APDS Symptoms

The Symptoms Or Sequelae Of APDS Have The Potential To Be Life-Threatening. Proper Diagnosis And Management Are Essential

Symptoms of APDS can vary, even among family members carrying the same genetic condition.1
APDS patients may present with recurrent sinopulmonary infections; severe herpesvirus infections, particularly Epstein-Barr Virus (EBV) and cytomegalovirus (CMV); lymphadenopathy, hepatomegaly, splenomegaly, and/or nodular lymphoid hyperplasia; autoimmune cytopenias; enteropathy; or lymphoma.1,2
APDS is a progressive disease that can lead to end-organ damage.1,3,4
Most commonly, manifestations begin in infancy with severe, recurrent sinopulmonary infections, while the lymphoproliferative and autoimmune disorders mentioned above often occur later in childhood.1

APDS SIGNS AND SYMPTOMS1

Lymphadenopathy
Autoimmune cytopenias
Lymphoma
Enteropathy
Severe herpesvirus infections, particularly Epstein-Barr virus (EBV) and cytomegalovirus (CMV)
Neurodevelopmental delay
Recurrent sinopulmonary infections
Bronchiectasis
Splenomegaly, Hepatomegaly
Dysregulated B and T cell phenotypes
Lymphadenopathy
Autoimmune cytopenias
Lymphoma
Enteropathy
Severe herpesvirus infections, particularly Epstein-Barr virus (EBV) and cytomegalovirus (CMV)
2
4
5
7
8
9
Neurodevelopmental delay
Recurrent sinopulmonary infections
Bronchiectasis
Splenomegaly, Hepatomegaly
Dysregulated B and T cell phenotypes

“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) or Hyper IgM. This leads to APDS patients being cared for by a variety of physicians, and symptoms being managed without recognizing the underlying genetic defect.”

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

Clinical Manifestations Of APDS*

People with APDS usually suffer from any two or more of the symptoms below.
Recurrent Sinopulmonary Infections
96–100% of cases1,5
Recurrent sinopulmonary infections include upper respiratory tract infections, otitis media (which can progress to a permanent hearing loss), sinusitis and pneumonia. These infections are typically the first disease manifestation and have been reported to appear as soon as early infancy.
Enteropathy
25% of cases1
Diarrhea, malabsorption, and colitis have been observed in patients with APDS.
Neurodevelopmental Delay
31% of cases1,6,9,11
Neurodevelopmental delay and neuropsychiatric disorders observed in patients with APDS include global developmental delay, isolated speech delay, mild cognitive impairment, learning disabilities, autism, Asperger syndrome, anxiety, depression, and behavioural disorders.
Persistent, Severe, or Recurrent Herpesvirus Infections
49% of cases1,6–8
Both acute and chronic viral infections or reactivations have been observed, particularly EBV and CMV. EBV and CMV infections, including chronic viremia and disseminated infections, are the most severe and have been reported to occur in 26% and 15% of patients, respectively. Herpes simplex virus (HSV) and varicella zoster virus (VZV) have also been seen in patients with APDS.
Autoimmune
Cytopenias
30% of cases9,10
In patients with APDS, cytopenias may affect multiple blood lineages and include anemia, thrombocytopenia, and leukopenia. Patients with APDS1 have been reported to be more frequently affected than patients with APDS2.
Failure to
Thrive
45% of APDS2 cases12
In patients with APDS2 in particular, height and weight may be impaired.
Lymphoproliferation
75% of cases1,6
Lymphoproliferation including lymphadenopathy, splenomegaly, and/or hepatomegaly has been reported to affect 75% of patients with APDS.

In the respiratory and gastrointestinal tracts, lymphoproliferation has been reported to appear in the form of mucosal nodular lymphoid hyperplasia. Nodular lymphoid hyperplasia in the gastrointestinal tract has been reported to be associated with enteropathy in patients with APDS.

The onset of lymphoproliferation with lymphadenopathy and splenomegaly has been reported to begin at a median age of 3 years.
Autoimmune and Autoinflammatory Disorders
28–42% of cases1,10
While cytopenias are the most common autoimmune diseases in APDS, other autoimmune and autoinflammatory conditions such as autoimmune thyroiditis, arthritis, glomerulonephritis, cirrhosis, sclerosing cholangitis, autoimmune hepatitis, diabetes, and eczema have been reported. Onset of autoimmunity has been reported to begin around 10.5 years of age.
Bronchiectasis
50% of cases1,13
Lung damage from infections, combined with lymphadenopathy and nodular mucosal hyperplasia, may progress to permanent damage in the form of bronchiectasis.
Lymphoma
13–30% of cases1,10,11
Lymphoma has been reported to have been the most common malignancy seen in patients with APDS and includes classical Hodgkin lymphomas as well as non-Hodgkin lymphomas such as diffuse large B cell lymphoma and marginal zone B cell lymphoma. The risk of lymphoma has been observed to have been greater in patients with a history of viral infections, particularly EBV.

Other malignancies such as leukemias may also affect patients with APDS, though less frequently than lymphoma. The cumulative risk for malignancy at 40 years of age was calculated to be 78% for patients with APDS2.

If You Suspect APDS, It May
Be Time To Test

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Recurrent Sinopulmonary Infections
96–100% of cases1,5
Recurrent sinopulmonary infections include upper respiratory tract infections, otitis media (which can progress to a permanent hearing loss), sinusitis and pneumonia. These infections are typically the first disease manifestation and have been reported to appear as soon as early infancy.
Enteropathy
25% of cases1
Diarrhea, malabsorption, and colitis have been observed in patients with APDS.
Neurodevelopmental Delay
31% of cases1,6,9,11
Neurodevelopmental delay and neuropsychiatric disorders observed in patients with APDS include global developmental delay, isolated speech delay, mild cognitive impairment, learning disabilities, autism, Asperger syndrome, anxiety, depression, and behavioural disorders.
Persistent, Severe, or Recurrent Herpesvirus Infections
49% of cases1,6–8
Both acute and chronic viral infections or reactivations have been observed, particularly EBV and CMV. EBV and CMV infections, including chronic viremia and disseminated infections, are the most severe and have been reported to occur in 26% and 15% of patients, respectively. Herpes simplex virus (HSV) and varicella zoster virus (VZV) have also been seen in patients with APDS.
Autoimmune
Cytopenias
30% of cases9,10
In patients with APDS, cytopenias may affect multiple blood lineages and include anemia, thrombocytopenia, and leukopenia. Patients with APDS1 have been reported to be more frequently affected than patients with APDS2.
Failure to
Thrive
45% of APDS2 cases12
In patients with APDS2 in particular, height and weight may be impaired.
Lymphoproliferation
75% of cases1,6
Lymphoproliferation including lymphadenopathy, splenomegaly, and/or hepatomegaly has been reported to affect 75% of patients with APDS.

In the respiratory and gastrointestinal tracts, lymphoproliferation has been reported to appear in the form of mucosal nodular lymphoid hyperplasia. Nodular lymphoid hyperplasia in the gastrointestinal tract has been reported to be associated with enteropathy in patients with APDS.

The onset of lymphoproliferation with lymphadenopathy and splenomegaly has been reported to begin at a median age of 3 years.
Autoimmune and Autoinflammatory Disorders
28–42% of cases1,10
While cytopenias are the most common autoimmune diseases in APDS, other autoimmune and autoinflammatory conditions such as autoimmune thyroiditis, arthritis, glomerulonephritis, cirrhosis, sclerosing cholangitis, autoimmune hepatitis, diabetes, and eczema have been reported. Onset of autoimmunity has been reported to begin around 10.5 years of age.
Bronchiectasis
50% of cases1,13
Lung damage from infections, combined with lymphadenopathy and nodular mucosal hyperplasia, may progress to permanent damage in the form of bronchiectasis.
Lymphoma
13–30% of cases1,10,11
Lymphoma has been reported to have been the most common malignancy seen in patients with APDS and includes classical Hodgkin lymphomas as well as non-Hodgkin lymphomas such as diffuse large B cell lymphoma and marginal zone B cell lymphoma. The risk of lymphoma has been observed to have been greater in patients with a history of viral infections, particularly EBV.

Other malignancies such as leukemias may also affect patients with APDS, though less frequently than lymphoma. The cumulative risk for malignancy at 40 years of age was calculated to be 78% for patients with APDS2.

If You Suspect APDS, It May
Be Time To Test

Learn more about navigateAPDS, our genetic testing program. Eligibility requirements apply.
Learn More
Recurrent Sinopulmonary Infections
96–100% of cases1,5
Recurrent sinopulmonary infections include upper respiratory tract infections, otitis media (which can progress to a permanent hearing loss), sinusitis and pneumonia. These infections are typically the first disease manifestation and have been reported to appear as soon as early infancy.
Enteropathy
25% of cases1
Diarrhea, malabsorption, and colitis have been observed in patients with APDS.
Neurodevelopmental Delay
31% of cases1,6,9,11
Neurodevelopmental delay and neuropsychiatric disorders observed in patients with APDS include global developmental delay, isolated speech delay, mild cognitive impairment, learning disabilities, autism, Asperger syndrome, anxiety, depression, and behavioural disorders.
Persistent, Severe, or Recurrent Herpesvirus Infections
49% of cases1,6–8
Both acute and chronic viral infections or reactivations have been observed, particularly EBV and CMV. EBV and CMV infections, including chronic viremia and disseminated infections, are the most severe and have been reported to occur in 26% and 15% of patients, respectively. Herpes simplex virus (HSV) and varicella zoster virus (VZV) have also been seen in patients with APDS.
Autoimmune
Cytopenias
30% of cases9,10
In patients with APDS, cytopenias may affect multiple blood lineages and include anemia, thrombocytopenia, and leukopenia. Patients with APDS1 have been reported to be more frequently affected than patients with APDS2.
Failure to
Thrive
45% of APDS2 cases12
In patients with APDS2 in particular, height and weight may be impaired.
Lymphoproliferation
75% of cases1,6
Lymphoproliferation including lymphadenopathy, splenomegaly, and/or hepatomegaly has been reported to affect 75% of patients with APDS.

In the respiratory and gastrointestinal tracts, lymphoproliferation has been reported to appear in the form of mucosal nodular lymphoid hyperplasia. Nodular lymphoid hyperplasia in the gastrointestinal tract has been reported to be associated with enteropathy in patients with APDS.

The onset of lymphoproliferation with lymphadenopathy and splenomegaly has been reported to begin at a median age of 3 years.
Autoimmune and Autoinflammatory Disorders
28–42% of cases1,10
While cytopenias are the most common autoimmune diseases in APDS, other autoimmune and autoinflammatory conditions such as autoimmune thyroiditis, arthritis, glomerulonephritis, cirrhosis, sclerosing cholangitis, autoimmune hepatitis, diabetes, and eczema have been reported. Onset of autoimmunity has been reported to begin around 10.5 years of age.
Bronchiectasis
50% of cases1,13
Lung damage from infections, combined with lymphadenopathy and nodular mucosal hyperplasia, may progress to permanent damage in the form of bronchiectasis.
Lymphoma
13–30% of cases1,10,11
Lymphoma has been reported to have been the most common malignancy seen in patients with APDS and includes classical Hodgkin lymphomas as well as non-Hodgkin lymphomas such as diffuse large B cell lymphoma and marginal zone B cell lymphoma. The risk of lymphoma has been observed to have been greater in patients with a history of viral infections, particularly EBV.

Other malignancies such as leukemias may also affect patients with APDS, though less frequently than lymphoma. The cumulative risk for malignancy at 40 years of age was calculated to be 78% for patients with APDS2.

If You Suspect APDS, It May
Be Time To Test

Learn more about navigateAPDS, our genetic testing program. Eligibility requirements apply.
Learn More

APDS Symptoms Can Have A Significant Burden On Patients And Their Families.9,14,15

In addition to the physical impacts of disease, hospitalizations and surgical interventions are common. Polypharmacy is often necessary to manage symptoms, and patients see multiple doctors throughout both the diagnosis and management stages.9

Video: APDS Mechanism of Disease

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* Findings are from global studies. Available data for APDS are limited.

References:

1. Redenbaugh V, Coulter T. Disorders related to PI3Kδ hyperactivation: Characterizing the clinical and immunological features of activated PI3-kinase delta syndromes. Front Pediatr. 2021;9:702872. 2. Lucas CL, et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88–97. 3. Nunes-Santos CJ, et al. PI3K pathway defects leading to immunodeficiency and immune dysregulation. J Allergy Clin Immunol. 2019;143(5):1676–1687. 4. Coulter TI, Cant AJ. The treatment of activated PI3Kδ syndrome. Front Immunol. 2018;9:2043. 5. Carpier JM, Lucas CL. Epstein-Barr Virus susceptibility in activated PI3Kδ syndrome (APDS) immunodeficiency. Front Immunol. 2018;8:2005. 6. Coulter TI, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597–606.e4. 7. Jamee M, et al. Clinical, immunological, and genetic features in patients with activated PI3Kδ syndrome (APDS): A systematic review. Clin Rev Allergy Immunol. 2020;59(3):323–333. 8. Cohen JI. Herpesviruses in the activated phosphatidylinositol-3-kinase-δ syndrome. Front Immunol. 2018;9:237. 9. Maccari ME, et al. Disease evolution and response to rapamycin in activated phosphoinositide 3-kinase δ syndrome: The European society for immunodeficiencies-activated phosphoinositide 3-kinase δ syndrome registry. Front Immunol. 2018;9:543. 10. Schworer SA, et al. Autoimmune cytopenia as an early and initial presenting manifestation in activated PI3 kinase delta syndrome: Case report and review. J Pediatr Hematol Oncol. 2021;43(8):281–287. 11. Elkaim E, et al. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study. J Allergy Clin Immunol. 2016;138(1):210–218.e9. 12. Moreno-Corona N, et al. Two monogenetic disorders, activated PI3-kinase-δ syndrome 2 and smith-magenis syndrome, in one patient: case report and a literature review of neurodevelopmental impact in primary immunodeficiencies associated with disturbed PI3K signaling. Front Pediatr. 2021;9:688022. 13. Condliffe AM, Chandra A. Respiratory manifestations of the activated phosphoinositide 3-kinase delta syndrome. Front Immunol. 2018;9:338. 14. Rider NL, et al. Health-related quality of life in adult patients with common variable immunodeficiency disorders and impact of treatment. J Clin Immunol. 2017;37(5):461–475. 15. Hitchcock I, et al. A qualitative study to explore the burden of disease in activated phosphoinositide 3-kinase delta syndrome (APDS). Orphanet J Rare Dis. 2024;19(1):203.

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