Research Seeks Cure for Primary Immune Deficiency Diseases

Dr. Hans Ochs

Seattle Children's researcher Dr. Ochs is looking at the connection between immune deficiencies and genes.

Primary immune deficiency diseases (PIDD), an umbrella term referring to more than 130 genetic defects involving the immune system, affect as many as 500,000 Americans and 10 million people worldwide.

People with PIDD are unable to fight off bacteria, viruses, parasites, fungi and malignant cells, which can lead to frequent infections that are difficult to fight, and to an increased incidence of cancer.

PIDD is not contagious; it is hereditary — parents can pass it to their children. According to the Centers for Disease Control and Prevention (CDC), many primary immunodeficiencies are the result of a single gene defect.

The diseases can strike males and females of all ages, with the more severe immunodeficiency diseases usually detected most frequently in children.

Early diagnosis and treatment of PIDD is essential to prevent the infections from causing permanent damage, especially to the lungs. The condition can go undetected because the symptoms appear as "ordinary" infections of the sinuses, ears or lungs, or as gastrointestinal problems or inflammation of the joints.

As a result, families and physicians are often unaware that the troubling conditions they see in the child are actually caused by an underlying defect of the immune system.

Signs, Symptoms and Treatment of Primary Immune Deficiency Diseases

How do physicians know if a child has a primary immune deficiency disease? A pattern of recurring illnesses may be explained by an underlying PIDD.

According to the Jeffrey Modell Foundation, some warning signs of PIDD that physicians should look for include:

  • Eight or more new ear infections within one year
  • 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
  • An infant's failure to gain weight or grow normally
  • Recurrent deep-skin or organ abscesses
  • Persistent thrush in mouth or elsewhere on the skin after age 1
  • Need for intravenous antibiotics to clear infections
  • Two or more deep-seated infections
  • A family history of PIDD

Dr. Hans Ochs, professor of pediatrics at Seattle Children's and the University of Washington, emphasizes that it's important to know the family's medical history.

"If a pregnant woman had a male sibling or other close male relatives who died prematurely of an infection or has other children with immune deficiencies, I'd recommend that the family be evaluated for a genetic form of PIDD and, if the disorder is X-linked, the woman undergo prenatal testing.

"That way we can take appropriate measures right after the baby is born. Also, some forms of PIDD diseases are associated with a tendency to bleed and the obstetrician may recommend a Caesarean section to prevent damage to the baby."

Infections in a patient with PIDD can be chronic and severe and re-occur frequently. These infections tend to require prolonged therapy. Patients also may respond poorly to a conventional course of antibiotics.

The treatment for immunodeficient patients depends on the severity of the infections and other health problems and the specific genetic defect that is involved.

Most patients require aggressive treatment with antibiotics or antiviral agents. Some also benefit from regular (every two to four weeks) antibody replacement therapy (often referred to as IVIG therapy), which works by replacing the antibodies that the body cannot make on its own.

Finally, some patients require bone marrow transplant or other alternative treatments. In the future, gene therapy may also be a viable treatment option.

Progress Seen in PIDD Research

About 50 years ago, doctors developed a way to prevent infections by replacing antibodies via infusion of gamma globulin, a component of blood serum that is high in disease-fighting ability.

Gamma globulin from many donors is pooled and, in recent years, is administered intravenously or subcutaneously, giving the patient the antibodies he or she needs. However, this is a control measure, not a cure; PIDD patients may need infusions their entire lives.

In fact, about half of the patients the PIDD clinic sees are adults. "Many of these individuals would have died in childhood if it weren't for antibiotics, IVIG or other treatments for infection," said Dr. Ochs.

Seattle Children's is one of only a few hospitals in the country researching and treating patients with PIDD and is a leader in developing new diagnostic techniques to combat PIDD.

By the early 1990s, Children's researchers, such as Dr. Ochs and Dr. David Rawlings, head of Children's Immunology division and associate professor of pediatrics and immunology at the University of Washington, were making the connection between immune deficiencies and genes.

New treatment possibilities

This opened new possibilities for treatment. Recent work at Children's and elsewhere, coupled with improved methods for gene sequencing and the human genome project, has led to rapid acceleration in identification of the genetic basis of many previously unknown immune disorders.

In recent years, a team of Children's researchers led by Drs. Ochs and Rawlings have helped open new treatment possibilities, such as gene therapy.

One important area of research focuses on removing stem cells from a patient, infecting the cells with a normal copy of the defective gene, and returning the stem cells to the patient.

"Most primary immune diseases begin in childhood, which means Children's sees a lot of these kids," said Dr. Rawlings. "As a result, we have developed an expertise no one else in the region has and we have become the referral center for children and adults with immune problems.

"We have genetic testing capabilities no one else has. We serve as an international center for prenatal and neonatal testing, and for testing of adults to identify carriers of immune deficiency disorders."

Dr. Ochs is also the primary investigator for a $12 million grant administered by the U.S. Immune Deficiency Network (USIDnet), an international consortium of 50 researchers and specialists in the field.

The consortium studies PIDD, educates young investigators about the disease and administers, reviews and provides grants. It also funds registries to track the long-term health of patients and provides an anonymous repository that makes DNA or cell lines generated from selected patients available in order to study molecular defects of these diseases.

The Immune Deficiency Foundation (IDF) and the Jeffrey Modell Foundation, two organizations founded by parents of children affected by PIDD, both support research in Dr. Ochs' laboratory in Children's Division of Immunology.

Additionally, the Jeffrey Modell Foundation recently made available matching funds for an endowment for a fellowship in primary immunodeficiency disease.