Approach

Attenuated WAS

Patients with attenuated WAS or X-linked thrombocytopenia (XLT) may require no treatment if they are asymptomatic. Symptoms of eczema and bleeding should be treated according to clinical severity. Elective splenectomy can be considered for management of severe thrombocytopenia.[22]

Most patients with attenuated WAS do not have significant problems with infection, but if frequent minor infections or any severe infections occur, prophylactic antibiotics should be started. If symptoms persist/worsen, or if specific antibody production is abnormal (as indicated by vaccine responses), intravenous or subcutaneous immunoglobulin is indicated and the patient's classification as attenuated WAS should be reviewed. Children with attenuated WAS should be vaccinated according to the national childhood vaccination program.

Development of autoimmunity or malignancy should be treated according to the type of pathology, and the patient should be reclassified as having severe WAS.

Severe WAS

All patients with severe WAS should have optimal prophylactic treatment until curative therapy such as bone marrow transplant is available.[23] Symptoms of eczema and bleeding should be treated according to clinical severity.

All patients with severe WAS should commence prophylactic antibiotics and immunoglobulin. Immunoglobulins (IgA, IgM, IgG) are obtained from pooled plasma from donors. Intravenous immunoglobulin is approved for use in primary immunodeficiencies and immune-mediated thrombocytopenia. Pneumococcal vaccine is recommended for all children <2 years, and for unvaccinated children between 24 and 59 months old who are at high risk for pneumococcal infections, unless they are on immunoglobulin therapy. Patients with severe WAS should not receive live vaccinations but should receive the inactivated influenza vaccination annually, as well as coronavirus disease 2019 (COVID-19) vaccinations.[24] Local guidance should be followed for patients who are moderately to severely immunocompromised.[24]

Splenectomy increases the risk of death from infection, particularly pneumococcal disease, which can be fatal even after successful bone marrow transplantation. In addition, relapse of thrombocytopenia is common post-splenectomy in severe WAS.[22] Therefore, splenectomy is avoided unless it is required for management of symptomatic thrombocytopenia.

Hematopoietic stem cell transplant (HSCT) should be performed where a matched sibling or matched unrelated donor is available. Outcomes for HSCT are excellent, with mean overall survival of >90% according to one report.[25] Haploidentical transplant is generally avoided as outcomes are poor. Gene therapy trials are in progress at some specialist centers as an option for patients with severe WAS who lack a suitable donor.[26]

Development of autoimmunity or malignancy should be treated according to the type of pathology.

Eczema

The goal of treatment is symptom control. Treatment regimens are similar to those for patients with atopic eczema, although it is often necessary to progress to second- and third-line treatment more rapidly, as WAS-related eczema often responds suboptimally to treatment. Early referral to a dermatologist is recommended.

Initial therapy should include emollients and mild topical corticosteroids. Moderate-strength topical corticosteroids are often required. In some cases only systemic corticosteroids afford good control. Topical tacrolimus can be used as a corticosteroid-sparing agent, although potential adverse effects should be fully discussed.

Bleeding and bruising

The goal of treatment is prevention of serious bleeding episodes, which are mostly intracranial and gastrointestinal. The majority of patients experience easy bruising and petechiae, and on the whole these are tolerated unless severe.

Oral aminocaproic acid in WAS children with acute bleeding is advised until the bleeding is controlled (with the exception of urinary bleeding, where aminocaproic acid can result in clots and urinary retention). Otherwise stable platelet levels can fall unexpectedly after intercurrent illness or as a result of autoimmune thrombocytopenia. Clinical monitoring is key. Onset of mucosal bleeding (mouth or rectal) should trigger urgent patient assessment and platelet count. Additionally, all patients should be assessed after a significant trauma, especially head injury.

Oral aminocaproic acid in WAS children should be considered if platelet levels fall significantly with moderate bruising or for bruising following trauma, and can be used for a period of several days to reduce bruising after a specific trauma or trialed as continuous treatment to reduce easy bruising.

In the event of bleeding, initial treatment is platelet transfusion. If the platelet count increments poorly, an autoimmune component should be suspected and second-line treatment commenced, which consists of a combination of systemic corticosteroids, high-dose immunoglobulin, and rituximab (anti-CD20 monoclonal antibody). If bleeding is intractable, splenectomy may be required. Curative therapy such as bone marrow transplantation should be considered after a severe episode of bleeding.

Autoimmunity

Treatment must be tailored according to the type of autoimmunity. Autoimmune cytopenias are common, and rituximab is generally effective. Specialist input may be required (e.g., rheumatology for vasculitis). All patients with autoimmunity are classified as severe and should be assessed for bone marrow transplantation.

Malignancy

Treatment must be tailored according to pathology and should be directed by specialist oncology input.

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