Diagnosing a primary immune deficiency (PI) can be complicated and lengthy. Almost everyone with a PI will concur that the time span between the initial symptoms and a firm diagnosis is very long, often taking years.
According to the Centers for Disease Control and Prevention (CDC), there are more than 400 types of PI.1 And, because treatment depends on the type of PI, it’s crucial for patients to receive a thorough workup from an immunologist who specializes in immune deficiencies to arrive at the correct diagnosis.
Challenges of Diagnosing PI
Getting sick is a normal part of life, but individuals with PI are often sick more frequently than what is considered to be “normal.” In fact, the hallmark of PI is recurrent infections. Therefore, it often takes quite some time for patients and/or physicians to realize the recurrent infections are a sign of PI.
Also, since PIs are rare, they are not the first thing on primary care providers’ (PCPs) minds when patients come in with an infection. And depending on the type of infection(s) with which patients present, PCPs may refer patients to a specialist for treatment. For example, it is common for infections to occur in the sinus cavities, so PCPs may refer patients to an ear, nose and throat (ENT) expert. In the short term, the ENT may focus on treating the infection for which the patients were referred, as opposed to considering there may be an underlying PI. However, when a clear pattern of symptoms emerges, PCPs or specialists can refer patients to an immunologist for further testing.
Path to Diagnosis
Diagnosing a PI involves carefully reviewing the medical history, performing a physical examination and conducting many different laboratory tests that measure the various components and functions of the immune system. Specifically, doctors must:2
- Completely review the patient and family history. The frequency, type and severity of infections should be reviewed, as well as whether there is a history of multiple courses of antibiotics needed to treat the infections. It should also be determined if there is a family history of PI.
- Conduct a physical exam. Patients with a PI may have an enlarged spleen, swollen lymph nodes, weight loss or poor growth.
- Order and interpret laboratory tests. A variety of tests should be conducted in stages, depending on preliminary findings.
Diagnostic Tests
Tests to diagnose a PI include, but are not limited to:
1) Blood tests. A variety of blood tests are conducted to identify specific immune system abnormalities.
A complete blood count (CBC) with differential shows the kind and quantity of white blood cells present in a patient’s blood (including neutrophils, lymphocytes, monocytes, eosinophils and basophils, all of which are key for protecting against and fighting infections). CBC results are compared with the reference range of values normally found in healthy people and, thus, reveal defects in the blood that could be caused by a PI.2
Lymphocyte surface marker tests count how many lymphocytes (T and B cells) are present, as well as how well they work.2
Additional blood cell tests are used to diagnose specific types of PIs, including granulocyte function tests (X-linked chronic granulomatous disease); B cell maturation tests in bone marrow (agammaglobulinemeas); cell protein expression (hyper-immunoglobulin M disorders and leukocyte adhesion deficiency); and switched memory B cells (common variable immunodeficiency disorder, hyper-IgE syndrome and CD40/CD40L deficiencies).2
2) Measurement of immune globulin levels. Immunoglobulins (or antibodies) are proteins that recognize infecting microorganisms and help immune cells destroy them. Most PIs cause the body to produce too few immunoglobulins (or none at all). Quantitative immuno- globulin level tests look at IgG, IgM, IgA and IgE to assess for a deficiency, or an excess, which is an important piece of the diagnostic picture.2
3) Antibody response to live vaccines. These tests are important because vaccines typically trigger the production of antibodies against the microorganism contained in the vaccine and prepare the body to fight off future infections. Some PIs cause this kind of immunity to fail.2
The most common live vaccine tests are the pneumococcal pneumonia, diphtheria and tetanus vaccines. During the tests, the patient’s blood is tested for antibody response in two phases. For example, in the instance of pneumococcal pneumonia, the blood is first tested for antibody response to pneumococcal serotypes. Next, the vaccine is administered. Then, approximately four weeks after the pneumococcal vaccine is administered, blood will be redrawn to evaluate antibody production.3 Antibody response to live vaccines can be conducted with a pure polysaccharide or a protein conjugated vaccine and depends on other testing and what the physician would like to assess. A robust response to a vaccine indicates protection against the different types of streptococcus pneumoniae and function on that part of the immune system.2
4) Complement protein tests. Complement proteins are serum proteins that kill microorganisms and assist other immune cells. Complement deficiencies (a group of PIs) are caused by defects in this system. The CH50 assay and AH50 assay are two common tests that detect complement deficiencies.2
5) Genetic testing. Genetic tests find mutations on genes that cause the PI. Gene testing is used to confirm diagnosis whenever possible. Newborn screenings for some conditions can also be performed. Genetic tests can help inform decisions about PI treatment, predict how PI will progress and help counsel patients who wish to have children about the inheritability of PI.2
Different PI Characteristic Effects on Immunoglobulins
| Example PI | IgG | IgA | IgE | IgM |
|---|---|---|---|---|
| Ataxia telangiectasia | Subclasses may be low | Often low | Often low | High (monomers) |
| XLA (Bruton disease) | Low | Low | Low | Low |
| CD40/CD40L deficiency | Low | Low | Low | Normal or high |
| CVID disorders | Low | Low | May be low | |
| Hyper IgE syndrome | Normal | Normal | High | Normal |
| IgG subclass deficiency | Total normal, one or more subclass low | Normal | Normal | Normal |
| SCID | Usually low | Usually low | Usually low | Usually low |
| Selective IgA deficiency | Normal | Low or absent | Normal | Normal |
| WAS | Often high | Often high | Low |
CVID: common variable immunodeficiency disorder; SCID: severe combined immunodeficiency; WAS: Wiskott-Aldrich syndrome; XLA: X-linked agammaglobulinemia
Source: International Patient Organisation of Primary Immunodeficiencies. Diagnosis of Primary Immunodeficiencies.
Accessed at www.immunodeficiencyuk.org/static/media/up/Diagnosisofpid2.pdf.
Importance of Diagnosis
Although complicated, time-consuming and, at times, considerably frustrating, it’s very important to conduct a thorough evaluation of multiple components of the immune system to rule out or confirm a PI. Equally important is working with an immunologist who specializes in immune system conditions. Immunologists are the best choice for conducting the assessments and deciding which tests to perform (and in what order) to arrive at a working diagnosis.
An accurate diagnosis points to the appropriate treatment. Treatments range from simple (watching and tracking symptoms) to complex (treatments that could include infusions of immune globulin and, in severe cases, stem cell transplant), depending on the type and severity of the PI.
For more information and valuable resources, visit the Immune Deficiency Foundation (www.primaryimmune.org) and the Jeffrey Modell Foundation (www.info4pi.org) websites.
References
- Centers for Disease Control and Prevention. Primary Immunodeficiency (PI). Accessed at www.cdc.gov/primary-immunodeficiency/about/.
- International Patient Organization for Primary Immunodeficiencies. Diagnosis of PID. Accessed at www.immunodeficiencyuk.org/static/media/up/Diagnosisofpid2.pdf.
- Immune Deficiency Foundation. Laboratory Tests. Accessed at primaryimmune.org/understanding-primary-immunodeficiency/diagnosis/laboratory-tests.
