Primary Immunodeficiency Disorders

In-Depth

We understand that you may want to learn more about your child’s PIDD in order to find the most appropriate treatment. We’ve provided some answers to commonly asked questions in the following pages, and our experts can explain your child’s condition fully.

What is the immune system?

The immune system finds and attacks infectious organisms, including bacteria, viruses and fungi. The immune system is made up of several different types of white blood cells. Each white blood cell type has specialized functions. For instance, neutrophils are important to fight bacteria and fungi, while lymphocytes generally fight viruses. Some T lymphocytes can kill other cells that are infected with a virus, and B lymphocytes make antibodies, which are proteins that fight infection. Usually, many different types of white blood cells work together to fight all kinds of infections. Thus, the immune system is truly a system, and a problem in any part of the system can cause minor infections to become serious ones.

What is primary immunodeficiency?

Primary immunodeficiency disorders (PIDDs) are a group of inherited conditions affecting the immune system. From the time of birth, the immune system of a child with a PIDD does not function properly and cannot fight off infections, due to a problem in white blood cells, such as T lymphocytes or B lymphocytes. A defective immune system can cause children to get sick faster and for longer periods of time from usual childhood infections. These children are also susceptible to infection from ordinarily harmless organisms. Most PIDDs are not deadly, but it is still important for it to be diagnosed and treated early so it does not become life threatening.

There are more than 180 known kinds of PIDDs. Some children with PIDD are born missing certain white blood cell types. For instance, children with severe combined immunodeficiency have an absence of T lymphocytes; those with Kostmann’s syndrome have no neutrophils. Children with other disorders, such as Wiskott-Aldrich syndrome, have normal numbers of lymphocytes, but their lymphocytes have only partial function.

There are six main types of PIDDs based on the part of the immune system that is affected

• B lymphocytes (antibody) deficiencies
• T lymphocyte deficiencies
• combined B and T cell deficiencies
• phagocyte defects
• complement deficiencies
• other forms and unknown causes

B cell deficiencies are the most common type of PIDD

What causes primary immunodeficiency disorders?

Acquired immune deficiencies occur after infections or environmental exposures in people who were previously completely healthy. PIDDs are present at birth, although the symptoms may not begin until later in life, sometimes even in teenage years or adulthood. Thus, PIDDs are not caused by environmental exposures, medications, trauma, diet or events occurring during pregnancy.

PIDDs are genetic disorders, meaning that every cell in the child's body usually carries a defective or mutated gene that causes the disease. Some children with PIDD have relatives with the same disorder. Sometimes the child's parents carry the gene, which puts future children at risk of being born with the same problem. Other times the child developed the defective gene spontaneously, in which case the child's future siblings would not be at risk.

Signs and Symptoms

Although the genetic defect causing the PIDD is present at birth, children with PIDD may not develop symptoms until they are several months old. In some cases, they are not diagnosed until later in childhood or even adulthood. Because PIDDs affect the immune system, children with these disorders develop frequent, severe or unusual infections. Often a simple cold will lead to severe bacterial infections, most commonly pneumonia, bronchitis, sinusitis and ear infections (otitis).

Warning signs that your child may have a PID:

• infections
  • 4 or more new infection in a year, including infections of the skin and mucous membranes in the eyes, mouth, and genital area
  • infections require intravenous antibiotics
  • 2 or more deep-seated infections such as septicemia
  • persistent thrush (a fungal infection of the mouth)
  • 2 or more serious sinus infections in a year
  • antibiotics have little or no effect over 2 or more months
  • 2 or more pneumonias within a year
• visible signs
  • severe eczema
  • serious skin infections
  • failure to grow and gain weight in infancy
  • enlarged lymph nodes
  • severe chronic digestive problems such as cramping, and diarrhea
• internal signs
  • autoimmune disorders such as lupus, rheumatoid arthritis, or type 1 diabetes
  • inflammation and infection of internal organs such as the liver
  • enlarged spleen
• PIDD in the family

A child that has only one of these symptoms or signs is unlikely to have PIDD. But if a child has several of these symptoms, or has repeated infections in a short period of time, the child could have PIDD.

FAQ

Q: Will my child be OK?

A: The majority of children with a PIDD live active lives. Sometimes so much so, their condition is not suspected. Early detection, diagnosis and treatment are critical in reducing the risk for chronic illness, permanent organ damage or even death.

Q: Could I have prevented my child from getting PIDD?

A: No. So far, research only shows genetics as the cause for PID. That being said, you can use proper hygiene, provide a healthy diet, avoid exposure to infections and take prescribed medicines to prevent infections from attacking your child’s compromised immune system.

Q: Can PIDD surface later in life, even though it is inherited?

A: Yes. There is a form of PIDD called common variable immunodeficiency that can have the onset of symptoms at any time in life, even though, for most people who are affected it is determined genetically.

Q: Can my child spread their PIDD or contract a PIDD?

A: No. A PIDD is inherited and genetic. So your child cannot give or get a PIDD from being in contact with another person or their germs. However, if your child does have a PIDD, they may be more vulnerable to infections.

Q: Is there a cure?

A: Yes. Stem cell transplantation uses stem cells from a donor, usually a parent or relative, to build a normally functioning immune system. The donor is usually a parent or a relative so the antigens are similar and the patient’s body accepts the donor’s stem cells. However, only the most serious PIDDs are treated this way. Most children with PIDD do not require stem cell transplantation.

Q: Are there other treatments for PIDD?

A: Yes. Many people with PIDD who don’t need a stem cell transplant will be treated with IgG replacement therapy. This provides them with antibodies they cannot make themselves. Many patients will also take various kinds of antibiotics and other medications to prevent certain types of infections.

Questions to ask your child’s doctor

After your child is diagnosed with a PIDD, you may feel overwhelmed with information. It can be easy to lose track of the questions that occur to you.

Lots of parents find it helpful to jot down questions as they arise- that way, when you talk to your child’s doctors you can be sure that all of your questions are answered. If your child is old enough, you may want to suggest that he or she writes down what they want to their health care provider too.

Here are some questions to get you started:

• How will PIDD medications or treatment impact my child’s academic performance?
• How may PIDD medications or treatment interact with my child’s other current medication regimens?
• Will my child’s diet need to change while receiving PIDD medications or treatment?
• What are some things I can do to minimize my child from being exposed to infections?
• How can I provide my child with the tools to help themselves if I’m not there?
• How will their PIDD impact their adult life?
• What support services are available to help educate my child about their PIDD?
• What are some steps I should take if my child suffers from a severe infection?
• What are some other conditions these symptoms could be a sign for?
• How can I tell if the symptom is for PIDD, another condition or maybe even a PID in combination with another condition?
• How can I prepare my child for any testing?

In addition to being prepared to ask questions, you may want to be prepared and have the information to be able to answer the following questions from your doctor:

• When did you first observe these symptoms in your child?
• What is the frequency of these symptoms?
• What is the usual duration of these symptoms?
• What is the frequency of infections?
• What is the usual duration of the infections?
• How does your child react to antibiotics for their infections?
• What was your previous antibiotic regimen for your child?
• Any family history of PIDD?

  Interactive learning
  Stem cells are a key part ofhematopoietic stem cell transplantation, which is currently the only known cure for PID. Learn from this interactive demonstration on stem cell research.

How we diagnose primary immunodeficiency

The first step in treating your child is forming an accurate and complete diagnosis. To determine your child's primary immunodeficiency disorder, Boston Children's doctors will use a combination of medical history, physical examination and laboratory tests.

Medical history

• Since these disorders are genetic, it is also important for us to obtain a full medical history of both your child and your family.

Physical examination

• This is important to look for signs of infection or other findings that can provide clues regarding specific PIDDs.

Tests

• Blood tests we perform will help us determine which immune system components responsible for fighting off infection are affected, such as white blood cells or antibodies. The type of abnormality identified will help determine what type of PIDD your child has.
• Other tests such as x-rays or CT scans may also be helpful to find infections or other clues regarding specific PIDDs.

Prenatal or newborn testing

• For mothers who have already had a child with a PID, prenatal testing can be done for subsequent pregnancies. Samples of amniotic fluid, blood or cells from the placenta are tested for PIDD in order to be prepared to start treating a child with PIDD soon after birth.
• Currently, Massachusetts is one of only a few states in the U.S. that conducts normal newborn screening for severe combined immunodeficiency (SCID).

Read our FAQs to learn more about tests, treatment or procedures.

How we address primary immunodeficiency

There are several treatments and care options to help manage the symptoms and allow your child live a healthy and active life. The most severe forms of PIDD may be cured by hematopoietic stem cell transplantation. However, most children with PIDD do not need this.

The National Institutes of Health recognizes three main stages of treatment for PID:

1. treat existing infections (treatment)
2. avoid further infections (prevention)
   • proper hygiene
   • healthy diet
   • avoid exposure
   • medication compliance
3. correct the immunodeficiency (cure)

Treatment

There are several treatments we may recommend to support and improve the function of your child's immune system, such as:

• gamma globulin (IgG) infusions - a procedure that supplements your child's immune system with additional antibodies.
• antibiotics - medications that either target a specific infection or act as a preventive treatment
  • In cases of extreme infections, patients may need intravenous (IV) antibiotics
• other drugs
  • Some specific PIDDs may be treated with medications that replace specific immune factors that are missing or that help defective white blood cells work better (for example, gamma interferon therapy for chronic granulomatous disease).

For some primary immunodeficiency disorders (PIDDs), these therapies can keep children healthy and active for many years. However, none of these therapies can cure the PIDD. The only known cure is hematopoietic stem cell transplantation or gene therapy.

Prevention

In addition to following the recommendations your doctors give for supportive care, there are steps your family and child can take to maintain the general health of a child with PIDD. Following a healthy diet, including avoiding raw or undercooked foods that may contain bacteria, using filtered or bottled water, avoiding exposure to infection and practicing good personal hygiene will help your child stay healthy.

Cure

Hematopoietic stem cell transplantation (HSCT)

Currently, HSCT is the only non-experimental cure available. You may have heard of a bone marrow transplant (BMT), which is a form of HSCT. HSCT is a very complex treatment, and not all children with PID are candidates for this therapy. Children with PIDDswho receive stem cell transplants are treated through Dana-Farber/Children's Hospital Cancer Care's Pediatric Stem Cell Transplantation Program. The combined Dana-Farber Cancer Institute and Boston Children's Hospital transplant team has more than 20 years of experience using stem cell transplantation to treat children with severe PIDDs.

• What is a stem cell?
• Stem cells are single cells with two unique qualities–they can make many copies of themselves and they can develop into a variety of specialized cells. These qualities make them promising new tools in medicine, allowing patients to receive needed cells or tissues or have diseased cells or tissues replaced with healthy ones.
  • Pluripotent stem cells are “master cells.” They're able to make cells from all three basic body layers, so they can potentially produce any cell or tissue the body needs to repair itself. They include embryonic stem cells, made from embryos, and induced pluripotent stem cells, which closely resemble embryonic stem cells and are created through genetic reprogramming.
  • Adult stem cells are specialized stem cells that give rise to one or more specific cells or tissues.
• What is a hematopoietic stem cell?
  • Stem cells that can form any type of blood cell, including red blood cells, white blood cells and platelets.
• How does HSCT work?
• HSCT gives the hematopoietic stem cells from the donor to the patient
• sources of hematopoietic stem cells:
• bone marrow
• cord blood-placenta blood obtained at birth
• chemotherapy
• Chemotherapy may be used to temporarily weaken the immune system so the body accepts the donor's stem cells.
• Chemotherapy may also be used to eliminate the patient's stem cells to make room for new stem cells.
• Who's a good donor?
• Somebody with tissue antigens similar to your child's
• What if the only donor I can find for my child is not a good match?
• T- cell depletion
• Remove the T-cells from the donor's stem cells before transplanted them to the host, or the patient.
• Stem cells carry T-cells which are used to attack foreign tissues. If the transplanted stem cells of the donor has T- cells that do not match with the patient's tissues, the donor's T-cells may attack the patient's tissues.

Gene therapy

Currently in the experimental phase, gene therapy addresses the problem by using the best donor possible, the patient.

How does gene therapy work?

1. Blood stem cells are isolated and removed from the patient's bone marrow.
2. A vector, a host virus, carries a healthy copy of the affected gene into the patient's stem cells to create corrected, healthy stem cells.
3. A virus is genetically altered into a harmless vector to carry the affected gene.
4. Corrected stem cells are injected to the patient's body.
5. The white blood cells that develop from the corrected stem cells produces the affected proteins correctly.

Coping and support

In addition to providing medical care, we strive to also meet all of your family's emotional and psycho-social needs. We know that unfamiliar places, especially hospitals, often create anxiety and fear for a child. Your child may feel anxiety because of their inherited condition. They may feel they are different than everyone else and want to live a normal life.

We also know this isn't an easy time for parents, who have their own fears and concerns when they learn their child has a PIDD. It may help to remember that there is nothing you could have done to prevent this condition from affecting your child. You or your child may want to seek genetic counseling to determine the risk for any future children, and to understand their options in this regard. In the long term, your child may also want to speak with a genetic counselor before starting his or her own family. Our center has accessible genetic specialists, as well as psychologists to help you navigate challenging decisions.

There's a lot of support available here at Children's for you and your family, and here are some of the ways we can help:

Patient education: From the office visit to pre-op to the recovery room, our nurses will be on hand to walk you through your child's treatment and help answer any questions you may have — How long will I be separated from my child during hospitalization? What will treatment be like? They will also reach out to you by phone, continuing the care and support you received while at Children's.

Parent to parent: Want to talk with someone whose child has been treated for PID? We can often put you in touch with other families who have been through similar experiences and can share with you their experience at Children's.

Faith-based support: If you are in need of spiritual support, we will help connect you with the Department of Spiritual Care (chaplaincy). Our program includes nearly a dozen clergy representing Episcopal, Jewish, Lutheran, Muslim, Roman Catholic, Unitarian and United Church of Christ traditions who will listen to you, pray with you and help you observe your own faith practices during your hospital experience.

Social work: Our clinical social workers have helped many other families in your situation. Your social worker can offer counseling and assistance with issues such as coping with your child's diagnosis, stresses relating to coping with illness, and dealing with financial difficulties.

Visit our For Patients and Families page for all you need to know about:

• getting to Boston Children's
• accommodations
• navigating the hospital experience
• resources that are available for your family

We are is home to the world’s most extensive research enterprise at a pediatric hospital, and our research informs our treatments.

Researcher Narayanaswamy Ramesh, PhD, conducts molecular studies on primary immunodeficiencies. Eventually his studies may lead to the development of a molecular framework for testing chemicals as potential therapeutic drugs. The immediate goals of his research are to:

• identify the molecular basis of novel immune deficiencies that affect cytoskeletal functions
• delineate mechanisms that couple T-cell receptor signaling to the remodeling of the actin cytoskeleton
• understand the role of cytoskelton remodeling in T cell function(s)

His recent investigations have focused on Wiskott-Aldrich syndrome (WAS), which is caused by mutation in the gene encoding for the WAS protein (WASP). Dr. Ramesh and colleagues have been interested in the role of WASP on the cytoskeleton — the cell's dynamic structural framework — which is composed of the protein actin and non muscle myosin. WASP is known to have a role in cytoskeletal remodeling, which is essential to immune-cell functions, such as activation and motion.

Recently, his laboratory identified a novel cellular protein that acts as a negative regulator of WASP. The researchers have demonstrated that the protein, which they have named WIP, acts with WASP to regulate cytoskeletal remodeling during immune-cell activation. WIP is multifunctional, acting as a molecular scaffold and linking a cellular signaling pathway(s) to actin in cytoskeletal remodeling. They are now studying the role of WASP and WIP in immune cell functions that require active cytoskeletal remodeling, such as chemotaxis, homing, and molecular events triggered by cell-cell and cell-matrix interaction.

Transatlantic research cooperation

Wiskott-Aldrich syndrome is a rare primary immune deficiency disease causing significant bleeding due to low platelet count and increased incidence of serious infections. Platelet cells are cells found in the blood that help control bleeding. Children's also has partnered with Genethon of France to get FDA approval for a Wiskott-Aldrich gene therapy trial.

A fishy solution for genetics research

Zebrafish are important for biomedical research because they are genetically similar to humans, can grow from an embryo to an adult within a few days and can lay more than 1,000 eggs a week. Learn how Children’s developed the iSpawn to help harvest the zebrafish eggs.