Wiskott-Aldrich syndrome (WAS)

Because individuals with WAS have abnormal B and T cell function, they should not receive live virus vaccines, such as rotavirus, MMR, and chickenpox, since there is a possibility that a vaccine strain of the virus may cause an infection. Other, non-live vaccinations can be given safely to individuals with WAS but may not generate protective levels of antibody.

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Since individuals with WAS have abnormal antibody responses to vaccines and to invading microorganisms, most are treated with immunoglobulin (Ig) replacement therapy to prevent infections. Because of the bleeding tendency in WAS, subcutaneous immunoglobulin replacement therapy (SCIG) is used with caution, but most individuals tolerate SCIG very well.

Individuals who have had a splenectomy (removal of the spleen) are particularly susceptible to rapidly progressing severe bacterial bloodstream infections. Ig replacement therapy combined with preventative antibiotics is particularly important in these individuals.

When there are symptoms of infection, a thorough search for bacterial, viral, and fungal infections is necessary to determine the most effective antimicrobial treatment. Because individuals with WAS cannot be vaccinated against chicken pox, complications of chicken pox infection occur occasionally and may be helped by early treatment following exposure with antiviral drugs, high dose immunoglobulin (Ig) replacement therapy, or varicella-zoster immune globulin (VZIG).

Because the benefit is short-lived, preventative platelet transfusions are not recommended in WAS to increase the platelet count in an attempt to prevent bleeding episodes. In cases of active bleeding or injury, especially if affecting the brain or the gut, platelet transfusions may be necessary to stabilize the individual and prevent organ damage. For example, if serious bleeding cannot be stopped by usual measures, platelet transfusions are indicated. Due to constant increased blood loss, iron deficiency anemia is common among individuals with WAS, and iron supplementation is often necessary.

The spleen is an organ in the abdomen that serves as a sort of "filter" for the blood. Abnormal platelets or platelets that have been coated with autoantibodies are often trapped by the spleen, where they are destroyed. For individuals with WAS, this may become a significant problem. Surgical removal of the spleen (splenectomy) has been performed in selected individuals with WAS/XLT in an attempt to correct thrombocytopenia, and in many cases, did increase platelet counts.

Since the spleen also filters bacteria out of the bloodstream, splenectomy significantly increases the susceptibility of individuals with WAS to bloodstream infections (sepsis) and meningitis caused by encapsulated bacteria like Streptococcus pneumoniae, Hemophilus influenzae, and others. In the absence of a spleen, these infections can be rapidly fatal, so it is imperative that splenectomized individuals receive prophylactic antibiotics on a daily basis for the remainder of their lives. Splenectomy does not prevent the other features of WAS and should only be used to control particularly severe thrombocytopenia and potential lethal bleeding.

The eczema in WAS can be severe and persistent, requiring constant care. Consultation with an allergist or dermatologist is often helpful for these individuals. At a minimum, regular application of a thick moisturizing ointment, not a lotion, at least twice a day is recommended. Excessive bathing may dry the skin further and worsen the eczema. Steroid ointments should be used to control inflammation in areas that are more significantly affected, but they may thin the skin with chronic use, so should be used sparingly and in consultation with an allergist or dermatologist.

IgE-mediated food allergy with anaphylaxis is common in WAS. Consultation with an allergist to assist in diagnosis and management of food allergies, including potential food challenges, is recommended. Epinephrine should be prescribed to those with IgE-mediated food allergy.

Autoimmune complications may require treatment with drugs that further suppress the individual's immune system. Systemic steroids (such as prednisone) are often the first immunosuppressant medication used to treat autoimmune disease and are often helpful in individuals with WAS. Since long-term use of high-dose steroid is associated with side effects, the dose should be reduced to the lowest level required to control symptoms and stopped if no longer needed. High-dose Ig replacement therapy may also be beneficial in treating autoimmune disease in some cases. Rituximab, a B cell-specific immunosuppressant, is effective in antibody-mediated autoimmune diseases, such as autoimmune hemolytic anemia.

Until recently, the only long-lasting treatment for WAS was transplantation of hematopoietic stem cells from bone marrow, peripheral blood, or cord blood. Individuals with WAS have some residual T cell and NK cell function despite having an immune deficiency, and this has the potential to cause rejection of transplanted donor cells. To prevent this, individuals must undergo conditioning, or treatment with chemotherapy drugs, to destroy their own immune cells before the donor stem cells are infused.

There are four potential donor types for any transplant:

1. Matched sibling donor.
2. Matched unrelated donor.
3. Haploidentical (half-matched) donor, typically a parent.
4. Cord blood donor.

In general, the risks of transplant rejection and graft versus host disease (GVHD) are decreased when the HLA types match completely between the donor and recipient.

In WAS, HSCT outcomes using an HLA-identical sibling donor are excellent, with an overall success rate approaching 90-100% at most centers. With improvements in conditioning regimens and supportive care, the outcome using cells from an HLA-matched unrelated donor approach those obtained with matched sibling donors. Transplants using fully or partially matched cord blood stem cells have also been quite successful.

Before the year 2000, transplantation with cells from a haploidentical (half-matched) donor was successful in only approximately 50% of cases. However, in more recent clinical trials, the success rate of haploidentical transplantation increased to 90% following the introduction of novel techniques to prevent graft-versus-host disease. There remains a slight, but significant, survival advantage if transplantation is performed in individuals less than age 5. After transplant, most individuals remain on immunosuppressant medications for a short period of time in order to decrease the risk of GVHD.

In gene therapy, a functional copy of the WAS gene is delivered into the individual's own bone marrow stem cells using a hollowed-out virus (viral vector). The blood cells derived from the individual’s bone marrow are then able to make WASp. Since the individual’s own cells are being modified, there is no risk for graft-versus-host disease like there is for HSCT.

The major risk of gene therapy is that the virus may insert a copy of the WAS gene randomly into one of the individual's chromosomes and cause increased production of one or more neighboring proteins that can cause cancer. Several years ago, gene therapy was used to successfully treat a small number of individuals with WAS, correcting their bleeding problems and immune deficiency. Unfortunately, most individuals participating in this trial developed leukemia as a result of the gene therapy virus inserting its DNA into a sensitive region of the individuals' chromosomes. Subsequent clinical trials using new viral vectors demonstrated excellent long-term outcomes without leukemia. The success of more recent gene therapy trials for WAS is very encouraging, but a number of problems remain to be solved before it becomes more broadly applicable.