlation between the level of sIgE antibodies in blood tests, the size of the rash produced by skin tests, and the likelihood that a person will develop an immune response when ingesting a particular food or being exposed to respiratory allergens, skin allergens. However, this new realization also creates some confusion for patients: they often confuse the level of IgE antibodies in the blood or the size of the rash after a skin test with the severity of the allergy. On social media sites, patients often share photos of their skin tests to highlight the extent of their allergies. In other words, they equate tests that only measure sensitivity or likelihood of a reaction with an accurate assessment of the degree of allergic reaction they would experience when exposed to allergens in their normal lives. Unfortunately, this is not the case.
"There is not a good correlation between the size of the skin test (the rash produced) or the level of antibodies and the severity of the reaction you will have. Sampson explained to me, "The only thing that matters is the likelihood of the reaction, not how bad the reaction is." ”
That's why the gold standard for diagnosing food allergies, both past and present, is a placebo-controlled, double-blind oral food challenge, often referred to as OFC.
Complex food allergy diagnosis
Although OFC is the best way to confirm a food allergy, they are the least likely test to perform. The reasons for this vary, but some of the most common causes are: the high cost of OFC because it needs to be tested in a hospital or other health care facility that is able to care for patients with anaphylaxis, the long time it takes to complete OFC because each allergen needs to be tested separately and the number increases over the days or weeks, and there is a risk because these tests can cause serious reactions in patients, especially small children. OFC makes parents particularly nervous and can also cause a lot of anxiety for children. In the absence of OFC, most food allergies are diagnosed by a detailed medical history, physical examination, skin prick test, and sIgE blood tests. (Tests that are not recommended include: intradermal tests because they can cause serious reactions; serum total IgE measurements, which only measure the presence of a comprehensive rather than specific allergic reaction; IgG tests, because everyone has an IgG response to food proteins; or any other test that claims to assess food allergies.) In general, an experienced allergist can accurately diagnose most food allergies. However, without an OFC, there is no way to confirm with absolute certainty whether someone has a typical food allergy.
In addition to these challenges, Sampson noted that testing in adults is not enough. Most allergy studies, especially those related to food, have been conducted in young children (which makes sense, since most patients develop food allergies for the first time in infancy or early childhood). This makes it more difficult to interpret the findings for adults and can lead to confusion.
The diagnosis of a food allergy is more complicated, as its main symptoms are very similar to other gastrointestinal disorders or diseases that are completely unrelated to allergies. There are also food-related disorders that are not mediated by IgE at all, such as food protein-induced enterocolitis syndrome, food protein-induced proctocolitis syndrome, and eosinophilic esophagitis. Enterocolitis syndrome is an immune-induced inflammation of the small intestine, usually triggered by milk or cereal, which can cause vomiting and diarrhea. Food protein-induced proctocolitis syndrome is an immune-induced inflammation of the colon, usually caused by cow's milk, that can cause blood in the baby's stool. Eosinophilic esophagitis is an inflammation caused by an excess of eosinophils (a type of white blood cell) in the esophagus and triggered by specific foods. These rare immune-mediated diseases (affecting approximately 0.5%, 0.12%, and 0.0005% of the total population, respectively) typically present in infancy or early childhood, but are not driven by the action of IgE antibodies. "Unfortunately," Sampson explained, "there are no good tests for these diseases." ”
Sampson told me that part of the problem with food allergy diagnostics and other allergy diagnoses is that we still don't really understand the immune mechanisms behind many allergies. And, as allergy rates continue to rise, this means we don't have enough diagnostic tools to deal with the severity of the problem.
A skin prick test is a good example. It remains the most common, achievable, and inexpensive initial allergy diagnostic test. However, 8%~30% of people have a positive skin test result (or rash) without showing any allergic symptoms. Still, skin test results are an important indicator of allergies, as studies have shown that 30%~60% of patients who are allergic to a certain allergen will develop allergies. If there's only one thing you can remember, then it should be: blood and skin tests only show sensitivity to specific allergens, they never confirm allergies. It can be said that any skin or respiratory allergy should be diagnosed by an allergist based on the patient's medical history and the symptoms that the patient experiences when exposed to allergens in a natural environment.
The objective science of allergy diagnosis is fraught with subjectivity. Many allergists rely on their intuition to interpret skin test results and diagnose allergies through years of clinical experience. As Parikh says, in the 21st century, interpreting allergy test results is as much a science as it is an art.
This article is excerpted with permission from Chapter 2 of "The Truth About Allergies" (CITIC Publishing House, April 2024 edition), "How are allergies diagnosed (not how are they diagnosed)?", with abridgement, and the subtitle is added by the editor.
About the Author
Theresa MacPhail: Medical anthropologist, author, and associate professor in the School of Humanities, Arts and Social Sciences at Stevens Institute of Technology. She received her Ph.D. in Medical Anthropology from the University of California, Berkeley, USA, and is a Fellow of the American Anthropological Association, a 2018 NEH (National Endowment for the Humanities) Public Scholar, with research and writing focused on the areas of global health, biomedicine, and disease.
About the translator
Qikai Qin is a postdoctoral fellow at Massachusetts General Hospital and Harvard Medical School, and holds a Ph.D. from ShanghaiTech University (School of Life Science and Technology and iHuman Institute).
Special Reminder
1. Enter the "Boutique Column" at the bottom menu of the "Huipu" WeChat official account to view a series of popular science articles on different themes.
2. "Back to Park" provides the function of searching for articles by month. Follow the official account and reply to the four-digit year + month, such as "1903", to get the article index in March 2019, and so on.
Copyright Notice: Personal forwarding is welcome, and any form of media or institutions may not be reproduced and excerpted without authorization. For reprint authorization, please contact the background in the "Huipu" WeChat public account.