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Steps to Diagnosing APDS

APDS is inherited in an autosomal dominant manner, meaning that a person needs a pathalogical variant from only one parent to have it themselves. 1-4

De novo variants have also been observed, and while the prevalence has not been fully assessed, a large cohort suggests that around 20% of APDS patients may have de novo variants. 1-4,6

However, APDS may be difficult to trace based on clinical history as symptoms can vary even within the same family. 1

As there is a 50% of chance of APDS being passed from parent to child, family members of patients with APDS should also be genetically tested.

As there is a 50% of chance of APDS being passed from parent to child, family members of patients with APDS should also be genetically tested.

Steps to Diagnose APDS

Recognize the symptoms. 5,6
  • Onset of symptoms under 12 years of age
  • Documented severe recurrent sinopulmonary infections ( > 2 events within 3 years of each other)
  • Bronchiectasis
  • Lymphadenopathy for greater than one month
  • Any nodular lymphoid hyperplasia
  • Chronic hepatomegaly or chronic splenomegaly
  • Severe, persistent, or recurrent herpesviridae infections (e.g., EBV, cytomegalovirus)
  • Autoimmune cytopenia
  • Enteropathy
  • Autoimmune cytopenia
  • Enteropathy
  • Lymphoma

People with two (2) or more of the aove symptoms should be considered for genetic testing.

Differential diagnosis

According to Nicholas Hartog, MD “Patients may have multiple complications though lack of unified diagnosis.”

Some individuals may be misdiagnosed with other primary immunodeficiencies such as Common Variable Immune Deficiency (CVID) or Hyper IgM Syndromes. 9

Individuals whose main symptoms are autoimmune cytopenias, lymphadenopathy, splenomegaly, hepatomegaly, nodular lymphoid hyperplasia, or lymphoma may be misdiagnosed with hematological disorders such as Autoimmune Lymphoproliferative Syndrome (ALPS), Evans syndrome, or simply refractory cytopenias.12,14

Laboratory findings and flow cytometry assess T and B cell function / morphology 2,6
  • Low to normal concentrations of IgG and IgA
  • Normal or elevated concentration of IgM
  • Reversed CD4/CD8 ratio
  • Reduced naive T cells (CD4 + CD8+)
  • Reduced CD4+ T cells
  • Increased transitional B cells
  • Reduced B cells

Note: Not all people with APDS will present with all of these laboratory findings.

Recognize the symptoms. 5,6
  • Onset of symptoms under 12 years of age
  • Documented severe recurrent sinopulmonary infections ( > 2 events within 3 years of each other)
  • Bronchiectasis
  • Lymphadenopathy for greater than one month
  • Any nodular lymphoid hyperplasia
  • Chronic hepatomegaly or chronic splenomegaly
  • Severe, persistent, or recurrent herpesviridae infections (e.g., EBV, cytomegalovirus)
  • Autoimmune cytopenia
  • Enteropathy
  • Autoimmune cytopenia
  • Enteropathy
  • Lymphoma

People with two (2) or more of the above symptoms should be considered for genetic testing.

Laboratory findings and flow cytometry assess T and B cell function / morphology 2,6
  • Low to normal concentrations of IgG and IgA
  • Normal or elevated concentration of IgM
  • Reversed CD4/CD8 ratio
  • Reduced naive T cells (CD4 + CD8+)
  • Reduced CD4+ T cells
  • Increased transitional B cells
  • Reduced B cells

Note: Not all people with APDS will present with all of these laboratory findings.

Differential diagnosis

According to Nicholas Hartog, MD “Patients may have multiple complications though lack of a unified diagnosis.”

Some individuals may be misdiagnosed with other primary immunodeficiencies such as Common Variable Immune Deficiency (CVID) or Hyper IgM Syndromes.9

Individuals whose main symptoms are autoimmune cytopenias, lymphadenopathy, splenomegaly, hepatomegaly, nodular lymphoid hyperplasia, or lymphoma may be misdiagnosed with hematological disorders such as Autoimmune Lymphoproliferative Syndrome (ALPS), Evans syndrome, or simply refractory cytopenias.12,14

Access the navigateAPDS Testing Program

navigateAPDS

Pharming Healthcare, Inc. a pharmaceutical company, has partnered with the genetic testing company Invitae to offer, at no-charge, genetic testing and counseling for individuals who may carry a pathogenic variant in one of two genes known to be associated with Activated PI3K Delta Syndrome (APDS), a rare primary immunodeficiency.

The navigateAPDS testing program helps eliminate barriers to genetic testing and increases certainty in obtaining a correct diagnosis by enabling patients suspected of having APDS, and their family members, to have access to genetic testing and counseling.

If you think you have a patient with APDS, test to know.

This sponsored, no-charge program is available to individuals in the U.S. and Canada who meet any two of the bulleted criteria below:

Clinical Features

  • Onset of symptoms under 12 years of age
  • Documented severe recurrent sinopulmonary infections (>2 events within 3 years of each other)
  • Bronchiectasis
  • Lymphadenopathy for greater than one month
  • Any nodular lymphoid hyperplasia
  • Chronic hepatomegaly or chronic splenomegaly
  • Severe, persistent, or recurrent Herpesviridae infections (eg, EBV, cytomegalovirus)
  • Autoimmune cytopenia
  • Enteropathy
  • Lymphoma

Laboratory

  • Hypogammaglobulinemia
  • Elevated levels of immunoglobulin M
  • Reduced number of CD3+CD4+ T cells; increased number of follicular helper T cells
  • Reduced number of naïve T cells

History

  • Primary Immune Deficiency diagnosis
  • Common Variable Immune Deficiency (CVID) phenotype or direct family member with CVID phenotype
  • Relative with PIK3CD or PIK3R1 genotype (first or second degree)

APDS is often inherited and therefore may be present in multiple members of a family.

It is recommended that family members of patients with APDS undergo genetic testing. 16

Or

Download and complete the test requisition form (TRF), scan and return via email to clientservices@invitae.com

This requisition form can be used to submit an order for the navigateAPDS Sponsored Testing Program, a program for genetic disorders brought to you by Pharming Healthcare, Inc.

Currently navigateAPDS testing is only available in the US and Canada.

Privacy and the Program

While Pharming provides financial support for this program, all tests and services are performed by Invitae.

Healthcare professionals must confirm that patients meet certain criteria to use the program. Pharming receives de-identified patient data from this program, but at no time would they receive patient identifiable information. Pharming receives contact information for healthcare professionals who use this program. Genetic testing and counseling are available in the US and Canada only. Healthcare professionals and patients who participate in this program have no obligation to recommend, purchase, order, prescribe, promote, administer, use or support any other products or services from Invitae or Pharming or any other commercial organizations.

For more information, visit www.invitae.com/navigateapds

Stay informed

Sign up for APDS updates

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. Angulo I, Vadas O, Garçon F, et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866-871. doi:10.1126/science.1243292
  3. Lucas CL, Zhang Y, Venida A, et al. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. J Exp Med. 2014;211(13):2537-2547. doi:10.1084/jem.20141759
  4. Deau MC, Heurtier L, Frange P, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene [published correction appears in J Clin Invest. 2015 Apr;125(4):1764-5]. J Clin Invest. 2014;124(9):3923-3928. doi:10.1172/JCI75746
  5. 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
  6. 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
  7. Fischer A, Provot J, Jais JP, Alcais A, Mahlaoui N; members of the CEREDIH French PID study group. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol. 2017;140(5):1388-1393.e8.
  8. Hadjadj J, Aladjidi N, Fernandes H, et al. Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes. Blood. 2019;134(1):9-21.
  9. 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
  10. Mayor PC, Eng KH, Singel KL, et al. Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry. J  Allergy Clin Immunol. 2018;141(3):1028-1035.
  11. Shapiro RS. Malignancies in the setting of primary immunodeficiency: Implications for hematologists/oncologists. Am J Hematol. 2011;86(1):48-55. doi:10.1002/ajh.21903
  12. Rotz SJ, Ware RE, Kumar A. Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults [published correction appears in Pediatr Blood Cancer. 2019 Apr;66(4):e27581]. Pediatr Blood Cancer. 2018;65(10):e27260. doi:10.1002/pbc.27260
  13. Sánchez-Ramón S, Bermúdez A, González-Granado LI, et al. Primary and Secondary Immunodeficiency Diseases in Oncohaematology: Warning Signs, Diagnosis, and Management. Front Immunol. 2019;10:586.
  14. Kulm E et al. Oral poster presented at 62nd ASH Annual Meeting; Dec 5-8, 2020.
  15. Rao VK, Oliveira JB. How I treat autoimmune lymphoproliferative syndrome. Blood. 2011;118(22):5741-5751. doi:10.1182/
  16. Chinn IK, et al. J Allergy Clin Immunol. 2020;145(1):46-69.

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