Introduction

Primary immunodeficiencies (PIDs) are a group of rare diseases which can severely affect individuals.¹ They are classified as conditions where the immune system isn’t functioning correctly. 

Individuals experiencing recurrent, persistent, and unusual infections may have a primary immunodeficiency. To confirm this diagnosis, they will be subject to many diagnostic tests. These include blood and genetic tests which can also be performed as prenatal tests when siblings have a primary immunodeficiency. Treatments focus on treating and preventing infections and using stem cells to have a better functioning immune system. 

Early diagnosis and treatment can reduce the risk of long-lasting effects from the infections an individual with PIDs may experience. This article aims to explore how PIDs are diagnosed as well as the treatments used to manage this group of conditions.

What are primary immunodeficiencies?

Primary immunodeficiencies (PIDs) are conditions where part of the immune system is either not working or is missing. There are over 450 different chronic conditions that are classed as PIDs. Individuals affected by PIDs have reduced or no natural defence and hence develop more infections than individuals without PIDs. They can take longer than average to recover with antibiotic treatments and tend to have a higher incidence of recurring infections. Individuals with PIDs can often experience severe infections requiring hospitalisation and unusual infections, which are infections caused by uncommon organisms. 

Diagnosis

Although PIDs are rare conditions, recurrent, persistent and severe infections may be an indicator of PIDs. If an individual is displaying these symptoms, there are several tests a General Practitioner (GP) can perform to aid in diagnosis. It is important to mention here that clinical symptoms of PIDs are highly variable, and it is also possible to have PIDs and not have an increased susceptibility to infections.²

Blood tests

When having PIDs blood tests, the levels of several factors are assessed: immunoglobulins (infection-fighting proteins), blood cells and immune system cells. This information determines whether there is an unusual level of these cells which can indicate something wrong with the immune system.

Additionally, blood tests can determine whether the immune system is responding correctly to foreign pathogens (organisms that cause disease). They assess whether the immune system is producing the proteins needed to destroy the pathogens. 

Genetic tests

Testing blood to look at the immune system defects is not the most conclusive test for PIDs. Throughout many years of developing DNA sequencing technologies, scientists have identified variants in over 350 genes that cause PIDs and are discovering more every year.³ Genetic testing allows suspected diagnoses to be confirmed as the genetic mutations can be detected. 

There are two main types of genetic tests used; these are called FISH and CMA. Fluorescence in situ hybridisation (FISH) is a test that uses fluorescence to locate the gene variant causing PIDs.⁴ They will do this using a blood sample and looking at it through a fluorescence microscope. Chromosomal microarray analysis (CMA) is a genetic test that can detect deletions and duplications of genes, these are types of mutations. In patients with primary immunodeficiencies, CMA has confirmed diagnoses of various chromosomal deletion syndromes (a mutation where certain genes have been deleted).⁵ These mutations are what cause the immune system to malfunction.

Prenatal tests

PIDs can severely affect individuals throughout their whole life. In cases where parents have a child with PID, they may consider prenatal tests when pregnant to assess whether the next child may have certain types of PIDs. This means they can be prepared and can start treatment soon after birth if needed. The types of tests that can be performed are DNA analysis, foetal blood analysis or enzyme analysis.

DNA from the foetus can be obtained either from a tiny sample of the developing placenta, a sample of the fluid surrounding the baby, or an isolation of foetal DNA from maternal blood. Once this DNA is obtained there are two techniques of DNA analysis:

• Mutation analysis
• Linkage analysis

Mutation analysis is usually performed if they know which mutation they are looking for. It is 100% reliable. Alternatively, linkage analysis can be used if the disease is well-characterised and the diagnosis is definite. 

In certain cases, there is a high likelihood that the cause of PID is of a genetic basis but the precise cause is not known. In these cases, DNA analysis would not provide much insight into whether or not the child will have the PID disorder. In these cases, it would be better to perform an analysis of foetal blood which is taken from the umbilical cord. In this test, the numbers and function of immune cells in the foetal blood are analysed. It is important to note that this test can only be performed if there is a recognisable pattern of abnormalities that have been previously seen in an affected child. This test is less reliable than genetic testing as results may be normal and the child could still develop it later in life. 

Additionally, enzyme analysis can be performed in certain specific immunodeficiencies where there is an enzyme that is known to be defective. This measures the concentration and/or function of this enzyme. 

Treatments 

The main treatment methods for PIDs are preventing and treating infections, treating the underlying cause of the condition and boosting the immune system. 

Treating infections

Individuals with PIDs tend to have more severe and persistent infections so require antibiotics typically for a longer course than is usually prescribed. In cases where infections aren’t responding to this treatment, it may require hospitalisation where intravenous (IV) antibiotics will be administered. Infections need to be managed at an appropriate time or they could cause long-lasting effects on the individual’s health.⁶

Avoidance of getting infections

One way to avoid becoming unwell is for individuals to take steps to prevent infections. Although it is not always possible to avoid infection there are methods to reduce the risk of infection. These include maintaining a high level of personal hygiene and washing hands frequently with soap. Additionally avoiding large crowds who may be carrying pathogens. 

Immunoglobulin therapy

Immunoglobulins are proteins made by white blood cells that help the body fight infection.⁷ When these are administered into the body they can help to fight pathogens. They can be injected into the body through an IV or can be inserted underneath the skin (subcutaneous infusion). The IV treatment is required every few weeks whilst subcutaneous infusion is needed once or twice a week. These treatments improve the body’s pathogen defences and significantly reduce the frequency and severity of infections.⁸

Stem cell transplantation

Stem cell transplantation can provide a permanent cure for many forms of life-threatening PIDs. This is where the individual with PIDs receives a transplantation of stem cells from an individual without PIDs. The stem cell donor must be an individual that has body tissue that is a close biological match to the recipient so it is usually a parent or sibling. Stem cells can be harvested through the donor’s bone marrow or a placenta at birth. 

This treatment, when successful, can result in a normally functioning immune system. However, stem cell transplantations don’t always work. Additionally, recipients often have to undergo chemotherapy or radiation to destroy functioning immune cells before transplantation. This can leave the individual more susceptible to infection as their immune system is compromised even further. 

Gene therapy

Gene therapy is only available for certain PIDs but clinical trials are undergoing to assess it as an option for treatment for many other types of PIDs. Gene therapy involves stem cells but doesn’t require finding a biologically matching donor. Stem cells are removed from the individual with PIDs and the gene that is missing or malfunctioning, causing the PID, is corrected.⁹ Then, the stem cells are reintroduced into the individual’s bloodstream via an IV infusion. This can correct the non-functioning parts of the immune system.

Summary

PIDs are conditions which can cause individuals to experience persistent, recurrent infections and severely affect their daily lives. It is key to get diagnosed early to receive the rapid treatment that is needed. Methods of diagnosis include blood tests and genetic tests. There is also the option to have prenatal tests to prepare for a child’s potential future treatment. Treatments focus on preventing and treating infections and boosting the immune system's function. Stem cell transplantations can provide a cure for PIDs but require a biological matching donor and aren’t always successful. Gene therapy is currently only used to treat certain types of PIDs but clinical trials are assessing whether this could be a treatment option for many more types of PIDs.