As a practicing pediatrician, I am frequently asked by parents if their child is unusually sick--could there be something wrong? I reassure them that children in day care, particularly from six to 30 months of age, typically get a new infection every three weeks (at least from my 30 years of research in day care centers). But a few children do have an underlying issue with their immune system. In this article, Ivan Chinn, MD, a pediatric immunologist at Duke, discusses the signs, symptoms, and treatments for primary immunodeficiency diseases.

--Dennis Clements, MD, PhD, MPH

What are primary immunodeficiency diseases?

One of the most important functions of the immune system is to protect us from bacteria, viruses, and fungi that can make us sick. Not all organisms are harmful--in fact, our intestines contain many bacteria that help prevent problems such as allergies and improper absorption of nutrients. The immune system identifies the difference between what is dangerous and what is not and prevents whatever is dangerous from harming us. Primary immunodeficiency diseases (PIDDs) are caused by mutations in genes that prevent the body from developing normal immune responses to infectious challenges. The mutations can either be inherited or appear randomly.  Because the immune system is compromised in PIDDs, harmful organisms usually cause recurrent and sometimes life-threatening infections.  In addition, since these diseases are genetic, they are generally considered to be lifelong conditions once they are diagnosed. 

How common are primary immunodeficiency diseases?

The most common PIDD is selective IgA deficiency, which has been reported as frequently as about one in every 300 to 400 individuals in the United States.  Although other PIDDs may occur less frequently, the actual rates of occurrence are not known because positive diagnoses are often not made.  As screening of newborns for important PIDDs becomes implemented as a standard practice, these statistics should become more accurate. 

What are the signs and symptoms of primary immunodeficiency diseases?

Signs and symptoms that often alert us of the possibility of a PIDD are well-summarized by the following "10 Warning Signs of Primary Immunodeficiency":

• Four or more new ear infections within one year, particularly after the first year of life.
• Two or more serious sinus infections within one year.
• Two or more months on antibiotics with little effect.
• Two or more pneumonias within one year.
• Failure of an infant to gain weight or grow normally.
• Recurrent, deep skin or organ abscesses.
• Persistent thrush in the mouth or significant fungal infections on the skin.
• Need for intravenous antibiotics to clear infections.
• Two or more deep-seated infections, including infections of the bloodstream.
• A family history of primary immune deficiency. 

What tests should be performed to look for a primary immunodeficiency disease?

Your child's pediatrician may consider testing blood to check the cell counts (complete blood count with manual differential) and immunoglobulin levels (humoral immune-competence profile). He or she may also order a chest x-ray to look for the presence of a thymus (gland in the chest), to examine the lungs, and to make sure the heart is in the correct position. Further testing should be performed in a specialized immunology clinic according to your child's medical history. These highly technical tests need to be ordered by a pediatric immunologist, geneticist, allergist, pulmonologist or infectious disease specialist and may include the following:

• Enumeration of lymphocyte subsets by flow cytometry.
• Cellular immunocompetence profile.
• Evaluation of immune responses to immunization challenges.
• Respiratory burst assay.
• Complement levels and functional assays.
• Innate immunity signaling tests.
• Genetic testing. 

How are primary immunodeficiency diseases treated?

Our patients are often given antibiotics or antifungal medications for prevention or treatment of infections. These medications need to be prescribed carefully because they can sometimes cause unwanted side effects or encourage the growth of bacteria that are resistant to antibiotics. Patients who lack the ability to make antibodies often require immunoglobulin replacement therapy.  Some patients, depending on the type of PIDD that has been diagnosed, may require bone marrow or umbilical cord stem cell transplantation or even thymus transplantation in the most severe cases. 

What are other possible explanations for recurrent infections in my child?

There are many other potential reasons for recurrent infections in children:

• Recurrent ear infections can be caused by poor drainage of the middle ear canals.
• Recurrent pneumonias can be caused by asthma or cystic fibrosis.
• Recurrent sinus infections can be caused by nasal allergies.
• Recurrent skin infections can be caused by eczema (dry skin).
• Recurrent throat infections can be caused by bacteria that thrive around the tonsils.
• Recurrent urinary tract infections can be caused by abnormal development of the kidneys, kidney ducts, or bladder. 

Multiple viral infections are normal and very common in children, especially in infants attending day care. Viruses can cause repeated infections of the ears, sinuses, lungs, throat, and gut. Thus, it may not be unusual for a child in day care to have more than four new ear infections in one year. In some children, the immune system develops and matures more slowly than others, which can increase the risk for infections. This process is considered normal, and we expect children with this issue to eventually outgrow the recurrent infections.  Sometimes, individuals can develop serious infections despite a normal immune system if organisms are particularly good at defending themselves against antibiotics or the human immune system.  The widespread use of antibiotics has made this problem worse, resulting in the growth of stronger and more aggressive bacteria, such as methicillin-resistant staphylococci. Finally, secondary immunodeficiency conditions can increase the risk for infections in a similar manner as PIDDs.  These conditions are acquired and include processes such as human immunodeficiency virus infection, cancer, diabetes, and medication use (e.g., immune suppression from steroids).  The infections resolve once the underlying issue is treated appropriately.  So while most children have infections, only a few have an underlying immune deficiency. 

If you are concerned that your child may have a primary immunodeficiency disease, please contact your child’s pediatrician for further evaluation.

-- Ivan Chinn, MD, is a member of the Duke Pediatric Division of Allergy and Immunology and is actively involved in primary immune disorders and immunodeficiencies, thymus transplantation for DiGeorge syndrome, evaluation of recurrent infections, and allergic diseases (including asthma, allergic rhinitis, food hypersensitivity).

-- Dennis Clements, MD, PhD, is the chief of primary care pediatrics at Duke Children's Hospital & Health Center.