Primary Immunodeficiency And Allergy

Introduction

Our immune system is one of the complex systems that keeps us safe from infections and other harmful diseases like cancer.¹ Have you ever wondered about immunological diseases and their consequences? In this article, we will focus on primary immunodeficiency and how it can affect our system, particularly allergies. So, let us delve into this topic. 

Primary immunodeficiency can also be called primary immunodeficiency disease/PID and they are a rare set of diseases that cause the patient to be vulnerable to microorganisms like bacteria, fungi, viruses and others, which if left untreated can have long-lasting health effects or even be fatal.¹ PIDs can also increase the risk of cancer and immune diseases including autoimmunity, inflammation and allergy.¹ 

Another aspect of this article will focus on allergies. So, what are allergies? They are among the most common diseases found in the world and affect many people worldwide.² Allergies occur when the immune system reacts to a foreign object, known as an allergen, and this causes the body to undergo an allergic reaction by releasing histamine and other mediators.² 

There is a link between PID and allergy that we will discuss in this article; one of the most common primary immune deficiencies is selective IgA deficiency, which can be either symptomatic or asymptomatic and causes the patient to have manifestations like allergy, autoimmunity and infections.³ 

Basics of primary immunodeficiency

Overview 

As mentioned previously, PID can affect our immune system and cause different manifestations; they are considered a group of rare hereditary heterogeneous diseases that arise from mutations in the genes responsible for the functionality of immune cells.⁴ Patients with PID are often underdiagnosed and underreported which makes detection and treatment harder.⁵

There are different types of deficiencies such as:^{1, 3, 5, 6, 7, 8, 9, 10}

• Antibody deficiency: this deficiency makes up the largest portion of PID with selective IgA deficiency being the most common type; which is defined as low serum IgA levels (≤ 7 mg/dL) but with normal IgG and IgM levels. This is seen in patients that are older than 4 years of age and have a normal immune system otherwise. This form of deficiency can be partial and is generally benign. However, patients with selective IgA deficiency are more prone to recurrent infections and developing allergies due to the passage of aeroallergens and food antigens (this is due to the loss of mucosal IgA).
• T-cell deficiency: this form of deficiency is linked to the low number of T-cells, which in a severe case can be life-threatening; T-cells provide us with immunity against multiple viral pathogens. 
• Combined immunodeficiency (SCID): this is usually a combination of a low T-cell number and a very low or absent B-cell number/function. This form can be severe and would require early detection for better treatment outcomes.  

Symptoms and representation

There are multiple clinical manifestations of PID and can vary based on the origin. However, some include:¹¹

• Recurrent infections: ear, sinus, and skin infections. Pneumonia, bronchitis, thrush and meningitis can also occur.
• Lack of growth in infants/failure to thrive
• Lack of weight gain.
• Digestive issues e.g. chronic diarrhoea.

Assessment of PID

Diagnosis and detection of PID can be done through multiple approaches:^{5, 12}

• Lab tests: this includes blood and genetic tests.
• Family history. 
• Evaluation by immunologists. 

Basics of allergy

Allergies or “atopy” are among the most common diseases worldwide.^{2, 13} It occurs when our body has an adverse reaction to an allergen or specific antigen.¹⁴ Allergies have multiple types, and they include:^{13, 14, 15, 16}

• Environmental:  this type of allergy affects around 20% of the population worldwide. Also, its prevalence has increased significantly in recent years due to genetic changes alone. Global trends of increasing urbanisation and fast population growth affect our lifestyle (e.g. diet, time indoors, physical activity) and environmental exposures to hazards such as air pollution, smoking, and mould that affect our allergic response and increase this disease prevalence globally.
• Food: food allergy occurs when a person ingests a specific food antigen, that in the normal setting is harmless to healthy individuals but causes an immunological response in people with allergies. Food allergy differs from food intolerance or toxins/pathogens found in certain foods. Intolerances are non-immune, driven by toxic, pharmacological, metabolic, and sometimes uncharacterised mechanisms. For example, milk intolerance is due to the lack of lactase enzyme and is not an allergy. Food allergies are defined as IgE and non-IgE-mediated allergies or a mix of the two. Some food allergies include peanuts, walnuts, eggs, wheat, shellfish, and celiac disease.
• Drugs: adverse drug reactions, known as ADRs, are reported in some individuals when taking certain medications. It is more reported in females (assigned at birth) than males (assigned at birth) due to females having higher levels of IgE (in adulthood). These reactions can be side effects or immunologically mediated drug allergies driven by adaptive or innate systems. However, most self-reported drug allergies are not true allergies; this is not due to an immune response but rather a side effect of the drug. Nonetheless, drug allergies do occur such as penicillin allergy. 

Types of allergic mechanisms

To further elaborate on allergic reactions, we will tackle their mechanisms; IgE mediated, non-IgE mediated and the mixed IgE and Non-IgE:^{16, 17, 18}

• IgE mediated: these reactions are usually quick with symptoms developing within minutes/hours of ingestion. In the example of food allergy, all patients with IgE-mediated allergies are sensitised to food allergens, which means that detectable levels of food-specific IgE can be a precursor to the development of food allergy; food antigens are mistaken for pathogens which cause danger and inflammation signals to be released in the area, this then activates naïve T cells into T helper cell 2 (Th2) phenotype, that then leads to more inflammation and consequently activation of B-cells and the release of specific IgE resulting in an allergic reaction. Several reactions can occur such as hives, redness and vomiting. More severe cases can lead to fatal anaphylaxis.
• Non-IgE mediated: these reactions are typically chronic and can be more complex to control with solely food avoidance. They arise from other components of the immune system other than the IgE, and their mechanism is less understood than the IgE-mediated one. Their symptoms are more localised in the intestines. However, they can also affect the skin and lungs. Examples of this include food protein-induced enterocolitis syndrome (FPIES). The reactions in non-IgE mediated allergy are related to the gastrointestinal tract: bloating, vomiting and diarrhoea.
• Mixed IgE and Non-IgE: these reactions include different types of disorders such as eosinophilic gastrointestinal disorders (e.g. eosinophilic esophagitis), and skin conditions like atopic dermatitis.

Signs and symptoms

There are several symptoms for allergies, varying based on type. Some of the symptoms include:¹⁹

• Runny nose/sneezing
• Pain or tenderness around the eyes, forehead, or cheeks
• Itchiness and hives
• Diarrhoea 
• Coughing or wheezing or breathlessness
• Swollen lips, mouth, throat, or eyes
• Feeling ill

Primary immunodeficiency and allergy

As mentioned before, PID can predispose patients to allergies and other diseases; by the disruption and dysregulation of the immune response and lack of clearance of allergens.¹⁴ Additionally, allergies and other disorders can mask the presence of PID; this is due to the similarity in clinical symptoms (e.g. recurrent infections) and delayed diagnosis of PID due to focusing on the treatment of other disorders such as management of allergies.¹ Hence, it is important to have the appropriate diagnosis and tests done to differentiate the two. 

Detection and differentiation

PID is usually diagnosed via lab tests (blood counts and immunological tests) and confirmation from immunologists. As for allergies, they are done through skin prick or patch tests, blood tests and diet changes to detect any changes in symptoms.¹⁹ Lab tests are done to confirm IgE-mediated allergies.¹² However, non-IgE mediated allergies are a bit harder to detect and are usually done by observing the improvement of symptoms upon the removal of the suspected food from the diet, and the return of symptoms once the food is reintroduced.¹⁸ This usually takes weeks or months to get done.

Therapeutic options

There are multiple options of treatment for both PID and allergy:^{11, 19}

• For PID:
  • Immunoglobulin replacement therapy or interferon-gamma therapy to improve the immune system efficiency.
  • Gene therapy to replace malfunctioning genes.
  • Growth factors to increase immune system cells (white blood cells).
  • Stem cell transplant to provide the body with functional immune cells.
  • Antibiotics in cases of infection. 

• For allergies: 
  • Medications like antihistamines, steroid tablets/creams.
  • EpiPens in severe allergic reactions. 
  • Desensitisation/immunotherapy is done via a medical profession and in a controlled setting; this is done by exposing the patient to the allergen over time, to help the body adapt to it and decrease the severe reactions. 

It is also worth keeping in mind that there are several steps we can take to avoid infections and the risk of symptoms appearing such as:¹¹ 

• Washing hands regularly.
• Avoid crowds and people who are ill.
• Having good oral hygiene.
• Maintaining healthy habits e.g. exercise, healthy diet, good sleep.

Summary

PIDs and allergies can both affect our lives in multiple ways. While allergies are very common, PIDs are rare. However, they can be under-reported and masked by allergies and other diseases. Hence, it is important to diagnose and approach these disorders appropriately to provide a better quality of life for our loved ones. Having the right diagnosis will allow us to treat it correctly and avoid adverse reactions such as anaphylaxis and even death!