Introduction

The immune system and its function are crucial to every human because it helps us fight against harmful agents and diseases that can develop within the body, such as cancer.¹ The body has two types of immune systems: the innate system and the adaptive system. The innate system consists of natural killer cells and phagocytes, which engulf foreign substances entering the body.¹ In the adaptive system, antibodies are produced to fight against pathogens that the body has encountered previously.¹ 

Thus, the immune system is essential for preventing any diseases from progressing to a fatal stage. However, when the immune system is not functioning properly, it can lead to a condition called immunodeficiency. During immunodeficiency, some of the elements (such as lymphocytes and phagocytes) may be either absent or not working correctly.² There are two types of immunodeficiencies: primary and secondary. 

In this article, we aim to examine primary immunodeficiency (PID) and its relationship with infections. People with PID have an immune system which does not work as it should, hence making them more susceptible to diseases and infections. It is thus important to understand PID and the need to prevent infections, as it is crucial in enhancing life expectancy.  

Understanding primary immunodeficiency

How does the immune system function?

As mentioned earlier, the primary function of the immune system is to defend our body against foreign substances entering the body that can cause harmful diseases and infections. The immune system consists of various components which act together to fight against these diseases and infections. 

Immune cells, also known as white blood cells or lymphocytes, are produced in the bone marrow.³ The innate immune system includes neutrophils and macrophages, which initiate the immune response by producing enzymes that can kill pathogens.⁴ During phagocytosis, these cells engulf and digest damaged or foreign substances.⁴ Lymphocytes, which are a part of the adaptive immune system, will then help destroy any other remaining foreign matter.⁴

The innate immune system’s initial defence mechanisms include the skin and the mucosal membranes, which hinder foreign substances from entering the body.⁵ If these barriers are breached and the innate immune system cannot effectively fight the disease or infection, then the adaptive immune system is activated. The adaptive immune system consists of T- cells, B- cells and antibodies.⁵ This system identifies and responds to specific pathogens more slowly, but creates a memory of them, allowing for a more efficient response if the same pathogen is encountered in the future.⁵

In the context of PID, both innate and adaptive immune systems can be affected. Disorders may involve defects in innate components like phagocytes or adaptive components such as T-cells and B-cells, leading to increased susceptibility to infections and other health issues.

Types of primary immunodeficiencies

Antibody deficiencies

Antibody deficiencies often develop from birth and lead to recurrent infections. These deficiencies occur when antibodies (immunoglobulins), which are produced by plasma cells, are absent. The causes of antibody deficiencies include inadequate B-cell maturation, missing enzymes, and failure in T-cell signalling.⁶ This can result in conditions such as common variable immunodeficiency (CVID) or specific antibody deficiency (SPAD). People with these conditions are more susceptible to infections and may require ongoing medical management to prevent and treat infections.⁶

T-cell deficiencies

T-cell deficiencies are inherited conditions characterised by either a complete absence of T-cells, a reduced number of T-cells, or T-cells that do not function properly.⁷ These deficiencies impair the immune system’s ability to respond to infections and other immune challenges.⁷ Examples include Wiskott-Aldrich syndrome, which involves a combination of T-cell dysfunction, eczema, and bleeding problems, and DiGeorge syndrome, which involves a reduced number of T-cells and can affect other parts of the immune system. These conditions often lead to severe infections and require early diagnosis and treatment.⁷ 

Severe combined immunodeficiencies

Severe Combined Immunodeficiencies (SCID) are characterised by deficiencies in both T-cells and B-cells, leading to recurrent infections caused by a wide range of organisms.⁸ For example, patients with SCID may experience frequent infections from bacteria, viruses, and fungi that a healthy immune system would typically manage. 

Phagocytic disorders

Phagocytes are a type of white blood cell that circulate throughout the body and engulf pathogens, such as bacteria and viruses, to help protect against infections. For example, neutrophils and macrophages are key types of phagocytes that play a crucial role in this process.⁹ In some conditions, such as chronic granulomatous disease (CGD), the ability of phagocytes to effectively engulf and destroy pathogens is diminished, leading to increased susceptibility to certain infections.⁹

Complement deficiencies

Complement deficiencies are disorders characterised by defects in the complement system, a group of proteins found in the blood that help the immune system eliminate infections.⁹ In complement deficiencies, such as those caused by deficiencies in complement components like C3 or C5, the immune system's ability to effectively respond to infections is impaired.⁹ This can lead to increased susceptibility to infections and autoimmune diseases.⁹

Impact of primary immunodeficiency on infections

PID significantly increases a person's susceptibility to infections because the immune system is not functioning properly. This means that the body has a harder time fighting off pathogens and may be more prone to various types of infections.

Types of infections associated with PID

Bacterial infections

People with PID often experience frequent and severe bacterial infections. Common examples include pneumonia, ear infections, and skin infections. For instance, someone with PID might get recurrent sinus infections that are difficult to treat with standard antibiotics.

Viral infections

Viral infections can also be more common and severe in those with PID. This includes infections like the common cold, influenza, or even more serious viruses like herpes simplex. Due to their weakened immune response, these infections might last longer or cause more complications.

Fungal infections

Fungal infections, such as candidiasis (thrush) or aspergillosis, can be a significant concern. These infections occur when fungi that are usually harmless grow out of control because the immune system isn’t able to keep them in check.

Opportunistic infections

These are infections caused by organisms that typically don’t cause disease in healthy people but can become problematic in those with PID. Examples include certain types of bacteria or fungi that normally wouldn’t cause issues but can lead to serious illness in someone with a compromised immune system.

Overall, PID can lead to a wide range of infections that are more frequent, severe, and harder to treat than in individuals with a healthy immune system. Managing PID often involves regular medical care to prevent and treat these infections effectively.

Diagnosis of primary immunodeficiency

Newborn screening

Newborn screening is performed shortly after birth to identify life-threatening conditions, including primary immunodeficiencies. Key components include:¹⁰

• Blood Test/Heel Stick: A small sample of blood is taken from the baby’s heel to screen for SCID and other conditions
• Hearing Screening: Checks for hearing issues, which are not directly related to primary immunodeficiency but are important for overall health of a newborn
• Pulse Oximetry Test: Measures oxygen levels in the blood to detect potential heart problems in a baby

Genetic testing 

Genetic testing identifies specific gene variants responsible for PID. By analysing the patient’s DNA, this testing can pinpoint mutations or abnormalities in genes that affect immune function, aiding in the diagnosis and understanding of PID.¹¹

Laboratory testing 

Laboratory testing is used to find out if a person has PID. Each primary immunodeficiency has a different kind of laboratory test to aid in its diagnosis. 

Antibody deficiencies 

The testing for antibody deficiency include:¹²

• Measurement of Immunoglobulin Levels: This test measures the levels of immunoglobulins (IgG, IgA, IgM, and IgE) in the blood to assess overall antibody levels.
• Specific Antibody Production Test: This checks the production of antibodies in response to vaccines. It measures whether the body is generating the expected immune response to vaccination or not.

T-cell deficiencies

To diagnose T-cell deficiencies, tests focus on measuring both the number and function of T-cells. Key tests include: ¹²

• Complete Blood Count (CBC): This test provides an overview of the different types of blood cells, including T-cells, to assess their quantity.
• Lymphocyte Count: Specifically measures the number of lymphocytes, including T-cells, in the blood to identify any deficiencies.

Severe combined immunodeficiencies

SCID is typically diagnosed around 6 months of age, often due to recurrent infections despite vaccinations. TREC (T-cell Receptor Excision Circles) testing is used to diagnose SCID by measuring the number of TREC in the blood. Low levels of TREC indicate impaired T-cell production, helping to confirm a diagnosis of SCID.¹³

Phagocytic deficiencies

In diagnosing phagocytic disorders, two key tests are used to measure the activity of phagocytes:¹⁴

• Dihydrorhodamine (DHR) Test: This test measures the production of hydrogen peroxide by phagocytes. Phagocytes use hydrogen peroxide to kill pathogens, so reduced levels can indicate a problem with phagocyte function.
• Nitroblue Tetrazolium (NBT) Test: This test assesses the ability of phagocytes to produce reactive oxygen species (ROS). In this test, phagocytes are exposed to a chemical that changes colour if they are functioning properly.

Complement deficiencies

To diagnose complement deficiencies, screening tests evaluate the function and levels of complement proteins in the blood. If there is a suspicion of related complications, such as meningitis, a CT scan may be performed to assess for any associated issues or damage.¹⁵

Treatment and management of primary immunodeficiency and infections

Antimicrobial therapies

Antimicrobial therapy plays a crucial role in managing PID. It includes antimicrobial prophylaxis, which is used to prevent infections in individuals with weakened immune systems, and antimicrobial therapy, which treats active infections. For example, when an infant is diagnosed with severe combined immunodeficiency (SCID), antimicrobial prophylaxis is employed to prevent infections due to their compromised immune system.¹⁶

This preventive approach is essential for minimising the risk of infections, while antimicrobial therapy is used to manage infections that do occur, helping to reduce their severity and duration. Together, these treatments are vital for controlling infections and improving the quality of life for patients with PID.¹⁶

Immunoglobulin replacement therapy

Immunoglobulin replacement therapy is used to treat patients with low immunoglobulin levels. The immunoglobulin is extracted from human plasma and can be given either intravenously (through a vein) or subcutaneously (under the skin). This treatment provides temporary support to the immune system and only works for up to 4 weeks, which means that repeated treatments are essential to treat antibody deficiency and maintain adequate levels.¹⁷ 

Stem cell transplantation 

For stem cell transplants, finding a donor whose cells closely match the patient's is usually important. The best donors are often close relatives like siblings, but sometimes unrelated people who are a good match can donate too. Umbilical cord blood from newborns is another option. In some cases, even a partially matched relative can be used if a perfect match isn't available.¹⁶

Gene therapy 

In gene therapy, stem cells from the patient’s own body are collected. These cells are then genetically modified to correct the defect causing the PID and reintroduced into the patient. Since this approach utilises the patient's own cells, perfectly matched donor genes are not required.¹⁶

Prevention strategies

The best strategy for managing PID and preventing it from becoming life-threatening is to practise some preventive actions and these are:

• Washing hands regularly
• Maintaining good dental health
• Being vaccinated
• Practising a healthy lifestyle by being active and eating healthy
• Staying away from crowds and other sick people

Summary

PID is a group of conditions that can be life-threatening if not treated promptly. These conditions occur when the immune system's T-cells, B-cells, antibodies, phagocytes, immunoglobulins, or complements are deficient. There are tests available to diagnose these conditions. While some treatments exist, certain therapies require donors or additional research before they can be used immediately. To avoid complications from untreated conditions, it is important to follow prevention strategies to prevent infections that can be fatal. More research is needed to develop faster and more effective treatments for PID.