Primary Immunodeficiency Disease: A Physician’s Perspective

DR. TERRY HARVILLE is associate professor of pathology at the University of Arkansas for Medical Sciences (UAMS) and associate professor of pediatrics at the Arkansas Children’s Hospital, both in Little Rock, Ark. In addition, he is medical director for the Special Immunology Laboratory and Molecular Diagnostics Laboratory at Arkansas Children’s Hospital, and medical director for the Histocompatibility Laboratory and the Immunogenetics and Transplantation Laboratory at UAMS. Dr. Harville is considered a leading expert in the evaluation and treatment of patients with complex immune disorders.

BSTQ: Tell us about your background and experience treating primary immunodeficiency diseases (PI).

Dr. Harville: Before getting into medicine, it struck me as odd that we treated so many diseases by giving “poisons” to patients in hopes that they would kill the disease but not the patient. It seemed that if we could manipulate the immune system, we could accomplish the goal of disease treatment without harm to the patient. Dr. Bob Good once described patients with immunodeficiencies as “experiments in nature” from whom we can learn and understand how the immune system works. All of this led me to become an immunologist. My initial work was primarily with the more severe immunodeficiencies and clinical practice of stem cell transplantation, primarily as inpatient care. My outpatient practice consisted of diagnosing the variety of immunodeficiencies that exist and especially diagnosing and treating patients with autoimmunities. In my current academic position, I teach, perform research and am the medical director of separate laboratories for the evaluation of patients for organ or hematopoietic stem cell transplantation and patients with suspected immune disorders.

BSTQ: What are some of the “red flag” symptoms of PI?

Dr. Harville: Patients who present with numerous or unusual infections should be immediately tested for PI, but it’s possible that patients without obvious problems with infections may be developing autoimmune disorders only to later experience recurrent infections. These patients may have their recurrent infections ascribed to the treatment for their autoimmunity, further delaying diagnosis. At the time of this interview, more than 275 gene mutations have been identified that may result in immunodeficiency or autoimmunity, sometimes in the same patient. Therefore, an emerging concern is that patients may be in the gastrointestinal clinic for problems with inflammatory bowel disease, in the rheumatology clinic with arthritis or lupus disease features, or in the pulmonary clinic with lung disease, and may not be recognized as having PI.

BSTQ:What are some of the misconceptions about PI within the medical community?

Dr. Harville: Many think that PI occurs in as few as one per 100,000 or one per million in the population. This prevents most physicians from considering that PI is as common as other conditions. Currently, it is believed that common variable immunodeficiency may occur in approximately one per 10,000, and that clinically significant antibody deficiencies may be present in as many as approximately one per 3,000, about the frequency of conditions such as cystic fibrosis. Therefore, we are in dire need to educate the medical community that PI is not “rare” but much more common than most have thought.

Another major misconception is that antibiotics are sufficient to treat most patients with PI, and that expensive immune globulin (IG) replacement is not required. To adequately treat most patients with antibody deficiency, IG replacement is required, and indeed, higher dosing is needed than what was previously thought to be sufficient.

BSTQ: How have treatment options evolved since you first began treating PI patients?

Dr. Harville: When I was beginning my training, we had intramuscular injections of gammaglobulin available, and testing was being done for the development of the intravenous (IV) forms. I participated in some of the testing for those “new” IVIG products. For safety issues, detergent treatment was developed for IVIG to inactivate enveloped viruses. And,  other modalities were developed to ensure safety, including pasteurization and nanofiltration. Other proprietary viral inactivation components have also been designed and tested. Thus, increased safety of the infused products derived from plasma has undergone tremendous change. Today, bone marrow stem cell transplantation for severe forms of PI has gone from arduous to routine, with 70 percent to 80 percent good outcomes improving to current outcomes in the high 90 percent range. Some transplants can be done essentially as outpatient procedures, decreasing the time required to be hospitalized.

BSTQ: What is the focus of current research?

Dr. Harville: Current research is focusing on identifying gene mutations that associate with PI. Now, patients can be stratified to study by the mutations present, as well as clinical features. I believe this will greatly push treatment options forward. A huge plus is that the cost of the genetic studies is coming way down. Soon, a person may be able to have his or her entire genome sequenced for less than $1,000. Currently, most immune testing costs more than this. With the proper computer analysis developed and available, all the genes associated with specific immune system activities and functions may be identified for each of us, and abnormalities may be more readily detected. Performed on infants, such testing may allow for identification of those at risk, who then can have appropriate further testing performed prior to complications of PI, and have the correct treatment started much sooner.