Primary immunodeficiency overview

by John Routes, MD

John Routes, MD, is medical director of Allergy and Clinical Immunology at Children's Hospital of Wisconsin, professor of Pediatrics and chief of the Section of Allergy and Clinical Immunology at The Medical College of Wisconsin and a member of Children's Specialty Group.

John Routes, MD, has been a leader in a first-of-its-kind screening test used to detect a rare and often undiagnosed immune system disease that is fatal without treatment. Children's Hospital of Wisconsin and the State Laboratory of Hygiene at the University of Wisconsin-Madison launched protocols to screen all newborns in Wisconsin for severe combined immunodeficiency disease, sometimes known as
John Routes, MD, has been a leader in a first-of-its-kind screening test used to detect a rare and often undiagnosed immune system disease that is fatal without treatment. Children's Hospital of Wisconsin and the State Laboratory of Hygiene at the University of Wisconsin-Madison launched protocols to screen all newborns in Wisconsin for severe combined immunodeficiency disease, sometimes known as "Bubble Boy Disease."
Primary immunodeficiency results from inherited genetic defects involving the immune system and immune responses. In aggregate they occur in as many as 1 in 2,000 live births. Primary immunodeficiency typically is classified according to the principle immunologic mechanisms affected. (See Table 1.) The early diagnosis of primary immunodeficiencies is essential and will markedly reduce the morbidity and mortality associated with recurrent infections. For example, severe combined immunodeficiency is uniformly fatal if undiagnosed, but long-term survival rates of more than 90 percent have been achieved with early bone marrow transplantation (at less than 3 months of age). Treatment with high-dose intravenous gamma globulin (IVIG) can prevent many of the infectious sequelae in patients with primary antibody deficiency states.

 

Many routine childhood vaccines use attenuated organisms. The use of such vaccines may lead to disseminated infections in patients with severe cellular immunodeficiencies and are contraindicated. Consultation with a clinical immunologist is indicated when attenuated vaccines are considered for patients with other forms of primary immunodeficiency. Irradiated, cytomegalovirus (CMV)-negative, lymphocyte-depleted cellular blood products should be administered to patients with cellular or combined immunodeficiency.

Several factors should influence the decision to evaluate patients for primary immunodeficiency. (See Table 2.) For example, a patient with a first pneumonia and a history of intractable sinus disease or recurrent gastrointestinal infections should be evaluated for primary immunodeficiency. The prevalence of autoimmune disorders is increased in many primary immunodeficiencies and autoimmunity in association with recurrent infections also warrants an evaluation for primary immunodeficiency.

There are several clues in the history and clinical presentation of patients with primary immunodeficiencies that suggest the type of immunologic defect present. (See Table 1.) The onset of diseases associated with cellular immunodeficiencies usually begins soon after birth or in early infancy. Infections with opportunistic or unusual pathogens, mycobacteria, disseminated viral infections and severe oral candidiasis may occur. Diarrhea and malabsorption are common and growth is delayed. In contrast, the onset of infections in patients with antibody deficiencies, uch as x-linked agammaglobulinemia (XLA), may be delayed for several months until maternal antibodies no longer are present. Recurrent and severe upper and lower respiratory tract infections are the usual mode of presentation. Complement deficiencies may present in a similar manner as antibody deficiencies or with recurrent Neiseria sp. infections. In contrast to patients with cellular immunodeficiencies, growth usually is intact in patients with complement or antibody deficiencies.

One common misconception is that opportunistic pathogens are overwhelmingly the cause of most infections in patients with primary immunodeficiencies. In fact, many infections in immunodeficient patients occur with pathogens that are common in the community. However, these infections may be of unusual severity and respond poorly to therapy. Finally, it also is essential to exclude secondary immunodeficiencies (such as lymphoproliferative disorders and malignancy, malnutrition, immunosuppressive drugs, protein losing states) in patients that present with recurrent infection.

Diagnostic workup

There are a number of readily available and fairly inexpensive screening tests that should be used in the evaluation of a patient for possible immunodeficiency. (See Table 3.) Abnormalities found in these screening tests indicate the need for more sophisticated studies in collaboration with a clinical immunologist. Consultation with a clinical immunologist is imperative when there is any question regarding interpretation of screening tests. The goal in the evaluation of immunodeficient patients should be to define the specific genetic abnormality whenever possible.

Other considerations

Education is important for optimal outcomes for patients and families with primary immunodeficiencies. They need to be well informed about the inheritance, clinical manifestations and treatment of their specific primary immunodeficiency. Patients and families should establish long-term relationships with health care providers, including physicians, nurses and social workers, to obtain the best outcomes for their diseases. Important resources for families and physicians include the Immune Deficiency Foundation (www.primaryimmune.org) and the Jeffrey Modell Foundation (www.jmfworld.org).

For more information, visit chw.org/pip.