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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 is a progressive disease that can lead to end-organ damage and early mortality.2 Most commonly, manifestations begin in infancy with severe, recurrent sinopulmonary infections, while the lympholiferative and autoimmune disorders mentioned above often occur later in childhood.3

COMMON APDS SYMPTOMS2

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) 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.

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Varying Clinical Manifestations of APDS

People with APDS usually suffer from any two or more of the symptoms below.

Ear, Sinus, and Respiratory Tract Infections - Frequent and severe ear, sinus, and/or respiratory tract infections have been reported to effect 96-100% of patients with APDS. Furthermore, 59% - 85% of patients experienced at least one episode of pneumonia. These infections typically start in infancy or early childhood, and can progress to permanent lung or hearing damage.

Recurrent Sinopulmonary Infections

96-100% of cases 2,4,5

Recurrent sinopulmonary infections are often severe and include upper respiratory tract infections, otitis media (which can progress to a permanent hearing loss), sinusitis, pneumonia, and bronchitis. These infections are typically the first disease manifestation and have been reported to appear as soon as early infancy.

Herpes Infections - People with APDS are particularly vulnerable to frequent, severe, or persistent herpesvirus infections, which have affected 36-49% of people with the disease. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) can cause mononucleosis and pneumonitis. CMV can also occur in the eye. Herpes simplex can appear as mouth or skin sores and eye infections. Varicella Zoster Virus (VZV) causes chicken pox or shingles. In some cases, EBV and CMV can be present in the blood. This is called "viremia." EBV has been shown to progress to lymphoma in 6% of people with APDS. Your provider may order antibody tests to determine if you have been exposed to or are currently fighting a herpes infection.

Persistent, Severe, or Recurrent Herpesvirus Infections

36-49% of cases 4,5

Both acute and chronic viral infections or reactivations have been observed, particularly EBV and CMV. EBV and CMV infections, including chronic virema and disseminated infections, are the most severe and have been reported to occur in 24-30% and 15-17% of patients, respectively. Chronic EBV infection can also lead to lymphoma in patients with APDS. Herpes simplex virus (HSV) and varicella zoster virus (VZV) have also been seen in patients with APDS. 2-5,7

Enlarged Tonsils, Lymph Nodes, or Spleen - Immune cells can build up in certain areas of your body, making them appear enlarged or swollen. This "lymphoproliferation” has occurred in the tonsils, lymph nodes, spleen, and/or liver of 71-89% of people with APDS. Often times, people have undergone surgery to have their tonsils, adenoids, or spleen removed before they are diagnosed with APDS.

Lymphoproliferation

71 – 89% of cases 2-5,7

Lymphoproliferation including lymphadenopathy, splenomegaly, and/or hepatomegaly has been reported to affect 71-89% of patients with APDS. In fact, organomegaly was the first clinical manifestation in 16% of patients. Surgical interventions have been common but results are mixed. Lymphoproliferation may progress to malignancy, and persistent or recalcitrant lymphoproliferation may suggest the need to evaluate for lymphoma.

In the respiratory and gastrointestinal tracts, lymphoproliferation has been reported to appear in the form of mucosal nodular lymphoid hyperplasia in 24-36% of patients with APDS. Nodular lymphoid hyperplasia in the gastrointestinal tract has reported to have been associated with enteropathy in just over a quarter of patients with APDS.

The onset of lymphoproliferation with lymphadenopathy and splenomegaly has been shown to begin at a median age of 3 years. 2-5

- 51% of people with APDS have been reported to experience digestive tract issues such as bowel inflammation or chronic diarrhea, typically starting around 5 years of age. Another common GI issue for people with APDS is called malabsorption. This means that the food you eat is not properly broken down in the small intestine. When this happens, the nutrients in the food are not absorbed and used, and the person is unable to gain weight, despite eating. This may also lead to fatigue.

Enteropathy

51% of cases 2

Chronic diarrhea, malabsorption, and colitis have been frequently observed in patients with APDS, and have been shown to occur at a median age of 5 years. Enteropathy may be associated with nodular mucosal hyperplasia in the gastrointestinal tract and failure to thrive. 2,4,5

Low Numbers of Blood Cells - Roughly 1/3 of people with APDS have reported having low numbers of blood cells, called cytopenias ("cyto" means cell; "penia" means deficiency). One type of cytopenia is anemia, which means low numbers of red blood cells. White blood cells (immune cells) and platelets can also be low in some types of cytopenia. These conditions usually have started later in childhood (around 10 years, on average) and can be detected in routine blood work. Cytopenias are usually a form of autoimmunity in APDS. This means immune cells are attacking these blood cells.

Autoimmune Cytopenias

30% of cases 2-5

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. 2-5

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.

Autoimmune and Autoinflammatory Disorders

17-42% of cases 3-5

While cytopenias are the most common autoimmune diseases in APDS, other autoimmune and autoinflammatory conditions such as autoimmune thyroidosis, 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. 2-5

Nodules in the Airway or Digestive Tract - Overproduction of B and T cells have been shown to appear as nodules in the airway or digestive tract for 24-36% of people with APDS. In the airways, these nodules make it hard for the lungs to work as well as they should. When the nodules appear in the digestive tract, they can cause gastrointestinal issues like diarrhea, abdominal pain or cramping, blood in stool, or the inability to absorb nutrients from food.

Neurodevelopmental Delay

27-31% of cases 2,4,5

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.2,4,5

Autoimmune and Autoinflammatory Disorders - In autoimmune and autoinflammatory diseases, the immune system mistakenly attacks the body, which has occurred in around 30% of people with APDS. This can affect nearly every organ system, and can result in conditions such as arthritis, diabetes, eczema, liver or kidney disease, and others. There is no one test to detect these different types of autoimmune and inflammatory disorders, but your provider may order a blood test called ANA that indicates general autoimmunity, and other antibody tests and imaging scans may also be ordered.

Failure to Thrive

45-52% of APDS2 cases 2,3,5

In patients with APDS2 in particular, height and weight may be severely impaired.
This inadequate growth may be associated with enteropathy. 2,3,5

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.

Bronchiectasis

51% of cases 2

Lung damage from infections, combined with lymphadenopathy and nodular mucosal hyperplasia, may progress to permanent damage in the form of bronchiectasis. Onset has been reported to have occurred at a median age of 11.2-13 years of age. 2-6

Lymphoma - Has been reported to develop in 12-25% of people with APDS. It tended to appear around 18-23 years of age, although it can occur even earlier, or not at all. In APDS, about 6% of lymphoma cases developed from chronic Epstein-Barr virus (EBV) infection. In other cases, lymphoma develop from prolonged dysregulation of the B and T cells; this means they grow out of control for a long time.

Lymphoma

12 – 25% of cases 2,4,5,7

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. Onset has been reported to occur at a median age of 18-23 years of age and was the initial diagnosis for 21% of patients. Lymphoma may result in early mortality, and it has been calculated that 62% of APDS fatalities are due to lymphoma.

Other malignancies such as leukemias and solid organ malignancy 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. s 2-5,7

APDS can have a significant burden on quality of life.2

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.2 These factors can cause patients to miss school, work, or social activities, and cause anxiety, depression and stress.9-11

Fatigue is also common among patients with primary immunodeficiencies such as APDS, and can negatively impact quality of life. 9-12

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.2 These factors can cause patients to miss school, work, or social activities, and cause anxiety, depression and stress.9-11

Fatigue is also common among patients with primary immunodeficiencies such as APDS, and can negatively impact quality of life. 9-12

Video: APDS Mechanism of Disease

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References:
  1. Lucas CL, Kuehn HS, Zhao F, 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. doi:10.1038/ni.2771
  2. Maccari ME, Abolhassani H, Aghamohammadi A, 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. Published 2018 Mar 16. doi:10.3389/fimmu.2018.00543
  3. Jamee M, Moniri S, Zaki-Dizaji 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. doi:10.1007/s12016-019-08738-9
  4. Coulter TI, Chandra A, Bacon CM, 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. doi:10.1016/j.jaci.2016.06.021
  5. Elkaim E, Neven B, Bruneau J, 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. doi:10.1016/j.jaci.2016.03.022
  6. Condliffe AM, Chandra A. Respiratory Manifestations of the Activated Phosphoinositide 3-Kinase Delta Syndrome. Front Immunol. 2018;9:338. Published 2018 Mar 5. doi:10.3389/fimmu.2018.00338
  7. Carpier JM, Lucas CL. Epstein-Barr Virus Susceptibility in Activated PI3Kδ Syndrome (APDS) Immunodeficiency. Front Immunol. 2018;8:2005. Published 2018 Jan 16. doi:10.3389/fimmu.2017.02005
  8. Wang Y, Wang W, Liu L, et al. Report of a Chinese Cohort with Activated Phosphoinositide 3-Kinase δ Syndrome. J Clin Immunol. 2018;38(8):854-863.
  9. Rider NL, Kutac C, Hajjar J, 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.
  10. Jiang F, Torgerson TR, Ayars AG. Health-related quality of life in patients with primary immunodeficiency disease. Allergy Asthma Clin Immunol. 2015;11:27.
    11. Kuburovic NB, Pasic S, Susic G, et al. Health-related quality of life, anxiety, and depressive symptoms in children with primary immunodeficiencies. Patient Prefer
    Adherence. 2014;8:323-330.
  11. Hajjar J, Guffey D, Minard CG, Orange JS. Increased Incidence of Fatigue in Patients with Primary Immunodeficiency Disorders: Prevalence and Associations Within the US Immunodeficiency Network Registry. J Clin Immunol. 2017;37(2):153-165.
  12. Seeborg FO, Seay R, Boyle M, Boyle J, Scalchunes C, Orange JS. Perceived Health in Patients with Primary Immune Deficiency. J Clin Immunol. 2015;35(7):638-650.
  13.  Tabolli S, Giannantoni P, Pulvirenti F, et al. Longitudinal study on health-related quality of life in a cohort of 96 patients with common variable immune deficiencies. Front Immunol. 2014;5:605.