Allergy: an overreaction of the body or overdiagnosis as a disease?

Allergy: An itch that goes around the world

All over the world, allergies are counted as one of the most common chronic diseases that impact millions of people every day. What makes them so common is the fact that they are an umbrella term for a plethora of diseases with different subtypes and affecting different organs: allergic rhinitis or inhalant allergy (eyes, nose, and airways), allergic asthma (lungs and airways), food allergy (mouth, skin, and systematic symptoms), eosinophilic esophagitis (respiratory and digestive tract), anaphylaxis (systematic symptoms), atopic dermatitis (skin), insect allergy (skin and systematic symptoms), and drug allergy (systematic symptoms). Due to the overwhelming data for all those allergy-related diseases, we will focus on allergic rhinitis or inhalant allergy, food allergy, and drug allergy in this blog.

Allergic rhinitis

According to the American Academy of Allergy, Asthma & Immunology, allergic rhinitis affects 10% to 30% of the population worldwide. 1 In a recent cross-sectional and multicentred study, the prevalence of allergic rhinitis was 8% (children), 24% (adolescents), and 10% (adults) in India. ²

Savouré et al. (2022) shared detailed information about the prevalence of allergic rhinitis all over the world.

(Fig. 1). ³

Food allergy

A European multicentre study from eight Western countries concluded that 1%-4% of school children suffer from food allergies. ⁴ The prevalence rate of food-specific IgE sensitisation for at least one food allergen was 19.1% in Indian children, although true food allergy was only proven in 0.14% of them. ⁵

Furthermore, Warren et al. summarised the prevalence of food allergies around the globe (Tab. 1). ⁶

Continent	Prevalence of food allergies	Age groups
North America	3.5–7.6% (Canada, Mexico, and USA)	0-17 years
Europe	1.7–9.3% (Austria, Belgium, Croatia, Denmark, Finland, France, Germany, Greece, Greenland, Iceland, Italy, Malta, Netherlands, Norway, Poland, Portugal, Slovenia, Sweden, Switzerland, and the UK)	0-20 years
Central and South America	0.6–5.5% (Brazil, Chile, and El Salvador)	4 months–15 years
Middle East	0.8–8 % (Israel, Kuwait, Lebanon, Turkey, and the UAE)	0-30 years
Africa	2–5% (Ghana and South Africa)	1–16 years
Asia, and Oceania	1.1–7.7% (Australia, China, Hong Kong, Japan, Singapore, South Korea, Taiwan, Thailand)	0-18 years

Drug allergy

The World Allergy Organization (WAO) defines drug allergy as ‘an immunologically mediated drug hypersensitivity reaction, which can be either IgE or non-IgE mediated’.

It is generally very uncommon, representing less than 10% of all adverse drug reactions. However, approximately 3%-6% of all hospital admissions are related to adverse drug reactions, and 10%-15% of people admitted to the hospital suffer from them. ⁷

A recent Polish study gave insight into common culprit drugs for adverse reactions: NSAIDs (67.5%), followed by antibiotics (54.3%), local anaesthetics (7.4%), general anaesthetics (2%), and other drugs such as antihypertensive drugs (4.6%), dietary supplements (3.2%), antihistamines (2.8%), and contrast agents (2.4%). ⁸

For decades, doctors and healthcare workers have noticed an increase in the prevalence of allergies. Numerous scientists have tried to investigate the reasons for this persistent rise and come up with different explanations. The “hygiene hypothesis” is generally accepted and states that exposure to germs and infections during childhood helps to “educate” the immune system. Therefore, a very clean and sterile environment would be counterproductive, as there are no stimuli for the immune system. This is directly linked with the idea of the “biodiversity hypothesis”, which highlights the importance of a diverse microbiome as it seems to promote immune balance and protect from allergy and inflammatory disorders. ^9,10

Furthermore, lifestyle changes, such as the increase of pollution in the environment (“pollution hypothesis”), were considered a reasonable explanation. Studies found a direct correlation between diesel exhaust and increased airway inflammation, allergies, and asthma exacerbations. ^11,12

Along with that, psychosocial factors, such as increased stress and fast-paced lifestyles, were also found to be accountable for an increased allergy prevalence. For all those reasons, allergies have been called the “epidemic of the 21st century”. ¹³

What you should know about Allergy: Symptoms, Diagnosis, and Treatment

Allergy is often referred to as an overreaction of the immune system since it attacks normally harmless substances. The mechanism behind allergies is well-understood, and scientists agree that IgE antibodies are the culprits that cause allergic reaction. ¹⁴

The symptoms can be diverse, according to the allergy-related disease: For allergic rhinitis, common symptoms are a running or blocked nose, sneezing, wheezing, and itchy and swollen eyes. For food allergies, itchiness in the mouth, rashes, diarrhea, vomiting, dizziness, and headaches are typical symptoms. However, some allergies, such as food and drug allergies, also lead to life-threatening anaphylaxis, where the body’s circulatory system and breathing drop abruptly due to the systemic allergic reaction. ^14,15

There are different types of allergies according to the offensive allergen: plant and tree pollen, house dust mites, mold spores, and pet hair (dog, cat, etc.) are the most common inhalant allergens ¹⁶, whereas milk, eggs, fruits (peaches and apples), nuts, wheat, soy, sesame, and seafood (shrimps and fish) tend to be the most prevalent food allergens ¹⁷. The onset of these allergies depends on the exposure; a European study found that shrimp allergies were one of the most common food allergies in Spain and Iceland, which are countries with the highest seafood consumption. ¹⁷ Another influencing factor is age. Children usually suffer from milk allergies from an early age, but they can develop tolerance, which is why fewer individuals have a milk allergy in adulthood. ¹⁸

The most common method to diagnose allergies is skin prick testing, where allergen extracts are applied subcutaneously or intradermally, and the reaction is read after a short time. Redness and wheal formation are positive signs for the test. Additionally, in-vitro tests are available where only the patient’s blood is needed. The levels of allergen-specific IgE antibodies are quantified with different methods, and higher levels of allergen-specific IgE confirm allergy. ¹⁹

However, for food allergies, the double-blind, placebo-controlled, food challenge is the gold standard, where the assumed culprit food is given to the patient in a safe setting and the reaction is monitored. Newer and safer methods, such as basophil or mast cell activation tests, can also be used to detect allergies. Basophils and mast cells are effector cells during an allergic reaction and cause the progression of symptoms: therefore, they can be tested in-vitro for IgE sensitisation against a suspected allergen. ²⁰

For drug allergies, patient history, a (double-blind placebo-controlled) drug challenge, and in-vitro testing for IgE, or basophil activation, test are the usual methods of diagnosis. ²¹

While allergies have several ways to be diagnosed, management is often not easy.

Allergic asthma and rhinitis can be managed effectively with medication such as nasal or oral corticosteroids, leukotriene receptor antagonists, antihistamines, mast cell stabilisers, and short‐term nasal decongestants. ¹⁵ Allergies that can lead to anaphylaxis are managed with strict avoidance and fast injections of epinephrine in cases of emergency. ²²

The first oral immunotherapy drug for peanut allergy, Palforzia, was approved by the US Food and Drug Administration and European Medicines Agency in 2020. ²³

However, for other food allergies, the recommended management is avoidance. In severe cases of milk allergy, avoidance and the use of specialised milk formulas are recommended to counteract possible malnutrition and severe reactions in infants. ²⁴

Another approach for allergy management is desensitisation. The patient is exposed to small amounts of the allergen with the hope that the immune system will gradually stop perceiving the allergen as dangerous and start developing tolerance. ²⁵

Achieving tolerance is also the aim of guidelines, which recommend an early introduction of allergenic foods in children at the age of 4 or 6 months. ^26,27

Trends in allergy: Self- and Overdiagnosis - A 21st century disease

Self-diagnosis is on the rise

Increasingly, more and more people complain about adverse reactions after eating and diagnose themselves with food allergies. As a result, they exclude important foods from their diet or replace them with costly substitutes. A Hungarian study with 501 suspected allergic patients reported that only 5 were diagnosed with a true IgE-mediated food allergy, and roughly half of them had an intolerance. Therefore, the authors concluded that true food allergies were overestimated and suggested that more education would be helpful for those patients. ²⁸

The prime example is milk allergy: A recent US study showed that nearly 1 in 20 Americans (4.7%) reported having a milk allergy, but only less than half of them (1.9%) had convincing symptoms, and a mere 0.9% had an actual diagnosis from a doctor. This indicates that many people are not aware of their health status and exclude nutritious foods from their diets. Studies have shown that the avoidance of cow milk can lead to reduced height, weight, and BMI in children allergic to cow milk. ²⁹

Similar results were also found with wheat allergies and gluten intolerance. Many people think that avoiding gluten would be beneficial for their health, as gluten could be harmful to them, so they follow a strict gluten-free diet. The reality is, however, very far from that. Doctors only recommend a strict gluten-free diet for celiac disease and wheat-allergic patients. ³⁰

Overdiagnosis for profit

The steep rise of milk allergies and prescriptions of specialised milk formula for children have steered controversy in the milk allergy research community in recent times. Scientists are accusing the current milk allergy guidelines of promoting overdiagnosis by stating common symptoms as indicators of allergy and blaming milk formula companies for influencing the guidelines by offering sponsorships. ^31-35

A UK study found that there were approximately 70 different local guidelines for milk allergies in children. The authors concluded that this may lead to confusion, and overdiagnosis and ultimately drive mothers to stop breastfeeding their children. As a result, more specialised infant formulas were prescribed, and the milk formula companies accumulated more money. ³³ Unsurprisingly, in the multibillion-dollar infant formula market, allergies continue to become a growing segment.

Thankfully, this trend is being recognised by scientists and doctors, and there are ongoing counter-initiatives to keep the diagnosis of milk allergy based on the interests of infants and patients without allowing milk formula companies to influence the diagnosis. ^31,33

Overdiagnosis for safety

Allergy against drugs is a serious health problem often associated with life-threatening situations and anaphylaxis. The diagnosis also has an unpleasant side effect: further treatments are difficult because of the use of replacement products instead of standard medication, which might be more expensive and less effective. ^36,37

Studies have shown that one of the most reported drug allergies is against antibiotics, and a higher prevalence is seen after frequent use or overuse. ³⁸ The incidence of penicillin allergy in the US is around 8%. However, in a large study of 500 patients, only 4 patients had a positive reaction after a drug challenge test, giving rise to the question of overdiagnosis. ^39,40

It is therefore concluded that patients who had an adverse drug reaction are wrongly labelled as ‘allergic’ to ensure safety and avoid a more severe reaction. Although this overdiagnosis in terms of safety might sound agreeable at first, management and the personal costs of the ‘allergic label’ have problematic consequences. Therefore, there is a new shift in this direction to improve the quality of life of these patients by ‘de-labelling’ them and proving they are not truly allergic. ^36,38

Adverse drug reactions and COVID-19 vaccines

The recent coronavirus pandemic and vaccines are critical topics that were discussed in association with drug allergies and the danger for allergic patients.

In Gallup’s March and April 2021 COVID-19 surveys from the US, 10% of participants stated that they would not get vaccinated because of ‘allergies or concern about allergies’ while another reason was to ‘wait until the vaccine is safe’. ³⁹Similar reactions were found in the Indian population. ⁴⁰

Although regular vaccines were studied for a longer time, the COVID-19 vaccines were shown to be safe for the general population. Serious allergic reactions are rarely documented but are slightly higher compared to traditional vaccines, which have rather mild local reactions. ⁴¹ However, no deaths due to anaphylaxis to COVID-19 vaccines has been confirmed in the scientific literature so far. The safety evaluation for allergic people is strictly defined by five steps: 1) if there was an anaphylaxis reaction to an injectable drug or vaccine containing PEG or derivatives before; 2) anaphylaxis to oral or topical PEG containing products; 3) recurrent anaphylaxis of unknown cause; 4) suspected or confirmed allergy to any mRNA vaccine; and 5) confirmed allergy to PEG or derivatives. ⁴²

The key to this problem is to educate and solve the concerns of the patients by explaining the mechanism, risks, and benefits of the vaccination. ⁴³

Conclusion

Although there are many ways to determine allergies, correct and accurate diagnosis and management can be challenging. Lately, a rise in self-diagnosis and overdiagnosis of allergies has been noticed, giving rise to serious concerns. In many cases, an appointment with a trustworthy doctor and a gold-standard method of diagnosis can help to confirm suspected allergies or lift the burden of unnecessary diet restrictions and drug avoidance. Self-diagnosis is not the way to handle health-related issues, and suspicions should always be confirmed by a certified doctor.

In case of doubts regarding the doctor or the guidelines, a second opinion from another doctor can help clarify the health status. As with the milk formula controversy, a new set of guidelines is on the way to correct the imbalance of the influence of milk formula companies. There is also a trend to “de-label” incorrectly diagnosed drug-allergic patients. With regard to the COVID-19 vaccine, guidelines for allergic patients are safe, but more educational work would be helpful to solve doubts in the population.

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