Activated Phosphoinositide 3-kinase δ syndrome

Synonyms

activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome, APDS, activated phosphoinositide 3-kinase delta syndrome,

Overview

Activated Phosphoinositide 3-kinase δ (PI3Kδ) Syndrome (APDS) is a rare, inherited inborn error of immunity caused by genetic mutations that lead to overactive PI3Kδ signaling, impairing immune cell function and causing chronic infections, lymphoproliferation (e.g., enlarged lymph nodes, liver, spleen), autoimmunity, and a higher risk of lymphoma. Diagnosis is challenging due to APDS’s rarity and complex presentation. Treatment focuses on managing symptoms with immunoglobulins, prophylactic antibiotics, and anti-inflammatory or immunosuppressive drugs, with new targeted therapies offering potential for specific inhibition of the PI3Kδ pathway. 

Symptoms

Symptoms of Activated PI3Kδ Syndrome (APDS) include frequent and severe ear, sinus, and respiratory infections, such as bronchitis and pneumonia. Other symptoms are lymphadenopathy (swollen lymph nodes), an enlarged liver and spleen (hepatosplenomegaly), autoimmune disorders, and a high risk of developing lymphomas. Chronic respiratory infections can lead to long-term lung damage like bronchiectasis.  

Causes

Activated PI3-kinase delta syndrome (APDS) is a primary immunodeficiency caused by germline genetic variants in either the PIK3CD gene (APDS1) or the PIK3R1 gene (APDS2), leading to the overactivation of the PI3Kδ pathway in white blood cells. This pathway is crucial for immune cell development and function, and its hyperactivation results in impaired immune responses and increased susceptibility to infections and other complications. 

Prevention

There is no known method to prevent Activated Phosphoinositide 3-kinase δ Syndrome (APDS) itself, as it is a rare genetic disorder present from birth. Prevention efforts focus on managing the condition by preventing or reducing infections, treating lymphoproliferation and autoimmunity, and mitigating potential complications like lymphoma. This involves treatments like antibiotic prophylaxis, immunoglobulin replacement therapy, immunosuppressants, rapamycin, and the targeted therapy leniolisib. Early diagnosis through genetic testing and comprehensive evaluation is crucial to initiate management and prevent disease progression. 

Diagnosis

Activated Phosphoinositide 3-kinase delta syndrome (APDS) is diagnosed through genetic testing, which is the definitive method for confirmation, though symptoms and family history are also considered. Key clinical signs to look for include frequent infections, lymphoproliferation, and autoimmune conditions. Lab tests can also show specific immune cell abnormalities like a lack of naive B cells and impaired antibody responses. 

Prognosis

The prognosis for Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) is variable but generally poorer than the global population, with a median overall survival of approximately 64 years in one study. The prognosis is significantly influenced by complications, particularly lymphoma and infections, with lymphoma being a major driver of mortality in affected individuals. Early diagnosis and the advent of new treatments, including hematopoietic stem cell transplantation (HSCT), may offer a better long-term outlook.  

Treatment

Treatment for Activated Phosphoinositide 3-kinase δ Syndrome (APDS) combines targeted therapy with supportive care, including the FDA-approved PI3Kδ inhibitor leniolisib, immunoglobulin replacement therapy (IRT), and prophylactic antibiotics and antivirals to prevent infections. Allogeneic hematopoietic stem cell transplantation (HSCT) is reserved for severe cases, while immunosuppressive drugs may be used to manage autoimmunity and lymphoproliferation. Treatment is individualized based on symptom severity and the specific genetic cause of APDS.