Find out about Activated Phosphoinositide-3 Kinase (PI3K) Delta Syndrome

APDS Symptoms

APDS has potential to be life-threatening. Proper diagnosis and management is essential.

Symptoms of APDS can vary, even among family members carrying the same genetic condition. ¹
While some APDS patients are asymptomatic, others present with severe, recurrent sinopulmonary infections; persistent, severe,
or recurrent herpesvirus infections, particularly Epstein-Barr Virus (EBV) and cytomegalovirus (CMV); lymphadenopathy,
hepatomegaly, splenomegaly, and/or nodular lymphoid hyperplasia; autoimmune cytopenias and autoinflammatory diseases;
enteropathy; or lymphoma.2


APDS Manifestations

“Typically, a person with APDS will present to a hospital within the first 5 years of life with a predominant and recurring respiratory tract infection. They can also present with swollen lymph nodes. Unfortunately, these general patient symptoms often result in medical professionals pre-diagnosing a range of autoimmune disorders before a primary immunodeficiency (PI) diagnosis is considered.

Even if a PI Classification is given, a patient can be misdiagnosed with Common Variable Immune Deficiency (CVID) and Hyper IgM. This leads to APDS patients being cared for by a variety of physicians, and managed by treatments that don’t address the underlying genetic defect.”

Nicholas Hartog, MD, is a board-certified pediatric and adult allergy and immunology physician.

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Varying Clinical Manifestations of APDS2,3


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Recurrent respiratory tract infections early in life are reported near universally in people with APDS; indeed, they may be the sole manifestation of the disease, and they may be both very frequent and severe with 85% radiologically confirmed with pneumonia.

Respiratory tract Infections
98% of cases

Bronchiectasis (abnormal widening of the bronchi or their branches) is one of the most common and debilitating consequences of recurrent respiratory infection, and compounds the the problem, increasing the host susceptibility to further lower respiratory tract infections.

63% of cases

Lymphadenopathy is common in APDS. When lymphadenopathy appears to persist or worsen despite treatment, further examination may be required to evaluate for malignancy. Lymphadenopathy refers to the enlargement of one or more lymph nodes found in the neck, armpits, chest, groin, and abdomen.

62% of cases

People with APDS often suffer from an enlarged spleen which is caused by persistent infections. An enlarged spleen can reduce the number of healthy red blood cells, platelets and white cells in your bloodstream, leading to more frequent infections. Anemia and increased bleeding also are possible.

57% of cases

Severe, persistent or recurrent herpes infections including: Epstein-Barr virus (EBV), Cytomegalovirus (CMV), Herpes Simplex virus (HSV), Varicella-Zoster virus (VZV)

Herpes Viremia
48% of cases

Clinical presentation of people with PI and autoimmunity is highly variable and requires in-depth diagnostics and precision medicine approaches. Cytopenias are the most common autoimmune disease in APDS, but conditions described include renal disease, inflammatory colitis, exocrine pancreatic insufficiency, seronegative arthritis, cirrhosis, and sclerosing cholangitis.

Autoinflammatory disorders
35% of cases

Cytopenias affect around 30% of people with APDS, usually later in life and frequently affecting multiple blood lines. The autoimmune origin of the cytopenias could be documented in the majority of people with APDS.

30% of cases

Neurodevelopmental abnormalities such as speech delay and global developmental delay have been reported in people with APDS.

Developmental Delay
22% of cases

Inflammation of the intestine. Structural or function defects on the small intestine may be seen in people with APDS.

20% of cases

People with APDS have increased risk of lymphoma. The incidence of lymphoma reported is as high as 13% and many of them had underlying EBV-infection.

13% of cases

Mechanism of Disease

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1. Singh A, Joshi V, Jindal AK, Mathew B, Rawat A. An updated review on activated PI3 kinase delta syndrome (APDS). Genes Dis. 2019;7(1):67-74. Published 2019 Oct 14. doi:10.1016/j.gendis.2019.09.015

2. All modified from: Coulter TI, et al. JACI. Vol 138:2, 2017. Based on patient cohort study n = 54

3. Modified from: Maccari ME, et al. Disease Evolution and Response to Rapamycin Phosphinositide 3-Kinase & Syndrome doi:10.3389/fimmu.2018.00543 Based on patient cohort study n = 77